Bilobe flap with auricular cartilage graft for nasal alar reconstruction

Makoto Katori Masataka Majima Depamment of Pharmacology Kitasato University School of Medicine Sagamihara, Kanagawa, Japan 228

Preventive Role of Renal Kallikrein-Kinin System in the Early Phase of Hypertension and Development of New Antihypertensive Drugs

Recent progress in hypertension therapy allows us to select appropriate drugs from the large variety of antihypertensive drugs for treating hypertensive patients, once hypertension is diagnosed. Antihypertensive drugs include angiotensin I converting enzyme (ACE) inhibitors, diuretics, calcium entry blockers, P-adrenergic receptor antagonists, a,-adrenergic receptor antagonists, centrally acting a2-adrenergic receptor stimulants, and so forth. It may be said that we are hardly in need of any more drugs against hypertension. Most of these drugs, however, are used for “therapeutic purposes” to suppress the symptoms of hypertension by mitigation of the increased vascular tone. We do not have any prophylactic drugs, since neither the primary cause nor the pathogenesis of essential hypertension has yet been properly identified, despite intensive research on the mechanisms involved in its development. ACE inhibitors are among the most effective antihypertensives. However, studies over a period of years on the genetic and environmental determiAdvancer m Phameculogy, Volume 44 Copyright 0 1998 hy Academic Press. All rights of reproductmn in any form reserved. 1054-3589/98 $25.00

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nants of hypertension, lipid abnormalities, and coronary artery disease in Utah in population-based multigenerational pedigrees (Williams et al., 1993) and related investigations revealed that the genetic loci for the structural genes for renin (Williams et al., 1993) and ACE (Jeunemaitre et al., 1992a) and the sodium antiport system (Lifton et al., 1991) were not DNA markers for hypertension. In contrast, segregating single-gene effects were found for several “intermediate phenotypes” associated with hypertension, including intraerythrocytic sodium levels (Hasstedt et al., 1988a), erythrocyte sodium-lithium countertransport (Hasstedt et al., 1988b), and total urinary kallikrein excretion (Berry et al., 1989).Furthermore, an important gene-environment interaction was found between urinary kallikrein and potassium intake (Hunt et al., 1993a,b; Williams et al., 1993).These studies on the genetic determinants of hypertension indicate that the renal kallikrein-kinin system may play an important role in the development of hypertension. Many reviews on the renal kallikrein-kinin system in relation to hypertension have been published (Levinskey 1979; Carretero and Scicli, 1980, 1990; Mayfield and Margolius, 1983; Scicli and Carretero, 1986; Margolius, 1989). A more recent review on the roles of the kallikrein-kinin system in human diseases, particularly in hypertension, has also been published (Margolius, 1995). A vasoactive polypeptide, bradykinin (BK), has been recognized as a potent vasodilating substance. A part of the hypertensive effect of ACE inhibitors was claimed to be attributable to the vasodilating activity of BK, because ACE inhibitors inhibit degradation of BK. As for the roles of the kallikrein-kinin system in the body, it is still too early to claim that entire features of this system and its roles have been clearly established, despite great research efforts and a considerable accumulation of knowledge. A major reason may lie in the difficulty of detecting BK in the blood and other biological fluids because of the extremely rapid destruction of BK (half-life: 17 sec) in the blood. This difficulty can probably be overcome by the detection of a rather stable metabolite of this peptide in biological fluids. The other chief reason that the roles of the kallikrein-kinin system in the body have not been clarified resides in the difficulty of complete elimination of this system from the body. A recent trend toward the use of knockout mice may open the door to an understanding of the roles of the kallikreinkinin system, but hypertension studies with knockout mice have not progressed. In the same context, a mutant strain of rats, Brown NorwayKatholiek (BN-Ka) rats, which have no kininogens in the blood and hence cannot generate kinins (see Section KC), may be a very useful model for studying the role of the kallikrein-kinin system in the body, particularly in the development of hypertension, since they may be considered natural knockout rats.

-

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Although the etiology of essential hypertension is still obscure despite all efforts to identify it, an ongoing series of studies with BN-Ka rats have led us to a reliable hypothesis on the role of the renal kallikrein-kinin system in this condition and also on its role in preventing the development of hypertension in the early stage. This chapter discusses the possible suppressive role of the renal kallikrein-kinin system in hypertension and, on this basis, will propose the novel types of antihypertensive drugs.

1. Renal Kallikrein-Kinin System A. The Kallikrein-Kinin System 1. General Aspects a. Generation of Kinin Bradykinin, the nonapeptide Arg'-Pro-Pro-GlyPhe-Ser-Pro-Phe-Arg', is a kinin that is biologically active and shows potent activities in smooth muscle contraction, vasodilatation, increased vascular permeability, pain sensation, natriuresis, diuresis, and renal blood flow increase. This peptide is released from precursor proteins, designated as kininogens, by proteolytic enzymes, called kallikreins. There are two kallikreins, plasma kallikrein and tissue (glandular) kallikrein, and two kininogens, high-molecular-weight (HMW) and low-molecular-weight (LMW) kininogens. As shown in Figure 1, plasma kallikrein is present in plasma in its inactive form, prekallikrein, which is directly activated by blood clotting factor XIIa (Nossel et al., 1972), and the resulting active kallikrein cleaves BK from HMW Kininogen. Factor XI1 is activated when it comes into

Plesma kallikrein svstem

Tissue kallikrein SVStem

negatively charged particle>. kiss. kaolin. LPS ctc. Plasma I

Prokallikrein

.*-

Plasma Prekallikrein

Kidney Glandular tissi e

2.Kallikrein 'Plasma b**'s

Tissue Kallikrein

SBTI

HMW Kininogen

+ Bradykinin +-

lidin

0

LMW K,ninogen

1

*.......... Kininases

Inactive Peptides [BK-( 1-8). BK-(l-7). BK-(1-6), BK-(l-5) etc.] FIGURE I Two kinin-releasing systems: plasma kallikrein and tissue (glandular) kallikrein. LPS, lipopolysaccharide; SBTI, soybean tripsin inhibitor.

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contact with a negatively charged surface, such as glass, kaolin, lipopolysaccharides, and so forth, in a self-containing positive-feedback process that requires the presence of HMW kininogen and is accelerated by plasma kallikrein (Kaplan et al., 1986). On the other hand, tissue kallikrein is released in its active form from cells of glandular tissues, such as those of the salivary glands, pancreas, sweat glands, and exocrine glands in gastrointestinal and bronchial mucosae, and from the tubular cells of the kidney, and cleaves Lys-BK (kallidin)(human)(Pierce and Webster, 1961) or BK (rat) (Kato et al., 1985) preferentially from LMW kininogen. Kallidin is rapidly converted to BK by aminopeptidases. Plasma kallikrein is inhibited by a soybean trypsin inhibitor, whereas tissue kallikrein is not, but aprotinin inhibits both kallikreins. The plasma kallikrein-kinin system is involved in shock or inflammation (Colman and Wong, 1979). Intravascular activation of the plasma kallikrein-kinin system triggers hypotension (Katori et al., 1989b), while the activation of this system in the perivascular space causes inflammatory responses (Uchida et al., 1983). Activation of the plasma kallikrein-kinin system results in the reduction or consumption of both prekallikrein and HMW kininogen in the plasma or in inflammatory exudate, but not of LMW kininogen. The tissue or glandular kallikrein-kinin system works independently of the plasma kallikrein-kinin system in vivo. Involvement of tissue kallikrein may be verified by reduction of LMW but not HMW kininogen levels. Renal kallikrein is one of the tissue kallikreins. The gene of murine tissue kallikrein belongs to a multigene family of similar serine proteases. Thirteen serine protease genes are localized on one chromosome in the rat (Inoue et al., 1989). The true tissue kallikrein gene in the kidney is composed of five exons and four introns and contains about 4.5 kb (Inoue et al., 1989). The nomenclature of the glandular kallikrein gene family has been standardized (Berg et al., 1992). The functions of this group of serine proteases are not completely known, but the amino acid sequences of the kallikrein gene family are mutually similar and share both substrate specificity and reactivity against inhibitors or antibodies. The kallikrein-like proteases purified from rat salivary glands include glandular (tissue) kallikrein (rKl), tonin (rK2), rK7, rK8, rK9, and rK10. In the rat kidney, rK1 and rK7 are the main proteases expressed (Clements et al., 1992). In humans, three serine protease genes, hK1 (glandular kallikrein), hK3 (prostate-specific antigen), and hK2, are present on chromosome 19 (Riegman et al., 1992). HMW and LMW kininogens are formed in the liver and are usually present in the plasma. It is reported that HMW kininogen is bound to the platelet and competes with fibrinogen binding to neutrophils and platelets (Colman, 1996). Kininogens are also present on the external surface of human neutrophils in their intact forms (Figueroa et al., 1992b). Plasma prekallikrein and coagulation factor XI are also anchored to the neutrophil

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membrane through attachment to the HMW kininogen (Henderson et al., 1994). As coagulation factor XI1 is also present on the exterior of the neutrophils, it is possible that kinin may, in some cases, be generated. Neutrophils also contain tissue kallikrein in intracellular stores (Figueroa et al., 1989).However, it is not likely that kinin plays a role in neutrophil passage through the endothelial cell layer during extravasation, since intravital microscopy analysis in the hamster cheek pouch reveals that neither soybean trypsin inhibitor nor aprotinin, a kallikrein inhibitor, largely inhibits the passage through the endothelial cell lines (Hatanaka and Katori, 1993). Both plasma and tissue kallikreins are rapidly (within 10 min) inactivated by inhibitors present in plasma, such as C, esterase inhibitors, antithrombin 111, a,-trypsin inhibitor and a2-plasmin inhibitor, and nonspecifically by a2-macroglobulin (Bhoola et al., 1992). Thus, intravenous administration of kallikrein causes only a transient fall of the systemic blood pressure (SBP) because of both this inactivation and the quick destruction of the kinin formed (Vogel and Werle, 1970). Intravenous injection of lipopolysaccharide from E . coli to rats, which activates factor XII, also causes only a transient fall of the SBP (Katori et al., 198913). Plasma inhibitors, such as al-antitrypsin inhibitor, were reported to inhibit urinary kallikrein (Geiger and Mann, 1976). However, kallistatin, a tissue kallikrein inhibitor, was isolated and purified (Zhou et al., 1992), and the cDNA sequence has now been clarified. The results are reviewed by Chao and Chao (1995).Kallistatin forms a specific and covalently linked complex with tissue kallikrein. It is a serine proteinase inhibitor that belongs to the serpin superfamily, which includes protein C inhibitor, al-antitrypsin, and a,-antichymotrypsin. Kallistatin inhibits human tissue kallikrein activity toward either kininogen or a synthetic tripeptide substrate. The cDNA sequence of the kallikrein binding protein, or kallistatin, shares a 68.8% identity with human al-antichymotrypsin. The major site of kallistatin synthesis is the liver, with low expression levels in the pancreas and kidney (Chao and Chao, 1995). Kallistatin may regulate clearance of tissue kallikrein in the organs and the plasma (Chao and Chao, 1995). b. Receptor Subtypes and Antagonists Two BK receptor subtypes have been identified: BKI (or B,) and BK2 (BJ (Regoli and Barabe, 1980). The B1 subtype was discovered in isolated rabbit aorta exposed to E. coli endotoxin, and des-Arg9-BK,a metabolite of BK, showed a much greater affinity for its contraction than did BK (Regoli and Barabe, 1980; Regoli et al., 1990). In contrast, the B2 receptors are ubiquitously distributed in the body and mediate most of the reported actions of BK. The BL receptors do not respond to des-Arg9-BK. Selective antagonists for the B1-receptor subtypes include [Leu9][des-Arg'O]kallidin and [Led][des-Arg'IBK, whereas HOE 140 (D-Argo[Hyp3,ThiS,DTic7,0ic*]BK) and WIN 64388 ([4-((2-[{(bis(cyc10hexylamino)methylene}amino]-3-[2-naphthyl]oxopropyl)amino}phenyl]-

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methy1)tributylphosphonium chloride monohydrochloride) are reported to be selective antagonists (Watson and Girdlestone, 1996).The rat B2 receptor consists of 366 amino acids and is a rhodopsin-type protein with seven transmembrane domains (McEachern et al., 1991). Human B2 receptor gene contains three exons separated by two introns, and the third exon contains the full-length coding region, which encodes a protein of 364 amino acids forming seven transmembrane domains (Ma et al., 1994). Antibodies to extracellular domain 3, particularly the amino acid terminal portion of the domain, efficiently interfered with agonist and antagonist binding, whereas those to extracellular domain 4 blocked binding of the agonist but not that of the antagonist (Alla et al., 1993, 1996). The B2 receptor is coupled with GqIl1.Binding of BK to the receptors increases intracellular calcium concentrations through activation of phospholipase C and releases arachidonic acid through activation of phospholipase A2 (Roberts, 1989). The human B1-receptorgene is located in close proximity to the B2-receptor gene (Chai et al., 1996). A review of the kallikrein-kinin system as a whole has been published (Bhoola et al., 1992). It was reported that after the binding of BK to the B2 receptor in bovine aortic endothelial cells, nitric oxide is produced and the intracellular calcium concentration is increased (Blatter et al., 1995; Wiemer et al., 1995). 2. Activation of Plasma Prekallikrein and Destruction of BradyMnin a. Activation ofplasma Prekallikrein As stated, plasma prekallikrein is present in an inactive form and is activated only when coagulation factor XI1 is activated to XIIa, so that kinin is not constantly released in the plasma by the plasma kallikrein-kinin system. The activation of factor XI1 is induced by exposure of plasma protein to negatively charged surfaces, such as lipopolysaccharides (Kaplan et al., 1986; Katori et al., 1989b; Uchida et al., 1983). Bacterial proteases liberate BK by activating the factor XIIprekallikrein cascade or, directly, by their proteolytic activity, from HMW or LMW kininogens or both (Maeda and Yamamoto, 1996). Most bacterial proteases are resistant to plasma proteinase inhibitors of the hosts, because most of the latter belong to a group of serine protease inhibitors, called the serpins, and because some bacterial proteases rapidly inactivate serpins (Maeda and Yamamoto, 1996). Plasma prekallikrein is not activated even when plasma is exuded into the perivascular space (Katori et al., 1989a). This was successfully demonstrated when the BK degradation products Arg-Pro-Pro-Gly-Ser (BK-[151) and Arg-Pro-Pro-Gly-Phe-Ser-Pro (BK-[1-7]), instead of BK itself, were measured in the rat pleural exudate after the intrapleural injection of histamine (Katori et al., 1989a).After this injection, plasma protein was exuded into the pleural cavity, but neither BK-[l-51, BK-[l-71, nor BK was detected in the pleural exudate (Majima et al., 1993b), whereas intrapleural injection

Renal Kallikrein-Kinin System in Hypertension

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of carrageenin generates a large amount of BK-[1-5] and BK-[1-7] in the exudate, since carrageenin activates factor XI1 in plasma protein (Majima et al., 1993b). Immunoreactive glandular kallikrein may be present in the plasma (Nustad et al., 1978; Rabito et al., 1979; Geiger et al., 1980; Lawton et al., 1981). The active kallikrein, however, is immediately bound to the large amounts of inhibitors present in the plasma to be inactivated (Lawton et a/., 1981), although there are reports that blood kinins can be generated (Scicli et al., 1982, 1983). Kallistatin, the tissue kallikrein inhibitor already mentioned, may be a major inhibitor of this protease in plasma (Chao and Chao, 1995). Factor XI1 is cleaved, not activated, by chymase released from rat mast cells during their degranulation on stimulation (Majima et al., 1987). b. Destruction of Bradykinin As is well known, there are two major kinindestroying enzymes in plasma: kininase I (carboxypeptidase N ) and kininase I1 (dipeptidylpeptidase, ACE). Neutral endopeptidase (NEP) also destroys BK, but its contribution to kinin hydrolysis in the plasma is negligible (Ishida et af., 1989). Therefore, as shown in Figure 2, BK is degraded by kininase I to des-[Arg9]BK or BK-[l-81 and by kininase I1 to des-[Phe*-Arg9]BKor BK-[I -71. Both degradation products are again degraded by kininase I1 (ACE)to Arg-Pro-Pro-Gly-Phe-Arg-Phe or BK-[1-51,which is relatively stable during the degradation of BK in plasma (Shima et af., 1992) and can be used as an indicator for the release of BK in vivo (Majima et al., 1993b, 1996b). It is claimed that the antihypertensive effect of ACE inhibitors may be due to the inhibition of BK degradation or to an increased level of BK in

Rat plasma

Rat urine

Bradykinin

Bradykinin

Bradykinin(1-8)

BradYkinin(1-7) Bradykinin(1-8)

kininase II

kininase II

+ /,,,

Bradykinin(1-5)

Bradykinin(1-6)

small peptide

small peptide

t

I

NEP. neutral endopeptidase CPY. carboxypeptidase Y-like exopeptidase

Arg-Pro~Pro~Glp%heker6Pro!Phe~Arg9 Bradykinin FIGURE 2 Pathways of BK degradation by rat plasma and rat urine. BK-(1-n) indicates BK degradation products with n amino acids from the N-terminal.

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Makoto Katori and Masataka Majima

the plasma, as well as inhibition of angiotensin I1 generation. This interpretation is based on the observation that the hypotensive effects of an ACE inhibitor, perindopril, in spontaneously hypertensive rats (SHRs) on lowand high-NaC1 diets are attenuated by a BK antagonist, HOE 140 (Bouaziz et al., 1994). In healthy subjects, plasma kinin levels are increased from 16.1 2 1.9 pmoYliter to 22.4 2 2.8 or 29.1 2 4.7 pmoYliter after administration of ACE inhibitors (Pelacani et al., 1994). Blood kinin levels in anesthetized rats are almost tripled (from 10 2 3 to 29 ? 7 pg/ml) by captopril (10 mg/kg i.p.) in normotensive Sprague-Dawley (SD) rats (Fig. 3 ) , Okamoto-Aoki SHRs, and Wistar Kyoto (WKY) rats (Majima et al., 1996b).Deoxycorticosterone acetate (D0CA)-saltrats showed higher kininase activity in the blood, but still the kinin levels are increased by a dose of captopril from 2.5 2 0.6 to 4.5 5 0.6 pg/ml (Majima et al., 1996b).Nevertheless, this increase in BK is not sufficient to reduce the SBP, since an intravenous infusion of nearly 1000 ng/min of BK is required to decrease the SBP in normotensive SD rats, and the BK concentration in the arterial blood during the infusion of 1000 ng/min of BK is 900 pg/ml (see Fig. 3 ) (Majima et a/., 1996b), so that in the anesthetized rats, the concentrations of BK in the arterial blood, which are required for reduction of the SBP, may be 30 times higher than those obtained after captopril treatment. The results are always true in SHRs, WKY rats, and DOCA-salt rats (Majima et al., 1996b). Therefore, it is difficult to conceive of a contribution of kinin to the SBP decrease during administration of ACE inhibitors. Cardiac tissue and endothelial cells contain local kallikrein. The beneficial effects of ACE inhibitors on cardiovascular injuries have been reported I

B

BnduLWnlnhvlrn

1

C

I 7"

FIGURE 3 Increased BK levels in the arterial blood after (A) captopril, (B) changes in heart rates and mean arterial pressures, and (C) arterial bradykinin levels during intravenous infusion of BK. Panels A and C indicate BK levels in arterial blood. Values represent mean 2 SEM from six rats (A) and four rats (B and C). The value after captopril is compared with that without captopril ( p < 0.05) (A). The values during BK infusion are compared with those without BK infusion ( * p < 0.05) (B). The dotted line in panel C indicates the BK value under the captopril treatment without BK infusion, and the BK values during BK infusion are compared with the values of the dotted line. From Majima et al., 1996b, with permission.

Renal Kallikrein-Kinin System in Hypertension

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(Linz et al., 1993). A good review on the kallikrein-kinin system, acting locally in endothelial cells, cardiac myocytes, and vascular smooth muscles, and on its roles in ventricular hypertrophy, myocardial ischemia, and remodeling has been published (Scholkens, 1996). Most of the beneficial effects of ACE inhibitors are reversed by pretreatment with a BK antagonist. HOE 140, and these effects may be related to the formation of nitric oxide and prostacyclin enhanced by BK (Linz et al., 1993). ACE inhibitors have been shown to be effective in inhibiting progression to renal failure by their reduction of proteinuria and inhibition of progressive decreases of the glomerular filtration rate in insulin-dependent diabetes mellitus (Lewis et al., 1993), in non-insulin-dependent diabetes mellitus (Mosconi et al., 1996), and in immunoglobin A nephropathy (Cattran et al., 1994). This may be attributable to inhibition of extracellular matrix growth enhanced by angiotensin 11. The patients who carry the deletion-deletion genotype in ACE gene polymorphism show higher ACE levels in the serum (Rigat et al., 1990) and rapid progress of the nephropathy and are sensitive to ACE inhibitors (Yoshida et al., 1995).

B. Full Set of Components of Kallikrein-Kinin System Expressed along Renal Distal Tubules The kidney expresses all of the components of the kallikrein-kinin system along its distal tubules, from the connecting tubule cells to the epithelial cells of the medullary collecting duct, as shown in Figure 4. This system works independently of that in other tissues. The tubular cells are surrounded

cortex

*

kallistatin mRNA

I

I

FIGURE 4 Lmcalization of the components of the renal kallikrein-kinin system along the nephron. GL, glomerulus; I’CT, proximal convoluted tubule; PST, proximal straight tubule; MD, macula densa; DCT, distal convoluted tubule; CNT, connecting tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct; IMCD, inner medullary collecting duct.

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Makoto Katori and Masataka Majirna

by capillaries, but still the kallikrein-kinin system seems to work independently of the plasma kallikrein-kinin system, as will be described in detail. 1. Kallikrein

It was reported (Kaizu and Margolius, 1975) that a suspension of rat cortical cells contains kallikrein activity. With the use of a single nephron preparation, it was found that more than 85% of the active and inactive kallikrein in the rat kidney is localized in the granular portion of the distal tubules and the cortical collecting duct (Tomita et al., 1981; Omata et al., 1982; Proud et al., 1983). No kallikrein was detected in the glomerulus, the thick ascending limb of Henle’s loop, the bright portion of the distal tubules (macula densa), or the light portion of the collecting ducts (Omata et al., 1982). Electron micrographic studies indicated that kallikrein was located only in the distal tubules (Ostravik et al., 1976; Ostravik, 1982). Elegant studies on immunoreactive kallikrein confirmed that kallikrein is localized exclusively in the granular cells of the connecting tubules of the distal nephron, where it is concentrated mainly on the luminal side of the cells and on both luminal and vascular sides of the nuclei, and is to a lesser extent associated with the plasma membranes and basolateral infoldings (Figueroa et al., 1984a,b).Subcellularly, kallikrein is distributed in the luminal membranes, basal membranes, rough endoplasmic reticulum. Golgi apparatus, and vesicles of the connecting tubule cells, suggesting that it is actively synthesized in these particular cells (Vio and Figueroa, 1985). More interestingly, as shown in Figure 5 , tissue kallikrein in the connecting tubule Intercalated cells

a

11

u

b$T--

CNT

FIGURE 5 (A) Diagram of the immunocytochemical localization of kallikrein and kininogen in the human nephron and (B)a schematic representation of the intermingled CNT cells and principal cells at the ]unction between CNT and CCD. AA, afferent arteriole; G , glomerulus; EA, efferent arteriole; PT, proximal tubule; LH, Loop of Henle; MD, macula densa; DCT, distal convoluted tubule; CNT connecting tubule; CCD, cortical collecting duct. From Figueroa et al., 1988, with permission.

Renal Kallikrein-Kinin System in Hypertension

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cells and kininogen in the principal cells of the collecting ducts coexist side by side in the same transitional tubules (Figueroa et al., 1988), indicating that kinins are generated in the lumen of the collecting tubules immediately after kallikrein excretion. The observation of a close anatomical contact between the kallikrein-containing cells and the afferent arteriole of the juxtaglomerular apparatus (Vio et al., 1988) may suggest that tissue kallikrein excreted on the basolateral side of the connecting tubules plays some role in the regulation of the diameters of the afferent arterioles of the glomerulus. Tissue kallikrein mRNA is expressed predominantly in the cells of the distal tubules and also in the vascular pole of the glomeruli (Xiong et al., 1989) and the connecting tubules of the outer cortex (El-Dahr and Chao, 1992).However, another report (Cumming etal., 1994) states that kallikrein is present in the granular peripolar cells of the human kidney, whereas mRNA is not found. Tissue kallikrein mRNA and protein are present in the walls of the renal blood vessels (Cumming et al., 1994). A study on human tissue kallikrein mRNA in diseased kidneys suggested that the tissue kallikrein gene in the kidney may not be constitutively expressed but is expressed in response to physiological and pathological stimuli (Cumming et al., 1994). However, this conclusion needs to be confirmed. 2. Kallikrein Inhibitors

Kallistatin is synthesized mainly in the liver. In the kidney, it is found only at lower expression levels, but its mRNA is detected most abundantly in the inner medullary collecting ducts, with only small amounts (about */lo) in the outer medullary collecting ducts, proximal convoluted tubules, and the glomeruli; no signals are found in the connecting tubules or the cortical collecting ducts (Yang et al., 1994). Kallistatin is colocalized with kallikrein in the human kidney, and an endogenous kallikrein-kallistatin binding-protein complex is found in the kidney, urine, and plasma (Chen et al., 1995). This may indicate that kallistatin efficiently inhibits kallikrein after kinin has been released and bound to the receptors in the collecting ducts. The expression of kallikrein-binding protein (KBP) is significantly lower in SHRs than in normotensive WKY rats or SD rats (Chao and Chao, 1988; Chao et al., 1990).Genetic linkage analysis shows a strong association between the KBP gene (or locus) and salt-induced hypertensive rats. Genetic differences at the KBP locus between the stroke-prone hypertensive rats (SHR-SP) and WKY rats may be related to enhanced sodium sensitivity in SHR-SP. Transgenic mice expressing rat KBP have a significantly higher survival rate in endotoxin-induced shock (Chao and Chao, 1995).

3. Kininogens Kininogen was detected in human urine (Hial et al., 1976; Pisano et al., 1978), but no intact HMW kininogen was found in the kidney or the urine (Proud et al., 1981). By the use of antibodies against the heavy (H)

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chain, which is common to HMW and LMW kininogens, LMW kininogen was isolated and the H-chain antigen was localized in the kidney, where it was diffusely distributed in the cells of the distal tubules and in the cortical and medullary collecting ducts. According to precise immunocytochemical studies (Figueroa et al., 1988), immunoreactive kininogen was localized in the principal cells of the collecting ducts and was restricted to the luminal portion of the principal cells (see Fig. 5). The close relationship between cells that contain tissue kallikrein and those that contain kininogen suggests that kinins could be generated in the lumen of the collecting tubules. The mRNA of LMW kininogen is expressed in the renal cortex and medulla (Iwai et al., 1988), suggesting the biosynthesis of LMW kininogen in the distal tubules. Using kininogen-deficient BN-Ka rats, it was reported that kininogen is synthesized in the tubular cells (Mimura et al., 1994). LMW kininogen was confirmed to be the source of kinin in the rat ureter after it was infused in kininogen-deficient BN-Ka rats (Hagiwara et al., 1994). The kininogen levels in the liver and the kidney are increased in turpentineinduced acute inflammation models in rats, but the kininogen mRNA is increased only in the liver (Chao et al., 1988). 4. Kininases

Kininases, which inactivate plasma kinins, are distributed mainly in two parts of the nephron: in the proximal tubules and in the medullary collecting ducts. The micropuncture technique revealed that almost all [3H]BKinjected into the proximal tubules is destroyed in the proximal tubules (Carone et al., 1976). It was reported that kininase I1 is concentrated in the proximal tubules along the brush-border membrane of the cells or in the S3 proximal tubule segments of the tubules (Nasjlewtti et al., 1975; Sudo, 1981; Marchetti et al., 1987; Ikemoto et al., 1990). Investigation of kininase activity in the individual segments with microdissection techniques indicated its presence not only in the proximal tubules, but also in the medullary collecting duct (Marchetti et al., 1987). A kinin-hydrolyzing enzyme, which does not respond to inhibitors of the kininase I and I1 families of enzymes, was reported and is localized along the cortical and medullary collecting tubules of the rabbit (Marchetti et al., 1987).In addition, a new kininase I-type (or carboxypeptidase-type) enzyme was purified from human urine and kidney tissue. It differs from circulating kininase I in size, inhibitory profile, and immunogenic specificity (Marinkovi et al., 1980). The degradation pathway of BK in rat urine is completely different from that in rat or human plasma (Shima et al., 1992), as shown in Figure 2. In plasma, the major metabolite of BK during prolonged incubation with diluted plasma in vitro is BK-[1-5] (Shima et al., 1992), whereas during the incubation of BK with rat urine, Arg-Pro-Pro-Gly-Phe-Ser, or BK-[1-61, is the major metabolite and BK-[l-51 is not detected (Majima et al., 1993a).

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Further analysis of kininases in rat urine revealed that the main kininases are NEP and carboxypeptidase Y (CPY)-like exopeptidase (Kuribayashi et al., 1993). CPY was originally found in yeast. This enzyme activity in rat urine was identified by the inhibitor spectrum and an antibody against a peptide fragment, but the structure could not be examined because of the small quantity of rat urine, so it is tentatively designated CPY-like exopeptidase. ACE inhibitors, such as captopril or lisinopril, scarcely inhibit the activity of these enzymes, but ebelactone B, isolated from the culture medium of Actinomycetes, selectively inhibits the activity of CPY in rat urine without inhibiting plasma kinases. Treatment of anesthetized SD-strain rats with ebelactone B during the infusion of physiological saline markedly increases the kinin levels in the urine and exerts diuretic and natriuretic actions (Majima et al., 1994a), indicating that CPY plays an active role in vivo by destroying kinin in the renal tubules. The other inhibitor, poststatin isolated from the fermentation broth of Streptomyces viridochromogenes,also completely inhibits the degradation of BK by rat urine without affecting that by rat plasma (Majima et al., 1993a), indicating that poststatin may inhibit both CPY and NEP. NEP is reported to be present in the outer surface of the brush-border plasma membrane of the proximal tubules (Shima et al., 1988) and to a lesser extent in the vesicular organelles, both in the apical cytoplasm and on the basal infoldings of the proximal tubule cells (Schulz et al., 1988). Stop-flow experiments suggest that NEP is also localized in the distal tubules (Sakakibara et al., 1989; Skidgel et al., 1984), but no immunolabeling of this enzyme is observed in the distal portion of the nephron (Schulz et al., 1988). Biochemical analysis of rat urine indicates that NEP accounts for 68% of the total kininase activity in rat urine, while kininase I1 and kininase I account for 23 and 9%, respectively (Ura et al., 1987; Ogata et al., 1989). Urinary NEP contributes more than half of the renal kininases in humans (Ura et al., 1993). The degradation rate of BK in human urine, however, is dependent on the pH of the urine. The inhibitory effect of phosphoramidon, an NEP inhibitor, became obvious at neutral pH, while that of ebelactone B, a CPY inhibitor, was clear at neutral and acidic pH (Saito et al., 1996). In addition, carboxypeptidase M is detected in human urine (Erdos, 1990), and prolyl endopeptidase (or postproline cleaving enzyme) is reported in the kidney tissue (Wilks, 1983). 5. Kinin Receptors

The [3H]BK binding capacities along the nephron of the rabbit are maximal in the cortical and outer medullary collecting ducts and marginal at the glomeruli, distal straight tubules, and distal tubules (Kauker, 1980; Tomita and Pisano, 1984).BK inhibits net sodium absorption without affecting the net potassium transport or the transepithelial potential difference (Tomita et al., 1985). BK inhibits net chloride absorption but does not affect

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the transepithelial voltage or the bicarbonate flux (Tomita et af., 1986).The B2receptor seems to be present in the tubular cells, since the natriuretic and diuretic effects of ebelactone B are antagonized by the selective B2 antagonist HOE 140 (Majima et af., 1994a). Using chemically cross-linked conjugates of bovine serum albumin with the Bz agonist of BK or the potent B2antagonist HOE 140, the receptor has been found in straight portions of the proximal tubules, in the distal straight tubules, in the connecting tubules, and in the collecting ducts of the rat kidney (Figueroa et al., 1995). The B2 receptors are present in the luminal membranes, in the basal infoldings of the tubule cells, and in the smooth muscle cells of the cortical radial artery and of afferent arterioles. The B2 receptors are colocalized with kallikrein and kininogens in the connecting tubules and the collecting-duct cell layers, respectively (Figueroa et af., 1995). The B2 receptor mRNA is colocalized with kininogen mRNA in the kidney, and the most intense signals are observed in the distal tubules and collecting ducts (Song et af., 1996).The B1receptor gene is reported to be present also in the kidney (Chai et al., 1996). In summary, renal distal nephrons possess a full component of the kallikrein-kinin system and work independently of the plasma kallikreinkinin system. The degradation pathway of BK in the urine is completely different from that in the plasma as regards the enzymes and the pathway responsible for its degradation.

II. Role of Renal Kallikrein-Kinin System A. Background of Roles of Urinary KalIikrein- Kinin System 1. Vasodilating Effect of Bradykinin

A highly original study by Frey and Kraut (1928)in Munich, Germany, showed that intravenous injection of human urine into the dog decreased the SBP and opened the door for subsequent studies on kallikrein in the urine, although the depressor effect had already been observed as early as 1909 (Abelous and Bardier, 1909). The peptide structure of BK was identified, and then kallidin, which is a product of glandular-urinary kallikrein, was identified as Lys-BK. Since then, many studies have focused on the vasodilating and hypotensive effects of these peptides. Intravenous or intra-arterial administration of BK or kallikrein induces renal arteriolar vasodilatation in normal human subjects (Gill et al., 1965; Bonner et af., 1990) and in anesthetized dogs (Webster and Gilmore, 1964; Nakano, 1965; Barraclough and Mills, 1965; Goldberg et af., 1965; McNay and Goldberg, 1966; Stein et al., 1971). Vasodilation is also observed in isolated blood-perfused canine kidneys and is partly attributable to prostaglandin generated by BK, since it is attenuated by indomethacin (McGiff et

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al., 1975). However, renal vasodilatation by exogenously administered BK or kallikrein does not necessarily provide evidence that the endogenous renal kallikrein-kinin system plays the same role in situ. Transgenic mice bearing an overexpressed human kallikrein have high levels of tissue kallikrein in their serum and various tissues and show sustained hypotension (Wanget al., 1994; Chao and Chao, 1996).Hypotension due to oversecretion of endogenous tissue kallikrein may be observed in patients who are deficient in alcohol dehydrogenases. In addition to flushing in the face after ingestion of alcohol, hypotension and tachycardia appear in such patients, and the concentration of LMW, not HMW, kininogen in the plasma is reduced, whereas this does not occur in normal subjects (Hatake, 1984). Hypotension after ethanol ingestion or acetaldehyde infusion was observed in rats that were treated with disulfiram (Uchida and Katori, 1986).Therefore, hypotension due to overexpressed kallikrein cannot simply be taken as evidence of the vasodilating role of the kallikrein-kinin system in the normal state. 2. ACE Inhibitors

The appearance of ACE-kininase I1 inhibitors accelerated clarification of the role of the renal kallikrein-kinin system in vivo. Administration of the ACE inhibitor SQ 20881 induces a significant increase in renal blood flow in dogs, together with a reduction of the mean aortic pressure and with a slight increase in urinary kinin excretion and renal venous kinin concentration (Nasjletti and Colina-Choourio, 1976). Circulating and urinary kinins are increased during continuous infusion of SQ 20881 to conscious dogs despite decreased excretion of urinary kallikrein by sodium deficiency (McCaa and McCaa, 1977). Studies reveal that renal hemodynamics in normal animals are not altered by the BK antagonists D-Argo[Hyp3,Thi5,R,D-Phe7]BK (ThP-BK) or HOE 140 (Roman et al., 1988; Zimmerman et al., 1990; Kon et al., 1993; Heller et al., 1994). In the same way, in normotensive rats, increased renal blood flow caused by an ACE inhibitor, captopril, was not altered by treatment with ThiSVR-BK (Mattson and Roman, 1991).In dogs, ThP-BK partially attenuated the increase in renal blood flow due to enalapril (Zimmerman et al., 1990), but in rabbits it did not significantly attenuate such increases induced by captopril or lisinopril (Hajj-ali and Zimmerman, 1991, 1992). HOE 140 also did not alter renal blood flow increases caused by ramiprilat or captopril in rabbits (Komers and Cooper, 1995) or by ramiprilat in rats (Chen and Zimmerman, 1994). In contrast, in hydropenic normotensive rats, renal blood flow increased by enalaprilat was decreased to a value similar to the preenalaprilat baseline by ThP-BK, suggesting the contribution of kinins to hemodynamic changes in the hydropenic state. A smaller contribution of kinin was observed in the renal blood flow increase caused by enalaprilat in the nonclipped kidney of two-kidney rats and in one-clip

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hypertensive rats, probably because the hypertension in the latter is highly angiotensin-dependent (Fitzgibbon et al., 1996).Peritoneal infusion of HOE 140 in salt-loaded pregnant rats induced no significant changes in systolic BP (SBP) or renal blood flow up to midterm pregnancy, but on the 21st day of pregnancy of salt-loaded rats, SBP decreased and renal blood flow increased. These changes were nullified by administration of HOE 140 (Madeddu et al., 1995a). Studies on increased diuresis and naturiuresis by exogenous BK were also reported in the middle of the 1960s. Intravenous injection of kinins or kinin injection into the renal artery increased diuresis and natriuresis (Webster and Gilmore, 1964; Gill et al., 1965), and this increase was observed despite antidiuretic hormone (ADH)infusion (Barraclough and Mills, 1965). The infusion of kinins into the renal artery increased renal blood flow without a significant change in glomerular filtration rate or absolute proximal reabsorption, but it also induced a marked increase in fluid delivery to the distal nephron and increased urine volume and sodium excretion (Stein et al., 1972). The natriuretic effect of kinins may be due either to inhibition of sodium reabsorption in the distal part of the nephron or to a change in deep nephron reabsorption due to the change in the blood flow. Diuresis and natriuresis may be due to increases in renal papillary blood flow due to kinins, which are generated in the distal tubules, and the increased papillary blood flow accelerates washing out of the medullary solute gradient. Simultaneous administration of enalaprilat (a kininase I1 inhibitor) and phosphoramidon (an NEP inhibitor) increases papillary flow by 50%, and this increase was blocked by a B2 antagonist, ThP-BK, suggesting that intrarenally formed kinins are important in regulating papillary blood flow (Roman et al., 1988). As NEP is one of the main kininases in the tubular lumen (see Section I.B.4) and kininase I1 may be present in the extraluminal space, inhibition of kinin degradation by both inhibitors may improve the survival of kinins generated in the collecting ducts. In volume-expanded rats administered 0.9% sodium chloride. ThiSy8-BKdecreased the basal papillary blood flow by 18%, prevented the rise in papillary blood flow during volume expansion, and also reduced cumulative sodium excretion over the 2-hr course of the experiments (Fenoy et al., 1988). Papillary blood flow seems to be regulated by kinins and prostaglandins (PGs), since in Munich Wistar rats the papillary RBC flow increased by captopril is not returned to its previous level by angiotensin I1 but is inhibited by a PG synthesis inhibitor, and the fall in vasa recta capillary pressure due to captopril is blocked by a kinin antagonist (Mattson and Roman, 1991).This decrease in the capillary pressure may be due to reduction of the outflow resistance from the vasa recta circulation (Mattson and Roman, 1991). Renal PGs moderate and mediate the actions of the renal kallikrein-kinin system (Ward and Margolius, 1979).In a study with a confluent monolayer of canine cortical collecting tubule cells (Garcia-Perez and Smith, 1984), BK released prostaglandin E2

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(PGE2) only when added to the apical surface of the cortical collecting tubule cells. Even if kinins play the role of vasodilatators in the papillary blood flow of the kidney, the major site of action may be on the luminal side of the collecting duct, since immunoreactive kallikrein is concentrated mainly on the luminal side of the granular cells of the connecting tubules (Figueroa et al., 1984a,b). The B2 receptors are reported to be present in the luminal membranes, in the basal infoldings of the tubule cells, and in the smooth muscle cells of the cortical radial artery and afferent arterioles (Figueroa et al., 1995). The major roles of kinin in the tubular lumen of the collecting ducts are its diuretic and natriuretic actions, since administration of phosphoramidon, an NEP inhibitor, increases diuresis (by 150/,)and natriuresis (by 37%) as well as doubles the kinin level in urine (Ura et al., 1987). Furthermore, intraduodenal administration of ebelactone B, a selective inhibitor of CPY (another kininase in rat urine), has caused a marked increase in diuresis (by 110%) and natriuresis (by 130%) in parallel with an increase in the kinin level (by 110%) (Majima et al., 1994a). Antibodies against kinins also decrease sodium excretion in volume-expanded rats by infusion of saline (Marin-Grez, 1974). In isolated, perfused rat cortical collecting ducts, BK inhibits net sodium absorption and net chloride absorption without affecting net potassium transport, bicarbonate flux, or the transmembrane potential difference (Tomita et al., 1985,1986). Therefore, the luminal role of BK seems to be evident. 6. Stimuli for Kallikrein Secretion in Kidney Stimuli for the secretion of urinary kallikrein may provide useful clues to the roles of the renal kallikrein-kinin system. However, these secretory stimuli remain unknown. Ultrastructural studies reveal that immunoreactive kallikrein is localized in association with ribosomes bound to the rough endoplasmic reticulum, free polysomes, the Golgi complex, and vesicles (Figueroa et al., 1984a,b), indicating that renal kallikrein is biosynthesized in the connecting tubule cells. The following observations may help to clarify the stimulation mechanism. 1. Sodium

A relationship between kallikrein and sodium in urine was observed in human subjects (Adetuyibi and Mills, 1972). However, in other clinical studies, no direct correlation between urinary sodium and kallikrein excretion could be shown in a large population of normal adults (Margolius et al., 1974a) or in hypertensive adults (Greco et al., 1974; Seino et al., 1975). A positive correlation between urinary kallikrein and sodium was also not found in over 600 normal children over a 5-year period (Zinner et al., 1976, 1978). This inconsistency may have arisen because the subjects were free

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to choose their own diets and there was no restriction on the sodium content or the volume of fluid that could be consumed. In animal experiments, a direct correlation between sodium and kallikrein excretion was observed in rabbits and rats on free salt and water intake, but not in rabbits whose dietary sodium intake was constant and either high or low (Mills and Ward, 1975). A positive correlation among urinary sodium, water, and kallikrein in rats fed low- and high-sodium diets was reported (Marin-Grez and Carretero, 1971; Croxatto et al., 1975). In a normal man, intravenous water loading during prolonged sodium restriction produced a significant increase in kallikrein excretion, but not during the period of normal sodium intake (Levy et al., 1977). Low dietary sodium intake or sodium restriction has constantly been observed to increase urinary kallikrein excretion in humans (Margolius et al., 1974a,b; Johnston et al., 1976; Abe et al., 1977; Levy et al., 1977) or rats (Geller et al., 1972; Bascands et al., 1987). In microdissected segments of the nephrons of rabbits (Omata et al., 1983),low sodium intake increases markedly the levels of both active and inactive kallikrein in the granular portion of the distal convoluted tubules and in the cortical collecting tubules (or connecting tubules) without altering either the distribution profile or the ratio of active to total kallikrein in the nephron or the urine. The effects of high sodium intake on urinary kallikrein excretion are still controversial. Acute sodium loading in rats induced an increase in urinary kallikrein excretion, but a second administration of sodium after a 40-minute interval did not increase the kallikrein concentrations in urine (Marin-Grez et al., 1984). Furthermore, rats fed a high-salt diet for 10 days showed a decrease in the total amount of immunoreactive kallikrein in the urine and in the kidney (Lieberthal et al., 1983). 2. Sodium-Retaining Steroid Hormones

The increase in kallikrein excretion due to prolonged sodium deprivation may be mediated by aldosterone release through activation of the reninangiotensin system by long-term restriction of sodium intake. In fact, a large accumulation of data indicates a positive correlation between the activity of sodium-retaining steroid hormone and the renal kallikrein-kinin system: urinary excretion of kallikrein is increased (1)in patients with primary aldosteronism (Margolius et al., 1971, 1974b; Miyashita, 1971; Seino et al., 1977), (2) in normal volunteers or patients with essential hypertension on a diet of low sodium or high potassium (Margolius et al., 1974a; Horwitz et al., 1975; Levy et al., 1977), (3) after treatment with Sa-fluorohydrocortisone (Adetuyibi and Mills, 1972; Margolius etal., 1974a),and (4)in Bartter’s syndrome (Lechi et al., 1976; Halushka et al., 1977). In addition, treatment of patients affected by primary aldosteronism or of normal volunteers with spironolactone, a selective antagonist of aldosterone, markedly reduced urinary kallikrein excretion (Margolius et al., 1974a,b; Seino et al., 1977), and

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also, the removal of aldosterone-producing tumors reversed the increased excretion of urinary kallikrein (Miyashita, 1971). On the basis of these observations, Margolius proposed that urinary kallikrein excretion is determined, at least in part, by the effective level of circulating sodium-retaining steroid hormone (Ward and Margolius, 1979). In isolated rat cortical cells in suspension, aldosterone (6.1 x 3.1 X M ) produced more kallikrein, and spironolactone (4.3 X lo-' - 2.2 X M) reduced it (Kaizu and Margolius, 1975). However, the concentrations of aldosterone used in this in vitro experiment are several orders of magnitude above the normal plasma concentrations (Mills, 1975). It remains unclear whether aldosterone acts directly on the connecting tubular cells to secrete renal kallikrein. Studies with the toad bladder indicate that aldosterone, like other steroids, probably acts to initiate transcription of mRNA that serves as a template for the synthesis of a protein or proteins, which facilitate the transport of sodium ions from the lumen of the distal tubules through the tubular cells and into the extracellular fluid (Haynes and Murad, 1985). Aldosterone also increases kallikrein release from rat renal cortical-cell plasma membranes and endoplasmic reticulum (Nishimura et al., 1980). The adrenalectomy decreases both the kallikrein content in the connecting tubules and the Na+/K+ adenosine triphosphatase ( ATPase) activity in rabbit microdissected nephron, but a single injection of aldosterone in the adrenalectomized rats restored Na+/ K' ATPase activity, while the kallikrein content did not return to normal (Marchetti et al., 1984). It is well known that continuous administration of sodium-retaining steroids to individuals on normal salt intake reduces the degree of sodium retention (August et al., 1958). During the development of the escape phenomenon, the excretion of kallikrein rises sharply from the third day onward (Adetuyibi and Mills, 1972; Edwards et al., 1973; Margolius et al., 1974a). This delay is rather difficult to explain by the direct action of aldosterone on the renal tubules. During the escape phase from the initial sodium retention, kallikrein and sodium excretions were very highly correlated, suggesting that kallikrein excretion rises in relation to sodium status and facilitates sodium excretion (Mills, 1975). 3. Potassium Administration of aldosterone enhances sodium ion reabsorption, increases the urinary excretion of both potassium and hydrogen ions, and induces hypokalemia and alkalosis. The possibility that increased plasma or intraluminal concentrations of potassium might accelerate kallikrein excretion cannot be excluded. Excretion of urinary kallikrein varies directly with potassium intake and parallels the excretion of aldosterone without increased excretion of sodium in both normal and hypertensive subjects. The increase brought about in urinary kallikrein excretion in hypertensive subjects by potassium intake is less than that in normotensive subjects, and

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the increase in white subjects is higher than that in Black subjects (Horwitz et al., 1978). The cells of connecting tubules, which synthesize and secrete urinary kallikrein, seem to be influenced by potassium. An electron microscopic study (Vio and Figueroa, 1987) revealed that a high-potassium diet produces hypertrophy and hyperplasia of the kallikrein-containing cells, including hypertrophy of the components of the Golgi complex and of the rough endoplasmic reticulum, and a larger number of secretory-like vesicles containing kallikrein. The results of this study suggest that a high-potassium diet increased the synthesis and secretion of kallikrein. It is well known that aldosterone is synthesized and released from the glomerulosa cells of the adrenals. The glomerulosa cell is sensitive to changes in external potassium concentration, and an infusion of 10 mEq of potassium over 30 minutes produces no measurable change in the serum potassium level in humans but does increase plasma aldosterone levels by 25% (Himathongkam et al., 1975).The transduction mechanism used by potassium is depolarization of the membrane with opening of the voltage-dependent calcium channels, and it is different from that used by angiotensin 11, which is receptor-mediated (Quinn et al., 1987). 4. Others

Intravenous infusion of vasopressin (ADH) was reported to stimulate both the release of urinary kallikrein and the intrarenal formation of kinin in the dog and rat (Fejes-Toth et al., 1980).This release of urinary kallikrein requires administration of ADH on water loading (Pisano and Marks, 1986), since ADH or water loading alone does not increase kallikrein excretion (Bonner et al., 1981; Zucker et al., 1983). In patients with posterior hypophysial diabetes inspidus, less kallikrein is excreted (Yamada et al., 1989), but in patients with the syndrome of inappropriate secretion of ADH, when they are allowed free access to water, urinary kallikrein excretion is increased (Tomita et al., 1983). Water-loaded rats administered ADH also increased their urinary kallikrein (Tomita et al., 1984). Decreased urinary excretion of ADH in rats with hereditary diabetes inspidus or in volume-expanded anesthetized rats was accompanied by reduced kinin excretion (Fejes-Toth et al., 1982; Kauker et al., 1984), whereas infusion of hypertonic saline or administration of ADH increased the kinin excretion (Tomita et al., 1984). Increased excretion of urinary kallikrein with arginine vasopressin was observed in isolated erythrocyte-perfused rat kidney (Stephens et al., 1988); cortical slices from rat, monkey, and human kidney (Grenfell et al., 1988); and collagenase-dispersed rat and human renal cortical cells (effective by 10-8-9M of arginine vasopressin) (Marshall et al., 1992). The action is not mediated by prostaglandins or by the V2-receptor subtype of this peptide. Oxytocin is a neurohypophysial hormone, with only two amino acids of its structure different from those of vasopressin. The basal plasma levels

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in normal males do not differ from those in nonpregnant females and in pregnant females before labor (Leake et al., 1981), and oxytocin is reported to show diuretic and natriuretic actions (Sawyer, 1952; Brooks and Pickford, 1958; Chan and Sawyer, 1958; Chan, 1961, 1988; Balment et al., 1980, 1986; Conrad et al., 1986; Brimble et al., 1991). Intravenous infusion of oxytocin into SD-strain rats accelerated kallikrein secretion in accordance with increases in urine volume and sodium excretion, and half of the diuretic and natriuretic actions of the hormone are due to the kallikrein-kinin system, as known from the inhibitory effects of the BK antagonist HOE 140 and the tissue kallikrein inhibitor aprotinin (Adachi et al., 1995).Thus, oxytocin may be considered a renal kallikrein releaser. It remains questionable whether endogenous oxytocin plays the same role. Renal perfusion pressure may be one of the major factors controlling urinary kallikrein excretion in anesthetized dogs (Bevan et al., 1974). Chronic arterial constriction of a kidney in conscious dogs and in anesthetized rats is associated with a lower kallikrein excretion from the stenotic kidney than from the contralateral kidney (Keiser et al., 1976a).In isolated perfused hog and rat kidneys, kallikrein excretion is also dependent on perfusion pressure (Maier and Binder, 1978; Bonner et al., 1983; Misumi et al., 1983). C. Studies on Rats with Congenital Deficiency of Kininogens in Plasma (BN-Ka Rats)

A large body of excellent studies has implied that the renal kallikreinkinin system participates in the regulation of electrolyte excretion and probably in development of hypertension. Despite substantial research efforts, however, the features of this system are unclear. The major reason for this obscurity of the roles of the kallikrein-kinin system resides in the impossibility of eliminating it from living animals. Use of so-called knockout mice may provide definite conclusions for some of these roles. Mice (not rats) that are homozygous for the targeted disruption of the gene encoding the Bz BK receptor have been reported (Borkowski et ul., 1995). They are fertile and indistinguishable from their litter mates by visual inspection except for the lack of responses by the ileum, uterus, and the superior cervical ganglion to BK. However, studies on renal function have not been reported. Katori and his group have used so-called natural knockout ruts, which are mutant rats devoid of plasma kininogens, and have clarified the physiological role of the renal kallikrein-kinin system and its role in development of hypertension. Their results are presented in the following section. 1. M u t a n t BN-Ka Rats

Damas and Adams, at the Katholiek University of Leuven, Belgium, reported mutant rats of the BN strain (Ratttrs norvegicus, BN/fMai), which

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are devoid of plasma kallikrein-like activity and show low levels of kininogen in plasma (Damas and Adams, 1980). This was also studied by another group (Oh-ishi et al., 1982). These BN-strain rats show a prolonged kaolinactivated partial thromboplastin time (APTT) because of the lack of HMW kininogen and the low level of plasma prekallikrein (Oh-ishi et al., 1984). They were designated BN-Ka rats (Oh-ishi et al., 1982), since the original report was published by the Katholiek University of Leuven. Further studies revealed that both HMW and LMW kininogens were almost absent from the plasma (Fig. 6 ) (Oh-ishi et al., 1986; Majima etal., 1991) and that BNKa rats are practically incapable of excreting kinin in the urine (Fig. 6) (Yamasu et al., 1989; Majima et al., 1991). Normal rats of the same strain were kept at the Kitasato University animal facilities and were designated BN-Kitasato (BN-Ki) rats (Oh-ishi et al., 1982). Normal BN-Ki rats show 20

EN-Ki

EN-Ki

T 50

EN-Ka

!

BN-Ke

FIGURE 6 Kininogen levels in plasma (upper panel) and urinary kinin excretion (lower panel) in normal Brown Norway Kitasato (BN-Ki)rats and mutant BN-Ka rats. Values are the means (+SEM) of four rats. BK eq, bradykinin equivalent. From Majima et al., 1991, with permission.

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the same levels of kininogens as rats of other strains, such as the SD strain (Majima et af., 1991). The mutant BN-Ka rats, although capable of producing kininogens in the liver, cannot release kininogens into the bloodstream because of the point mutation of Ala’63to threonine in the common heavy chain of the structures of both kininogens (Hayashi et af., 1993).The HMW and LMW kininogens and prekallikrein mRNAs that are present in the liver of BN-Ka rats are of a similar size and abundance to those in BN-Or1 rats (Lattion et al., 1988). In a carrageenin-induced rat pleurisy model, mutant BN-Ka rats showed less plasma exudation and lower exudate volume in the pleural cavity than did normal BN-Ki rats, indicating that the plasma kallikrein-kinin system has a definite role in inflammation (Oh-ishi et al., 1987). The roles of the kallikrein-kinin system in inflammation, using mutant BN-Ka rats, are described in a review article in Japanese (Oh-ishi, 1993). Other review articles on mutant BN-Ka rats in relation to hypertension have been published (Majima and Katori, 1 9 9 5 ~Katori ; and Majima, 1996). BN-Ka rats, in which kininogens are congenitally deficient in the plasma, have no apparent symptoms. Changes in SBP during growth in mutant BNKa rats are the same as in normal BN-Ki rats, when they feed on a diet containing 0.3% NaCl and drink distilled water (see Fig. 14) (Majima et al., 1991). The dose-response curve of the increase in SBP for angiotensin I1 injected intravenously into anesthetized mutant BN-Ka rats is not different from that in normal BN-Ki rats, suggesting that the arteriolar smooth muscle in mutant BN-Ka rats is not more sensitive to this vasoconstrictive peptide than that of normal BN-Ki rats (Majima et al., 1994b). Breeding of mutant BN-Ka rats between sisters and brothers is difficult, since the breeding rate is low. A congenital deficiency of kininogens in the plasma was also reported in humans (Colman et al., 1975; Lacombe et al., 1975; Wuepper et al., 1975; Donaldson et al., 1976). In the first case in Japan (Hayashi et al., 1978; Oh-ishi etal., 1981), twin sisters (Fujiwara trait), who showed prolongation of AP?T, were congenitally deficient in HMW and LMW kininogens in the plasma and had reduced levels of plasma prekallikrein. HMW kininogen and plasma kallikrein are essential in the activation of coagulation factor XI1 (Kaplan et al., 1986).However, the sisters displayed no apparent clinical symptoms and underwent appendectomy without excessive bleeding (Hayashi et al., 1978).The susceptibility to salt and the incidence of hypertension have not been studied. A similar kininogen-deficient family was also reported in Japan (Nakamura et al., 1983). As with these patients, mutant BN-Ka rats showed no apparent disorders or symptoms when they are fed a normal or low-sodium diet. However, the following experimental results clearly indicate that mutant BN-Ka rats are very sensitive to ingested salt and respond with sodium accumulation and consequent hypertension. Further-

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more, sodium accumulation is also readily induced by aldosterone released by a nonpressor dose of angiotensin 11. 2. High Sensitivity t o Mild Salt Loading in Mutant BN-Ka Rats

It is well known that increasing amounts of NaCl in the diet cause hypertension. As Figure 7A shows, the SBP of normal BN-Ki rats, measured by the tail cuff method, was increased when the dietary concentration of NaCl exceeded 4 % (Majima et al., 1 9 9 3 ~ )In . contrast, kininogen-deficient BN-Ka rats showed an increase in SBP after receiving only 2 % of NaCl in their diets. Figure 7B shows the changes in the SBPs of rats of both strains fed with a 2% NaCl diet for 4 weeks. In the mutant BN-Ka rats, the SBP increased up to 167 ? 4 mm Hg, whereas that of normal BN-Ki rats did not change during the 4-week period. During the period of feeding with the 2% NaCl diet, both strains of rats showed increases in water intake and urine volume, but mutant BN-Ka rats ingested more water and excreted less urine than did the normal BN-Ki rats (Table I) (Majima et al., 1993c), so that the tentatively calculated difference (water intake minus urine volume) was much greater in the former than in the latter, which was constant during the 4-week period. Urinary excretion of sodium also increased, but mutant BN-Ka rats excreted less than the normal BN-Ki rats (see Table I). Urinary excretion of potassium and creatinine did not differ between normal BN-Ki rats and mutant BN-Ka rats. Despite the reduced excretion of sodium and water in mutant BN-Ka rats, their serum sodium levels increased slightly, whereas those of normal BN-Ki rats were constant. Interestingly, the sodium levels in the erythrocytes during the 2% sodium loading were increased significantly in the mutant BN-Ka rats but remained constant in the normal BN-Ki rats (see Table I). Plasma renin activity was reduced and then tended to increase, but there was no difference between the two strains. A causal effect of the kininogen deficiency on the increased SBP was examined with a 7-day subcutaneous infusion of LMW kininogen administered by a mini-osmotic pump, implanted subcutaneously in the back, from day 8 in kininogen-deficient BN-Ka rats fed a 2 % NaCl diet (Majima et al., 1 9 9 3 ~ )The . infusion lowered the SBP to control levels and caused increases in urinary kinin, sodium excretion, and in urine volume. In contrast, subcutaneous infusion of HOE 140 in normal BN-Ki rats fed a 2 % NaCl diet resulted in an increase in SBP to 166 ? 23 mm Hg, which was significantly higher than the SBP of normal BN-Ki rats receiving the physiological saline vehicle. The increase in SBP in the normal BN-Ki rats was accompanied by reduced excretion of urinary sodium and reduced urine volume. These results clearly indicate that kininogen-deficient BN-Ka rats have difficulty in excreting sodium and water and are extremely sensitive to ingested salt. In these rats, ingestion of 2 % NaCl in the diet causes an accumulation of sodium in the erythrocytes, water retention in the body,

A 220

0

5 tn

B

9 weeks of age

200

1

2% NaCl Dlet rn

180 1

B K U (1137-12) BKKl (n=7)

160

140

120

I

30.3%

1

I

I

I

2

4

6

8

NaCl In Dlet (96)

, -J

120

7

8

9

10

11

Age (weeks)

FIGURE 7 Changes in SBP in normal BN-Ki rats and mutant BN-Ka rats given NaCI-loaded diets. Both strains of rats were fed 2 to 8% NaCl diets from the age of 7 weeks for 2 weeks (panel A) and a 2 % NaCl diet between the ages of 7 and 11 weeks (panel B). Values are means (?SEMI of 7 to 12 rats. Values in BN-Ka rats were compared with those in BN-Ki rats of the same age. **p < 0.01. ***p < 0.001. From Maiima et a[., 1 9 9 3 ~ )

with permission.

TABLE I Effect of 2% NaCl Diet on the Levels of Parameters in Mutant BN-Ka Rats and Normal BN-Ki Rats

7 Parameters

Strain

0.3% NaCl

Water intake (mu24 hr)

BN-Ka BN-Ki BN-Ka BN-Ki BN-Ka BN-Ki BN-Ka BN-Ki BN-Ka BN-KI BN-Ka BN-Ki BN-Ka BN-Ki BN-Ka BN-Ki BN-Ka BN-Ki

17.4 t 2.1 18.6 t 2.4 7.7 t 0.6 8.1 t 0.3 10.1 t 2.9 11.0 f 3.5 8.7 ? 0.2 8.1 t 0.6 29.5 t 0.9 33.7 f 1.3 6.9 t 0.3 6.8 t 0.3 139.3 t 0.7 139.1 t 0.6 3.80 t 0.15 3.63 t 0.33 17.5 t 1.1 17.3 t 0.6

Urine volume (mu24 hr) Water intake-urine volume (mV24 hr) Urinary sodium (mg/24 hr) Urinary potassium (mg/24 hr) Urinary creatinine (mg/24 hr) Serum sodium (mmouliter) RBC[Na]i (mmoVliter) Plasma renin activity (ng/min/hr)

8

9

10

2% NaCl 34.7 t 3.7 24.6 t 2.7 15.9 t 0.9 17.9 t 1.0 19.0 t 2.5" 7.1 t 2.0 98.5 t 8.6' 143.1 t 3.4 43.4 t 6.9 47.8 t 2.6 9.1 2 0.7 10.0 t 1.1 142.3 2 1.1 140.2 t 0.9 3.63 t 0.15" 3.30 t 0.16 10.3 t 1.6 10.6 f 1.6

Values are mean t SEM of five to eight rats. After measurement at 7 wk of age, diets were changed from low NaCl (0.3%)to 2% NaCI. Values in BN-Ka rats were compared with those in BN-Ki rats at the same age; *p < 0.05. RBC; erythrocyte.

35.3 2 3.4 30.1 -t 3.3 12.4 f 1.2' 18.8 2 1.3 21.7 t 2.7" 11.7 t 4.0 82.3 t 11.5' 147.2 t 9.8 40.0 t 6.5 41.7 t 6.4 9.6 t 0.6 9.6 f 0.7 143.0 t 0.2" 140.0 t 0.4 5.04 t 0.58" 3.23 t 0.17 18.7 f 2.1 16.2 t 3.8

30.6 f 2.3" 18.4 t 2.6 9.5 t 1.4 10.7 2 2.3 21.4 t 2.5" 8.0 2 3.7 68.4 t 12.6 83.4 f 13.6 42.8 t 9.0 37.6 f 9.9 9.3 2 0.7 8.6 f 0.6 140.2 t 1.5 138.0 t 0.6 4.82 t 0.45' 3.06 t 0.34 23.0 t 3.9 23.0 t 3.2

Renal Kallikrein-Kinin System in Hypertension

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and subsequent hypertension, which are directly related to kininogen deficiency or lack of kinin generation. It must be remembered that excretion of active urinary kallikrein, not urinary prokallikrein, is also reduced by the intake of more than 4% of NaCl in the diet (Majima et al., 1993c), so that the increased SBP in normal BN-Ki rats resulting from dietary NaCl concentrations of over 4 % could be related to reduced excretion of urinary active kallikrein. 3. Sodium Accumulation by Nonpressor Dose of Angiotensin I1 in Mutant BN-Ka Rats

Angiotensin I1 is recognized as a vasopressor peptide. Several observations (Majima et al., 1994c) indicate that a subthreshold dose of this peptide causes sodium accumulation in kininogen-deficient BN-Ka rats. Subcutaneous infusion of a nonpressor dose (20 pgldayhat) of angiotensin I1 in normal BN-Ki rats with a mini-osmotic pump for 2 weeks did not change the SBP, but the same treatment in mutant BN-Ka rats caused hypertension (180 t 8 mm Hg) (Fig. 8A), suggesting that hypertension is probably not attributable to direct vasoconstriction by this peptide but to other factors. The heart rate was also increased markedly (Fig. 8B). Serum sodium levels were significantly raised and hematocrits were reduced in deficient BN-Ka rats. The sodium levels in erythrocytes rose gradually during subcutaneous infusion of angiotensin I1 in mutant BN-Ka rats (Fig. 8C) and those in the cerebrospinal fluid (CSF) were also increased from 138.6 2.9 to 146.8 t 2.3 mmol/liter ( p < 0.05) (Fig. 8D), suggesting that sodium accumulated in the body fluid and the cells. Urinary active kallikrein and prokallikrein levels were significantly increased during the angiotensin I1 infusion in both BN-Ka and BN-Ki rats, but there were no differences between the two strains. Urine volumes and urinary sodium excretion were gradually increased during angiotensin I1 infusion in normal BN-Ki rats but not in mutant BN-Ka rats. Sodium accumulation and hypertension may be attributable to aldosterone release by the infused angiotensin 11. As indicated in Figure 8, simultaneous subcutaneous infusion of spironolactone, an aldosterone antagonist, with angiotensin I1 in mutant BN-Ka rats in the second week of the angiotensin infusion period returned the high SBP, the accelerated heart rate, and the raised sodium levels in erythrocytes and CSF to normal BN-Ki rat levels during the spironolactone treatment, indicating that the aldosterone released by the angiotensin had induced both the hypertension and the increases in these variables. Urinary secretion of aldosterone was increased during the angiotensin infusion, but there was no difference between the two strains of rats. As in salt experiments, supplementation of LMW kininogen in deficient BN-Ka rats in experiments with nonpressor doses of angiotensin markedly decreased the SBP, heart rate, and erythrocyte sodium levels, whereas administration of HOE 140 to normal BN-Ki rats increased these variables.

*

Age (wwks)

7 7

8

10

9 Age (weeks)

D

150,

'I

3

7

8

9

Age (weeks)

1

1

0

130 7

8

9

Age (weeks)

FIGURE 8 Changes in (A)SBPs, (B) heart rates, (C) sodium concentrations in erythrocytes (RBC[Na],),and (D) CSF in normal BN-Ki rats and mutant BN-Ka rats during infusion of a low dose of angiotensin I1 (Ang 11). Values are shown as means 2 SEM. After BP measurement at 7 weeks of age, Ang I1 (20 @day per rat s.c.) was infused for 2 weeks. Spironolactone (50 mg/day per rat s.c.) was given to Ang &treated BN-Ka rats for 7 days. Values in BN-Ka rats were compared with those in BN-Ki rats at the same age: " p < 0.05, * * p < 0.01, * * * p < 0.001. Values in BN-Ka rats with spironolactone were compared with those in BN-Ki rats receiving only Ang 11: # p < 0.05. Modified from Majima et al., 1994c, with permission.

Renal Kallikrein-Kinin System in Hypertension

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These results clearly indicate that kininogen-deficient BN-Ka rats, which are incapable of generating kinin in the renal tubules, do not show any apparent symptoms when fed 0.3% NaCI. However, once excess sodium is given or once sodium starts to accumulate as a result of aldosterone release after a low dose of angiotensin 11, sodium accumulates in cells, such as erythrocytes, and CSF, since deficient BN-Ka rats show decreased excretion of sodium from the kidney, which is incapable of kinin generation in the renal tubules. The supplementation of LMW kininogen in deficient BN-Ka rats and that of BK B2-receptorantagonist in normal BN-Ki rats demonstrates a direct causal relation between kininogen deficiency and sodium accumulation. Accordingly, the role of the renal kallikrein-kinin system may be hypothesized to be the excretion of excess sodium. It was reported (Berry and Rector, 1991) that nearly 95% of the sodium filtered by the renal glomeruli is reabsorbed before reaching the cortical collecting ducts. Furthermore, the tubuloglomerular feedback system may regulate the glomerular filtration rate, depending on the sodium concentrations in the macula densa of the tubules. Thus, if the amount of sodium exceeds the reabsorptive ability of the tubules preceding the connecting tubules, sodium may reach the cortical collecting duct, where the BK B2 receptors are distributed and the reabsorption will be inhibited by kinin. 4. Hypothesis Regarding Role of Renal Kallikrein-Kinin System

From the preceding observations, we! propose the hypothesis that the renal kallikrein-kinin system acts as a floodgate for excess sodium. As shown in Figure 9, normal rats or normal BN-Ki rats fully open the floodgate of the renal kallikrein-kinin system. Once sodium begins to accumulate in the body as a result of either excess salt loading or aldosterone release due to angiotensin 11, the gate opens: the kinin generated in the collecting duct inhibits sodium reabsorption and accelerates the excretion, thus preventing sodium accumulation. In contrast, lack of kinin generation in the collecting duct, as in mutant kininogen-deficient BN-Ka rats, closes the floodgate, and a low dose (2%)of NaCl or a release of aldosterone by angiotensin I1 may initiate the accumulation of sodium in the serum, CSF, and erythrocytes. In this context, it is interesting that diuretics increase urinary kallikrein excretion (Levinskey, 1979). Acetazolamide, which acts on the proximal tubules, and furosemide and bumetamide, which act on the ascending limb of Henle’s loop, accelerate kallikrein excretion. Thiazides, which act on the distal tubules, also increase urinary kallikrein excretion. Increased excretion of sodium, potassium, and water by diuretics is accompanied by an increase in urinary kallikrein excretion. Increased concentrations of sodium and potassium in the connecting tubules may mimic the excess sodium in the body, and the increased concentrations in the lumen may then trigger kallikrein secretion from the connecting tubules.

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Makoto Katori and Masataka Majirna

Normal (BN-KI, WKY) Na+

.Ald

SHR

Deficient (BN-Ka) NI+

Na+

.....- .........

.....- ........ Na'

FIGURE 9 Role of the kallikrein-kinin system (KKS) in the kidney. BN-Ki, normal BN-Ki rats; BN-Ka, kininogen-deficient BN-Ka rats; Ang, angiotensin 11; Ald, aldosterone; WKY, Wistar Kyoto rats; SHR, spontaneously hypertensive rats. From Majima and Katori, 1995c, with permission.

In summary, despite extensive past research, the role of the renal kallikrein-kinin system is not fully clear. However, studies with mutant kininogen-deficient BN-Ka rats, which are incapable of kinin generation in the urine, lead us to propose that a major role may be the secretion of excess ingested sodium or of sodium that tends to accumulate as a result of aldosterone release.

111. Reduced Function of Renal Kallikrein-Kinin System in Hypertensive Patients and Hypertensive Models

A. Hypertensive Patients In 1934, Elliot and Nuzum (1934) reported significantly lower urinary kallikrein levels in hypertensive patients without clinically apparent renal disease than in normotensive subjects.

Renal Kallikrein-Kinin System in Hypertension

I77

As shown in Figure 10, Margolius et al. (1971) reported lower levels of urinary kallikrein in patients with essential hypertension than in a control population, normal levels in patients with renal artery stenosis, and raised levels in patients with pheochromocytoma and primary aldosteronism. Since that time, a large number of studies have been carried out in various human cases and animal models of hypertension; they showed similar findings of lowered kallikrein excretion in hypertension (Margolius et al.,l974b; Carretero et al., 1974; Seino et al., 1975; Horwitz et al., 1978; Abe et al., 1978; Lechi et al., 1978; Keiser, 1979; Mersey et al., 1979; Shimamoto et al., 1981; Favre etal., 1985; Ura etal., 1985).However, there are indications that variables such as race and renal function must be considered before drawing this conclusion (Levy et al., 1977). Both whites and Blacks with essential hypertension excrete less kallikrein in their urine than do their respective controls, but the mean value in normotensive Blacks is lower than that in normotensive whites and is not different 45 Phaechromocytoma

0

A Renal artery stenosis

40

2

0

Primary aldosteronism

35

* 0

30

T

2b

4

25

5g 20

.. .. a

15t

Control

0

. 8.

A

Essential Secondary Hypertension

FIGURE I 0 Urinary kallikrein excretion in control and hypertensive patients. From Margolius et al., 1971, with permission from The Lancet Ltd.

I78

Makoto Katori and Masataka Majima

from that in hypertensive whites during normal sodium intake (Carretero and Scicli, 1978).All groups have greater urinary kallikrein activity on a low-sodium diet than on unrestricted sodium intake, but the increase in Black hypertensives is small. Increments of plasma renin activity on sodium restriction are similar in all groups. Patients with malignant essential hypertension excrete less urinary kallikrein than do those with nonmalignant essential hypertension (Hilme et al., 1992).However, some studies report that white patients with uncomplicated essential hypertension show normal kallikrein excretion rates, normal plasma renin activities, and normal aldosterone levels (Lawton and Fitz, 1977);only hypertensives over 40 years of age excrete significantly less urinary kallikrein (Koolen et al., 1984).The population with low kallikrein excretion may represent 20% of hypertensive patients (Zschiederich et al., 1980).The report that a low kallikrein excretion rate may be accompanied by low plasma renin activity (Shimamoto et al., 1989)was not confirmed by another report (Holland et al., 1980),which stated that there is no significant difference between the urinary kallikrein excretion of either Black or white patients with low-renin essential hypertension and that of those with normal-renin essential hypertension. Therefore, the concept of a reduced kallikrein excretion in essential hypertension is still controversial. This controversy may be due to the heterogeneity of the subjects used in population studies. However, Japanese patients with low-renin hypertension, who are a relatively homogeneous population, show significant reductions in both active urinary kallikrein and kinin excretion together with increased levels of a kallikrein-inhibiting substance and kininase in the urine and with reduced levels of kininogen (Nakahashi et al., 1983). Epidemiological surveys in children also indicate that the urinary kallikrein concentration in casual urine is significantly lower in Black children than in white children and is positively correlated with the urinary creatinine and urinary potassium concentrations but is inversely related to the urinary sodium concentration (Zinner et al., 1971).Families with the lowest mean kallikrein concentrations tended to have higher BPs than did families with the highest concentrations, although the positive correlation was weak and subject to many variables (Zinner et al., 1976).The significant inverse relationship between urinary kallikrein level divided by creatinine concentrations and the BP in both white and Black children was confirmed after 4 years (Zinner et al., 1976).The familial aggregations of BP, BP rank, and concentration of kallikrein in casual urine were relatively stable in children over an 8-year period of observation (Zinner et af., 1978). In addition, urinary kallikrein excretion was decreased in hypertensive patients with mild renal insufficiency (Holland et af., 1980)and markedly decreased in those with reduced glomerular filtration rates, as in those with hypertension (Mitas et al., 1978).Renal parenchymal diseases accompanied by hypertension, such as chronic glomerulonephritis, are associated with

Renal Kallikrein-Kinin System in Hypertension

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diminished urinary kallikrein activity (Holland et al., 1980). Therefore, the reduced level of urinary kallikrein in hypertension should be distinguished from that due to impaired renal function. Some studies suggest a strong influence of urinary kallikrein excretion on the salt sensitivity of BP in normotensive patients (Bonner et al., 1993). In a randomized, cross-over, double-blind study, the urinary excretion of active kallikrein was significantly lower in salt-sensitive hypertensive patients than in salt-resistant hypertensives, and showed an inverse correlation with plasma atrial natriuretic peptide (ANP) levels (Ferri et al., 1994).

B. Animal Models of Hypertension Many animal models of hypertension have been reported. Interestingly, most of the genetically hypertensive and experimentally induced animal hypertension models show reduced excretion of urinary kallikrein. 1. Genetically Hypertensive Animals

Genetically hypertensive New Zealand-strain rats excreted reduced levels of urinary kallikrein (Carretero et al., 1976). The urinary excretion of kallikrein by hypertensive Fawn-Hooded ( FHNErjd) male and female rats was less than that of Wistar rats (and males excreted less than females) from 1.5 months before the hypertension developed at the ages of 2 months (males)and 4.5 months (females) (Gilboa et al., 1984).FH male rats excreted more sodium and urine than did any other group. Only FH male rats developed proteinuria, but neither an inhibitor of urinary kallikrein nor increased degradation of this enzyme in the urine was found (Gilboa et al., 1984).SHRs from the NIHFZZ-24 strain were reported to excrete less kallikrein at 23 weeks, and the level was not increased by dietary sodium restriction (Geller et al., 1975). Milan hypertensive strain (MHS) rats (Bianchi et al., 1974a) also excrete reduced levels of urinary kallikrein (Porcelli et al., 1975). In Okamoto-Aoki SHRs, kallikrein excretion was subnormal (Keiser et al., 1976b; Ader et al., 1985, 1987; Arbeit and Serra, 1985; Praddaude et al., 1989). A time-course study (Ader et al., 1987) revealed that the urinary excretion of active and total kallikrein was significantly lower in SHRs on a normal sodium diet from 4 through 15 weeks of age. The average values of active and total kallikrein activity in these SHRs were 69.5 and 67.4%, respectively, of those values in age-matched WKY rats at all stages of the development of hypertension and even after a plateau of the SBP was reached at 10 to 11 weeks. SHRs exhibited a lower urinary excretion of sodium and water than did WKY rats together with a higher cumulative sodium balance at all ages studied and a higher cumulative water balance only at 7 and 8 weeks of age (Ader et al., 1987). In experiments to examine the responses of SHRs and WKY rats to an acute decrease in renal perfusion pressure, the slopes of the regression lines correlating urinary kallikrein to systolic

I80

Makoto Katori and Masataka Majirna

arterial pressure and to urinary excretion and cumulative sodium and water balance were significantly less steep in SHRs than in WKY rats, indicating reduced urinary kallikrein excretion (Ader et al., 1987).These strain differences were not related to urine flow, sodium excretion, or glomerular filtration rate (Ader et al., 1985). The reduced urinary kallikrein excretion in SHRs was also confirmed during the early stages of hypertension, and the difference was largest at weanlings (4 wk old) (Mohsin et al., 1992), but the difference in the urinary kallikrein level between SHRs and WKY rats disappeared when the systolic pressure reached a plateau at the age of 10 weeks. This result does not agree with the report that a lowered excretion of urinary kallikrein persists after the BP has reached a plateau (Ader et al., 1987). The reason for this discrepancy is not clear. The reduced excretion of not only sodium, but also potassium and creatinine with an increased serum creatinine level from the age of 4 weeks (weanlings) (Mohsin et al., 1992) may suggest renal insufficiency. In studies on clearance and micropuncture, abnormalities in glomerular function during development of the hypertension were observed in 6-weekold SHRs (Dilley et al., 1984). Transgenic mice that overexpress human tissue kallikrein show significantly lowered BP (Wang et al., 1994). This hypotension is reversed by intramuscular delivery of the rat KBP gene (Ma et al., 1995). Supplementation of human tissue kallikrein in hypertensive rats by injecting a kallikrein gene construct into the skeletal muscle (Xionget al., 1995)or by intravenous injection of human kallikrein plasmid DNA (Wang et al., 1995a) also causes sustained reduction of SBP. It is not known whether the reduction in BP due to the increased kallikrein activity is mediated by increased kinin levels either in plasma or in urine. 2. Experimental Hypertensive Models

Rats treated with deoxycorticosterone (DOC) plus 1% salt or with DOC alone excreted lower amounts of urinary kallikrein when hypertension was present (Keiser et al., 1976b). Rats with renovascular hypertension have decreased kallikrein levels both in renal tissue and in urine (Carretero et al., 1974; Keiser et al., 1976b). In two-kidney, one-clip Goldblatt hypertensive rats, the urinary kallikrein levels were low in the urine of the stenotic kidney but normal in that of the contralateral kidney (Girolami et al., 1983). In Dahl salt-sensitive rats fed a normal sodium diet (0.45% NaCI), the urinary kallikrein level assessed on the basis of the kinin-generating activity was lower than the level determined by direct radioimmunoassay for the enzymic protein (Carretero et al., 1978). The level of urinary protein was higher in these rats (Carretero et al., 1978). The lower level of kallikrein may be due to inhibitors leaking from the plasma. As in hypertensive patients, in hypertensive animals the urinary kallikrein activity in urine that was reduced

Renal Kallikrein-Kinin System in Hypertension

181

by renal function impairment due to continuing hypertension should be carefully distinguished from the original reduction of kallikrein activity. 3. Dahl Salt-sensitive Rats

The Dahl salt-sensitive rat model merits discussion, since the hypertension that results from ingestion of excess sodium is caused by an interaction of genetic and environmental factors. Continuous administration of ~-3,5,3'tri-iodotyronine with 7.3% NaCl to SD rats resulted in two opposite predispositions to hypertension due to NaCl ingestion in the offspring: one group became salt-sensitive and hypertension-prone (S),and the other, salt-resistent and hypertension-resistent (R) (Dahl et al., 1962a).This suggests that hypertension may be induced by genetic factors concomitantly with environmental factors. S rats develop experimental hypertension not only after ingestion of excess sodium (7.3% NaCl), but also after injection of DOC acetate (D0CA)-salt or unilateral renal artery compression without salt (Dahl et al., 1962b, 1963) or after cortisone administration or adrenal regeneration (Dahl et al., 1965). In DOCA-salt hypertension, S rats become hypertensive more rapidly than do R rats (Dahl et al., 1963). These findings suggest that Dahl salt-sensitive rats share the features of kininogen-deficient BN-Ka rats. This hypertension-prone genotype in Dahl S rats may reside in the kidney. When R-strain rats are united to S-strain rats in parabiosis, the former develop sustained hypertension when a high-NaCI diet is consumed by the pair (Dahl et al., 1967; Iwai et al., 1969; Knudsen et al., 1969). This is more clearly demonstrated using a kidney homograft. The SBP of R recipient rats is raised after transplantation of the kidney from S rats even on a lowsodium diet, and a renal homograft from the R-strain rats leads to a sharp fall in BP in hypertensive S recipients (Dahl et al., 1974; Dahl and Heine, 1975). These results suggest that certain factors in the kidneys may trigger the development of hypertension. Plasma renin activity is lower in S rats than in R rats (Rapp et al., 1978), although L-tri-iodothyronine is reported to increase angiotensinogen mRNA levels in a rat hepatoma cell line (Chang and Perlman, 1987). Dahl S rats had less urinary kallikrein activity than did R rats (Rapp et al., 1978; Arbeit and Serra, 1985). This difference is not interpreted simply as a reduced excretion of renal kallikrein, since the urinary protein excretion rate in S rats is greatly elevated (proteinuria) as the hypertension develops (Sustarsic et al., 1981; Rapp et al., 1982a). Daily administration of dexamethasone for 7 days caused marked suppression of urinary kallikrein excretion in both S and R rats, together with increased urinary protein in S rats but not in R rats (McPartland et al., 1981). Treatment with DOC increases urinary kallikrein in R rats but not in S rats, while S rats respond to sodium deficiency with increased urinary kallikrein excretion. Mild glomerular and distal tubular scarring is found in S rats, and these lesions correlate well with increases in BP and proteinuria. No such lesions appear in control or DOC-treated R rats (Rapp et al., 1982b).

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Makoto Katori and Masataka Majirna

Furthermore, long-term treatment of S rats with taurine retards the development of hypertension and increased urine volume and urinary kallikrein in concomitance with increases in renal kallikrein gene expression. The BK B2 antagonist HOE 140 does not modify the BP in S rats receiving taurine with a high-salt diet (Ideishi et al., 1994). Long-term infusion of tissue kallikrein, which does not affect the development of the BP in S rats, decreases urinary protein excretion, increases the glomerular filtration rate, and improves glomerulosclerotic lesions and tubular injuries (Uehara et al., 1994). In contrast, Arbeit and Serra (1985) reported that the lower level of urinary kallikrein is due to decreased excretion of renal kallikrein rather than to greater amounts of inhibitors in the urine, an abnormality in the enzyme, or an inactive enzyme. Another report (Rapp et al., 1984) stated that the isoelectric focusing pattern of urinary kallikrein of S rats shows that kallikrein has a lower sialic acid content than that of R rats, and that treatment of kallikrein from R rats with neuraminidase converts it to the Stype pattern on the gel. The study on transplantation of kidneys to bilaterally nephrectomized recipients revealed that the BPs of the cross-transplanted groups become intermediate between those of the control groups with transplanted kidneys (R/R and S/S), where the kidney genotype-recipient genotype is indicated by R/S and S/R. The rank order of urinary kallikrein excretion is R/R = R/S > S/R = S/S (Churchill et al., 1995). Therefore, even in the Dahl-strain rats, although the reduced excretion of urinary kallikrein may be secondary to renal injury, it may cause the hypertension.

C. Genetic Background 1. Animal Experiments

In addition to the separation of Dahl salt-sensitive rats and Dahl saltresistant rats from one group, stated in Section III.B.3, separation of Okamoto-Aoki spontaneously (genetically) hypertensive rats from WKY rats also indicates the importance of genetic factors in the development of hypertension. Other genetically hypertensive rat strains have also been reported (Keiser et al., 1976b; Carretero et al., 1976; Girolami et al., 1983; Gilboa et al., 1984). The most convincing evidence that the kidney is the site of the genetic factor is provided by experiments on cross-transplantation of kidneys between normotensive and spontaneously hypertensive strains (Bianchi et d., 1974b; Kawabe et al., 1978), as stated in Dahl-strain rats. Normotensive recipient rats that received SHR donor kidneys, even in the prehypertensive stage (5-6 wk of age), had significantly higher BP and serum urea levels (Bianchi et al., 1974b). When F1 hybrids between SHRs and Wistar rats received a kidney from SHRs, they showed higher BPs than did the Wistar rats and low renin activity in both the plasma and the kidney (Kawabe et al., 1978).

Renal Kallikrein-Kinin System in Hypertension

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The renal involvement in the development of hypertension is suggested by the results of electrolyte-balance studies that demonstrate a period of mild sodium and water retention in SHRs. Dietary sodium restriction retards the development of hypertension in SHRs but does not prevent it (Beierwalter et al., 1982). In Milan hypertensive-strain (MHS)rats younger than 9 weeks of age, the sodium retention observed is due to a significantly lower urinary excretion of dietary sodium (Bianchi et al., 1975). It is quite feasible that the mechanism of development of hypertension may spring from abnormalities in the renin gene. In an Fz population derived from crossing Dahl salt-sensitive (S) rats and salt-resistant (R) rats, a DNA restriction fragment length polymorphism (RFLP) in the renin gene cosegregated with BP (Rapp et al., 1989). In Southern blotting with cDNA and an oligonucleotide probe of the SHR renin gene, a deletion of around 650 base pairs was found in the first intron (intron A) of the SHR gene, in comparison with the WKY rat gene (Samani et al., 1989). However, another study (Kurtz et al., 1990), which examined the inheritance of a DNA RFLP in the renin gene in an F2population derived from inbred SHRs and inbred normotensive Lewis rats, indicated that the BP in rats that inherited a single SHR renin allele ( 1.7-kb band) was significantly higher than that in rats that inherited only the Lewis renin allele (2.9-kb band). However, the crossed Dahl saltsensitive rats described here exhibit the 2.7-kb band, which is close to that seen in Lewis rats, and Dahl salt-resistant rats exhibit a 1.7-kb band, which is also carried by SHRs. Thus, although a structural alteration in the renin gene may be present in congenitally hypertensive rats, considerable difficulties remain before the hypertension in these animals can be explained by the altered renin gene. Although the inherited susceptibility or resistance to the effect of salt is polygenetic, the kidney appears to play a primary role through electrolyte regulation in the determination of BP (Dahl et al., 1972, 1974; Dahl and Heine, 1975). This role may be explained on the gene basis (Pravenec et al., 1991).Molecular evidence of an association between a sequence alteration in the kallikrein gene family and the transmission of increased BP has been presented. In recombinant inbred (RI)strains derived from SHRs and normotensive BN rats, the RI strains that inherited the RFLP of kallikrein from the SHR progenitor strains (6.4-kb fragment) show significantly greater median systolic, diastolic, and mean arterial pressures than do the RI strains that inherited it from BN progenitor strains (Pravenec et al., 1991), suggesting that the kallikrein RFLP may be more meaningful to raise the SBP. 2. Hypertensive Patients

Segregation analysis of a large number of Utah pedigrees, covering 1.2 million subjects (approximately 30% of the current Utah adult population) as well as 140,000 Utah death certificates over a 20-year period, was carried

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Makoto Katori and Masataka Majirna

out to find the genetic and environmental determinants of hypertension, lipid abnormalities, and coronary arterial disease (Williams et al., 1993). a. Renin-Angiotensin System According to the aforementioned and related studies, the genetic loci for the structural genes for renin (Naftilan et al., 1989), ACE (Jeunemaitre et al., 1992a),and the sodium antiport system (Lifton et al., 1991) were not found to be DNA markers for hypertension. Angiotensinogen shows moderate hypertension susceptibility, and the angiotensinogen variant, found to be a promotor of hypertension, is present in approximately 30% of the general population (Jeunemaitre et al., 1992b; Williams et al., 1993). Another review (Corvol, 1995) indicated that the genes of the renin-angiotensin-aldosteronesystem are directly responsible for some types of hypertension, such as Liddle’s syndrome, but in familial essential hypertension, neither renin nor ACE genes contribute to a large extent to the genetics of hypertension, at least in humans. An ACE gene polymorphism may be a strong marker of coronary and cardiac diseases and of diabetic complications. Angiotensinogen gene polymorphism appears to be linked to hypertension, and molecular variants of this protein are associated with high BP in various populations and ethnic groups. An angiotensin I1 ATI-receptor variant is associated with essential hypertension, and this gene variant together with ACE gene polymorphism increases the relative risk of myocardial infarction. Mice made deficient in the angiotensinogen gene by a gene-targeting method cannot maintain normal SBP (Tanimoto et al., 1994), and they die gradually after birth (Tanimoto et al., 1995). In contrast, when the angiotensin I1 type-Ia receptor gene is made deficient in mice by a gene-targeting method, they also cannot maintain normal SBP, despite markedly high renin activity in plasma (Sugaya et al., 1995), but no deaths in infant mice were observed. The difference in the early death rates may have been due to residual secretion of aldosterone in the latter mutant mice mediated by angiotensin I1 type-I1 receptors present in the adrenal glands, whereas the former may fail to secrete aldosterone because of the lack of angiotensin I1 generation. These observations throw some light on the importance of the renin-angiotensin-aldosterone system in the maintenance of normal SBP through aldosterone release. On the basis of the clinical usefulness of ACE inhibitors in the treatment of hypertension, it is proposed that locally generated angiotensin I1 may contribute to the secondary structural changes seen in cardiovascular disorders, such as cardiac hypertrophy and remodeling, coronary artery disease, and atherosclerosis (Lindpaintner et al., 1992; Dzau et al., 1994; Falkenhahn et al., 1994). As ACE inhibitors also inhibit endogenous kinin degradation, the useful effects may be attributable to locally generated kinin. A review on the local actions of the kallikrein-kinin system in endothelial cells, cardiac myocytes, and vascular smooth muscle cells, and on its roles in ventricular

Renal Kallikrein-Kinin System in Hypertension

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hypertrophy, myocardial ischemia, and remodeling has been published (Scholkens, 1996). b. Urinary Kallikrein and Potassium In the Utah studies (Williams et al., 1993), it is interesting that segregating single-gene effects are found for several “intermediate phenotypes” associated with hypertension, such as total urinary kallikrein excretion (Berry et al., 1989), as well as intraerythrocytic sodium levels (Hasstedt et al., 1988a) and erythrocyte sodium-lithium countertransport (Hasstedt et al., 1988b). A particularly interesting finding is the important interaction between urinary kallikrein and potassium intake (Hunt et al., 1993a; Williams et al., 1993), indicating that hypertension may develop through an interaction of genetic factors and environmental factors. A large-scale epidemiological study provides some information about possible longer term relations between urinary kallikrein and BP (Zinner et al., 1971, 1978). In a population of more than 700 healthy children aged 2 to 14 years, a familial aggregation of high BP was found in children studied for 15 years, as described in Section 1II.A. A study of 405 normotensive adults and 391 youths in 57 Utah pedigrees provided evidence that total urinary kallikrein excretion was highly familial, with 51% of the total variance attributable to a dominant allele for high total urinary kallikrein excretion and 27% attributable to the combined effects of polygenes and shared family environment (Berry et al., 1989). Individuals with the high total urinary kallikrein excretion genotype were significantly less likely to have one or two hypertensive parents (Berry et al., 1989). Using the large Utah pedigrees, significant statistical urinary potassium interaction with the inferred major gene for kallikrein was found (Hunt et al., 1993a). The heterozygote kallikrein group (with a frequency of 50%) showed a significant association between urinary kallikrein and urinary potassium, whereas there was no association with potassium in the low homozygotes. This study predicted that an increase in urinary potassium excretion in these pedigrees would be associated with high heterozygote kallikrein levels similar to those in the homozygotes, and that a decrease in urinary potassium excretion in heterozygous individuals would be associated with kallikrein levels similar to the levels in homozygous individuals with low kallikrein (Hunt et al., 1993a). Because, in the steady state, urinary potassium represents dietary potassium intake, this study suggests that an increase in dietary potassium intake in 50% of these pedigree members, estimated to be heterozygous at the kallikrein locus, was probably associated with an increase in an underlying genetically determined low kallikrein level. This is particularly interesting when the enhanced effect of potassium on the excretion of renal kallikrein is considered (Vio and Figueroa, 1987) (see section II.B3). Urinary potassium, pH, and SBP differences explained 34% of the differences in kallikrein levels between monozygous twins (Hunt et al.,

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Makoto Katori and Masataka Majirna

1993b), suggesting the existence of an additional unmeasured environmental variable that is associated with decreased kallikrein excretion and elevated BP. On the basis of these observations, Williams et al. (1993) proposed the following hypothesis (Fig. 11):Subjects can be divided into three kallikrein genotypes; approximately half will be heterozygous for this single-gene trait. In the population with the heterozygous genotype, low-potassium intake would have a high susceptibility to hypertension, whereas high-potassium intake would reduce the risk of hypertension. Kallikrein levels in approximately 30% of the population are low in “low homozygotes,” who have a high risk of hypertension. Approximately 20% of the population are, according to segregation analysis, “high homozygotes,” who have a low risk of hypertension regardless of potassium intake (Williams et al., 1993). The antihypertensive effect of dietary potassium intake has been not fully cleared, but a randomized, crossover, double-blind study conducted for 4 days on 22 patients 60 years old and older revealed a decrease in SBP during potassium chloride ingestion (120 mmol/day) (Smith et al., 1992). More sodium, potassium, and aldosterone were excreted during the daytime, while urinary kallikrein was excreted at a fixed rate throughout both day and night (Staessen et al., 1993); therefore, a long-term study may be necessary. KALLiKREiN GENE HYPOTHESIS KALLGENE GENOTYPES

r: 1-

+ +DietaryK+

=

1

bRiSkHBP

Heterozygotes

1\ 1

Susceptible

Low

Low Risk

Hlgh

Dietary Potassium intake

FIGURE I I Diagram of the hypothesis that the interaction between urinary kallikrein genotypes and potassium intake accounts for the degree of risk of hypertension. Kallikrein excretion is low in “low (kallikrein) homozygotes” who have a high risk of hypertension. “High (kallikrein) homozygotes” are at a low risk of hypertension regardless of potassium intake. Approximately half of the general population with the heterozygous kallikrein genotype would have either a high or low susceptibility to hypertension, depending on whether potassium intake is low or high. HBP, high blood pressure. Reprinted by permission of Elsevier Science Inc. from Genetic basis of familial dyslipidemia and hypertension: 15-years results from Utah. Williams etal., AmericanJournal of Hypertension, 6,319s-327s. Copyright 1993 by American Journal of Hypertension, Inc.

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Nevertheless, it is highly likely that ordinary essential hypertension occurs in people who have susceptibility genes at both angiotensinogen ( Jeunemaitre et al., 1992b) and kallikrein loci, as long as they consume a high-sodium and low-potassium diet (Williams et al., 1993).

D. Sodium Accumulation Due to Failure of Renal Kinin Generation as a Cause of Hypertension The large volume of accumulated results may implicate the causal role of reduced excretion of renal kallikrein in hypertensive patients and in hypertensive animals. However, these results are occasionally controversial, and no definite conclusions can be drawn from them because it is impossible to eliminate kinin generation in living animals. The gaps in our knowledge of the linkage between urinary kallikrein and hypertension have already been successfully, at least partially, filled with rats showing congenital kininogen deficiency in the plasma, namely, the BN-Ka rats described in Section 1I.C. 1. Sodium Accumulation and Hypertension in Mutant BN-Ka Rats

As mentioned in Section II.C, mutant BN-Ka rats are capable of producing kininogens in the liver but are unable to release them into the bloodstream because of a point mutation, so they are practically incapable of generating kinin in the urine, as shown in Figure 6. Nevertheless, the SBP increase in mutant BN-Ka rats with age is not different from that in normal BN-Ki rats when both are fed a diet containing 0.3% NaCl (see Fig. 14), and the responsiveness of the arterioles of mutant BN-Ka rats to intravenous angiotensin I1 does not differ from that in normal BN-Ki rats. In Section II.C.2, it was stated that mutant BN-Ka rats are highly sensitive to excess sodium in a diet with 2% NaCI. They fail to excrete the excess sodium and accumulate it in the CSF and in cells such as the erythrocytes (Majima et al., 1 9 9 3 ~ ) . Consequently, the systemic pressure is increased. Sodium accumulation is also easily induced by continuous subcutaneous infusion of angiotensin 11, which does not increase the BP of normal BN-Ki rats (Majimaetal., 1994c).Sodium is accumulated in the CSFand erythrocytes through aldosterone release, and the SBP is increased. The resulting failure of kinin generation in the collecting duct of the nephron causes reduced excretion of excess sodium and leads to sodium accumulation in the body and to hypertension. Mutant BN-Ka rats show no proteinuria or renal dysfunction on diets with 0.3 and 2.0% NaCl contents (Majimaet al., 1993c)or on administration of a nonpressor dose of angiotensin I1 (Majima et al., 1994c), as far as the serum and urinary creatinine levels are taken as parameters, so that hypertension due to renal dysfunction can be excluded. Four-week-old SHRs (weanlings) showed higher plasma renin activity than did WKY rats, and this higher activity was spontaneously restored to

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the level in WKY rats at the age of 7 weeks (Mohsin et al., 1992). Since urinary kallikrein excretion in SHRs is lower than that in WKY rats, the predisposition to sodium accumulation in the body may already be apparent in weanlings at the prehypertensive stage, as was seen in the experiment with kininogen-deficient BN-Ka rats that became hypertensive during infusion of a nonpressor dose of angiotensin I1 (see Section II.C.3). Therefore, as Figure 9 shows, the floodgate of SHRs for excretion of extra sodium may be narrowed. The elevated plasma renin activity at the prehypertensive stage and the reduced urinary kallikrein may accelerate sodium accumulation, so these predispositions in SHRs may lead to the hypertension. It has been considered that hypertension is attributable to an increase in circulating blood volume due to the accumulation of sodium in the body. However, the following experiment supports the belief that sodium plays a pivotal role for induction of hypertension. 2. Sodium Accumulation as Major Factor in Blood Pressure Rise in Mutant BN-Ka Rats

A large volume ( 6 ml/kg/hr) of NaCl solution was infused intra-arterially for 4 days into conscious, unrestrained rats through an indwelling catheter (Majima et al., 1995a). As shown in Figure 12, infusion of normal BN-Ki rats with 0.15 or 0.3 M NaCl solution increased neither the mean arterial pressure nor the sodium levels in the serum, CSF, or erythrocytes. By contrast, infusion of the same volume of 0.3 M NaCl solution into mutant

*

130120.

FIGURE I 2 Changes in the mean BPs during the intra-arterial infusion of NaCI solution into conscious deficient BN-Ka rats and conscious normal BN-Ki rats. Values show the means t SEM from five rats. Sodium chloride solutions (0.3 or 0.15 M) were infused (6 ml/kg/hr) into the abdominal aorta for 4 days from 10 weeks of age. Values from rats infused with 0.3 M sodium chloride solution (closed circles) were compared with those infused with 0.15 M sodium chloride solution (open circles) on the same day. "p < 0.05, * * p < 0.01. From Majima et al., 1995a, with permission.

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kininogen-deficient BN-Ka rats significantly increased the mean arterial pressure, and there were concomitant increases in the sodium levels in the serum, CSF, and erythrocytes, whereas infusion of 0.15 M NaCl solution in mutant BN-Ka rats did not change these parameters. Sodium excretion and urine volume in mutant BN-Ka rats during the infusion of 0.3 M NaCl solution were not significantly less than those values in normal BN-Ki rats, since the large volume of sodium infusion had already increased the excretion extensively, even in normal BN-Ki rats (Majima etal., 1995a). The hematocrit values were not significantly changed in either strain by either concentration of the infusion. Thus, kininogen-deficient BN-Ka rats are fully capable of excreting sodium and water, even if a large volume of “physiological saline solution” (0.15 M ) is rapidly infused. However, these rats fail to excrete sodium if the concentration is doubled. Failure of sodium excretion by the kidney immediately accelerates the accumulation of sodium in the body, particularly in cells such as erythrocytes and in CSF, and then the SBP rises. The hypertension is already observed within the first hour of continuous intra-arterial infusion of 0.3 M NaCl solution in mutant BNKa rats. These results clearly indicate that a large volume of physiological saline solution alone, rapidly infused intravenously, does not cause hypertension and that a slight increase in sodium concentration over the physiological sodium concentration raises the systemic pressure. 3. Mechanisms of Blood Pressure Rise Due to Sodium Accumulation

Intra-arterial infusion of 0.3 M NaCl solution for 4 days into conscious and unrestrained mutant BN-Ka rats not only increased sodium levels in CSF and erythrocytes, but also raised the sensitivity of the arterioles to vasoconstrictive substances (Majima et al., 1995a). As shown in Figure 13, dose-response curves of the arterioles of mutant BN-Ka rats against angiotensin I1 shifted to the left after infusion of 0.3 M NaCl solution, causing approximately a 10-fold increase in the arteriolar responses to angiotensin 11, and the arteriolar sensitivity to norepinephrine also increased 30fold (Majima et al., 1995a); however, the sensitivity of the arterioles of normal BN-Ki rats was not changed after infusion of either 0.15 or 0.3 M NaCl solution. The increased sensitivity in the BN-Ka rat arterioles suggests that sodium accumulation in the cells may extend to the vascular smooth muscle cells. It is reported that early cultured vascular smooth muscle cells from SHRs show enhanced Na+/H’ exchange or Nat influx (Berk et al., 1989). A similar increase in responsiveness was reported in hypertension models and hypertensive patients. Enhanced sympathetic control of the heart at baseline and in response to adrenergic stimulation was observed in a conscious canine perinephritic hypertension model during the development of hypertension (Gelpi etal., 1988; Shannon et al., 1991). The enhanced vascu-

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Makoto Katori and Masataka Majima

70 60

1

BN-Ka

50 40

30 20 10

0 1

10

100

1000

1

10

100

1000

prnollkg, La.

Angiotensin II FIGURE I 3 Changes in mean BPs (MBP) after a bolus intra-arterial injection of angiotensin I1 to NaCI-infused, conscious, deficient BN-Ka rats and conscious, normal BN-Ki rats. Values show the means (tSEM) from six rats. Sodium chloride solution (0.3 or 0.15 M) was infused ( 6 ml/kg/hr) into the abdominal aorta for 4 days from 10 weeks of age. Values from rats infused with 0.3 M sodium chloride solution (closed circles) were compared with those infused with 0.15 M sodium chloride (open circles). * p < 0.05, * * p < 0.01. Values represented by open triangles are those of untreated rats. From Majima et al., 199Sa, with permission.

lar responsiveness may be attributed to al-adrenergic receptor density in the membrane preparations from aortic tissue (Uemura et al., 1993). Perfused segments of second-order mesenteric resistance arteries from SHRs show greater sensitivity to norepinephrine than those from WKY rats, probably because of depressed endothelium-dependent dilatation, since removal of the endothelium abolished the difference in sensitivity to norepinephrine between the two strains (Falloon et al., 1993). In humans, normotensive subjects with positive family histories of hypertension are characterized by a higher sensitivity to angiotensin I1 in the systemic and renal circulations than are those with negative histories (Widgren et al., 1992).In normotensive subjects with positive family histories of essential hypertension, the responsiveness of the BP to infused norepinephrine is elevated, and increases in potassium intake may improve the norepinephrine hypersensitivity and simultaneously lower the BP to the normotensive range (Weidmann, 1989). Furthermore, in patients with borderline hypertension and mild hypertension during isometric exercise at 30% of maximum force for 3 minutes, the increase in BP was mainly associated with increased peripheral resistance (de Champlain et al., 1991). A diet containing 2% NaCl (Majima et al., 1993c),intravenous infusion Of 0.3% NaCl solution over 4 days (Majima et al., 1995a),and subcutaneous infusion of angiotensin I1 (Majima et al., 1994c)cause sodium accumulation

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in CSF and an increased heart rate together with hypertension. This is of particular interest, since it has been reported (Sasaki et al., 1984) that bolus injections of increasing concentrations of NaCl into the cisterna magna of SD-strain rats enhances the discharge of the sympathetic nerves in a concentration-dependent manner and increases SBP. Increased sympathetic drive is observed frequently in young hypertensive patients, particularly during the initial stages of hypertension (Eagan, 1989). These results are important for comprehending the mechanism of development of hypertension. In contrast to the general opinion that hypertension can be induced by a large increase in vasoconstrictive substances, sodium accumulation in the body may be essential for inducing hypertension, since hypertension can arise from increased sensitivity of the arterioles to vasoconstrictive substances through the accumulation of sodium in the cells, including, probably, vascular smooth muscle cells, and by that in CSF, which heightens sympathetic tone. Therefore, the reduced function of renal kallikrein in hypertensive patients and animals plays an essential role in the development of hypertension. Indeed, as discussed, hypertensive patients and hypertensive animals show reduced excretion of kallikrein. 4. Role of Renal Kallikrein-Klnin System in Early Stage of Hypertension

Even if the renal kallikrein-kinin system plays a suppressive role, in which the kinin generated excretes excess sodium from the kidney, the system does not need to play that role for the entire period of hypertension. In fact, the renal kallikrein-kinin system acts only at the beginning of the developmental stage. Figure 14 indicates the time course of BP in a DOCAsalt (1%sodium in drinking water) hypertension model in mutant BN-Ka rats and normal BN-Ki rats that were unilaterally nephrectomized at 7 weeks of age (Majima et al., 1991). The systolic BP (SBP) of normal BN-Ki rats increased gradually and reached a plateau 11 to 12 weeks after the start of the treatment. In contrast, that of mutant BN-Ka rats reached a plateau 2 weeks after the beginning of the treatment. This indicates that the renal kallikrein-kinin system plays the suppressive role in the early phase of hypertension in normal rats. Excretion of renal active kallikrein and prokallikrein started to increase immediately after the beginning of the treatment in both BN-Ki and BN-Ka rats (Fig. 15), reaching peaks at 10 weeks of age and declining thereafter (Katori et al., 1992). There was no difference in kallikrein excretion in either strain of rats. However, urine volume and urinary sodium were increased only in normal BN-Ki rats, the levels in mutant BN-Ka rats remaining unchanged, because of the lack of kinin generation. It is important to know that BP increases markedly when the renal kallikrein excretion passes its peak at 10 weeks of age. Supplemental evidence is seen in the results of treatment of DOCA-salt-induced hypertension in normal BN-Ki rats with ebelactone B, which inhibits CPY-like exopep-

I92

2o l

Makoto Katori and Masataka Majima

mmHg

DOCA 5mglkg

180

f

m m

2

n

160-

U

0

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Katholiek(def.1 1001

L,

I

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Kitasato(norm.) A - - - - A

.

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,

10

15 20 Weeks FIGURE I 4 Changes in systolic BP of normal BN-Ki rats and BN-Ka rats under no treatment and during DOCA-salt treatment with age. The ordinate shows SBPs, (mm Hg), and the abscissa indicates age in weeks. Values are shown as means 2SEM from 5 to 16 rats. Pressures were plotted against age under no treatment (open circles for BN-Ka and open triangles for BNKi). Closed circles (BN-Ka) and closed triangles (BN-Ki) indicate SBP during DOCA-salt treatment after removal of left kidney at 7 weeks of age (ope).Rats received 1%NaCl drinking water immediately after the operation and subcutaneous injection of DOCA once a week from the eighth week (DOCA). BP values of BN-Ka rats were compared each week with those of BN-Ki rats. * p < 0.05, * * p < 0.01. From Majima et al., 1991, with permission.

tidase in urine. Infusion of ebelactone B to normal BN-Ki rats from the age of 8 weeks for 7 days markedly suppressed the increase in the development of hypertension (Majima e t al., 1995b) (see Section IV.A.l). Furthermore, as shown in Table 11, elevation of SBP in DOCA-salt-treated SD rats was almost completely prevented by prolonged administration of ebelactone B (5 mg/kg, p.0. t.i.d.) from 6 to 10 weeks of age. In contrast, an ACE inhibitor, lisinopril ( 5 mg/kg, p.0. t.i.d.), did not modify the high BP (Ito et al., 1997). Conversely, infusion of a kallikrein inhibitor, aprotinin, in normal BNKi rats during DOCA-salt treatment for 1 week from week 8 increased the SBP (Majima e t al., 1991). Similar results in DOCA-salt rats were reported after treatment of Wistar rats with the BK B2 antagonist HOE 140 (Madeddu e t al., 1993a,b). Long-term blockade of BK receptors by HOE 140 from the prenatal stage to the early postnatal phase in Wistar rats receiving a high-sodium diet elevated BP, with increased sodium levels in the serum and erythrocytes (Madeddu et al., 1995b). Since antagonism to BK reduces

Renal Kallikrein-Kinin System in Hypertension

A AuIz4n1

*O

1

I93

i ; I00 ma-trritrd

*

d- BN-KIta

.I

BN-Kath DOCA-salt

> 1

3

5

0 a

5

IS

10

20

D 700 1

-..I 5

15

10

201&0

x

L

20

w

5

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IS

20

10

15

20

AUlZahr

f. 1

& L.

-

5

40

El&?

0 Weeks

5

Weeks

FIGURE I 5 Changes in urinary excretion of active (A) kallikrein, and (B) prokallikrein, (C) urine volumes, (D) sodium excretion, and (E) potassium excretion during the periods of no treatment and under the DOCA-salt treatment in mutant BN-Ka (B/N-Kath)rats and normal BN-Ki (Bm-Kita) rats. Values indicate means (*SEM) from four to eight rats, and those under the treatment were compared with those of nontreated groups. " p < 0.05, " " p < 0.01. Ope., uninephrectomy, followed by DOCA-salt treatment. From Katori et al., 1992, with permission.

renal sodium excretion and increases BP, it is obvious that the renal kallikrein-kinin system plays a suppressive role in the early stage of the development of hypertension. The contribution of the renal kallikrein-kinin system in the early stage of the development of hypertension is not limited to the DOCA-salt hypertension model but is also seen in Okamoto-Aoki SHRs in which BP reaches a plateau at 8 weeks of age. Subcutaneous infusion of ebelactone B by an osmotic pump from the age of 4 weeks for 4 weeks significantly suppressed the BP rise in SHRs (unpublished data). Inhibition of renal kallikrein in SHRs by continuous subcutaneous infusion of aprotinin, an inhibitor of kallikrein and polyvalent serine esterases, for 7 days from the age of 7 weeks significantly increased SBP during the

194

Makoto Katori and Masataka Majirna

TABLE II Prevention of the Development of Hypertension in DOCA-Salt-Treated SD Rats by ProlongedAdministration of Ebelactone B Kininase inhibitors Weeks

Vehicle

6 (before) 7 8 9 10

135 144 157 188 195

t2 C2 23 t 12 2 8

Ebelactone B 137 138 138 146 146 t

2 1

Lisinopril 136 -C 3 145 t 2 156 t 7 194 t 9 209 ? 9

t1 L2

t3 C 3

NS

T

Mean -t s.e.m., n = 5-10. The inhibitors (5mg/kg p.0. t.i.d.) were administered. *p < 0.01, compared with vehicle-treated rats (vehicle). NS, not significant (tested by repeated ANOVA). Units are given in mmHg.

development of hypertension (Mohsin et al., 1992). Although SHRs excrete less renal kallikrein, the urinary kallikrein that is excreted at the reduced level accelerates sodium excretion and suppresses sodium accumulation, and SBP increases during the development of hypertension in SHRs.

E. Difficulty of Secretion, Not Synthesis, of Renal Kallikrein in SHRs It has been reported (Praddaude et al., 1989) that the reduced urinary kallikrein levels (68-66%) of SHRs in urine is not due to a defect in synthesis by the renal cortex at birth but to a defect in prokallikrein activation, since total kallikrein is not reduced in the renal cortex of newborn SHRs when compared with the level in WKY rats, while active urinary kallikrein is reduced. During the development of hypertension between the ages of 4 and 1 2 weeks, the renal content of both active kallikrein and total kallikrein relative to the renal cortex weight is reduced, although the active kallikrein content per gram of cortex weight is increased at 4,8, and 12 weeks of age (Praddaude et al., 1989). In another study on renal kallikrein in SHRs (Figueroa et al., 1992a), in which BP reached a plateau at the age of 30 weeks, the kallikrein activity in the urine, measured by amidase activity, was markedly lower at 52 and 78 weeks in SHRs than in WKY rats, but the enzymatic activity of renal tissue kallikrein was higher in SHRs than in WKY rats and increased with the BP. When the rats were 78 weeks old, renal tissue kallikrein values and kallikrein activity excreted in the urine showed a substantial reduction

Renal Kallikrein-Kinin System in Hypertension

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together with a reduction in the cells of the connecting tubules. Human biopsy specimens also showed tubular atrophy and fibrosis, indicating that reduced urinary kallikrein excretion in advanced hypertension is probably secondary to a loss of distal tubular mass. This study clearly indicates that the mechanism causing reduced excretion of urinary kallikrein in the early stage of the development of hypertension is different from that in the advanced stage. In a study (Fuller et af., 1986) using a cDNA probe to rat pancreatic kallikrein for hybridization histochemistry, no differences in renal kallikrein mRNA levels were found between adrenalectomized rats and those treated with 9a-fluorocortisone, corticosterone, or dexamethasone, or between hypertensive rats and their appropriate controls. The reduction must therefore have occurred at the posttranscriptional level. However, one report ( Wang et af., 1995b) stated that the proximal promoter region of the rat renal kallikrein gene interacts differently with trans-acting factors in the kidney of normotensive and hypertensive rats, and this could be responsible for the renal kallikrein excretion in SHRs. As discussed in Section 11.B.4, intravenous infusion of oxytocin (1030 nmol/kg/min) in 0.9% NaCl solution in anesthetized male SD rats induces diuresis and natriuresis, and more than half of this effect is attributable to the kallikrein excreted by oxytocin (Adachi et al., 1995), indicating that oxytocin may be a renal kallikrein releaser. Infusion of young WKY rats with oxytocin significantly increased urine volume and urinary sodium concomitantly with increases in the excretion of active kallikrein (Majima et al., 1996a). In contrast, the oxytocin infusion of young SHRs does not increase the urinary excretion of active kallikrein, but decreases the urine volume and sodium excretion during the period of infusion. The active kallikrein level in the kidney tissue of WKY rats is not changed by oxytocin infusion, while that of SHRs is slightly increased. These results suggest that reduced excretion of active kallikrein in the urine during oxytocin infusion in SHRs may be due to difficulty in excretion, not in synthesis.

F. Possibility of Involvement of Cytoskeleton Protein with Point Mutation in Development of Hypertension Bianchi's group proposed the hypothesis that a point mutation of the cytoskeleton protein, adducin, may be related to the development of hypertension on the basis of the findings of a large volume of studies. They observed that MHS rats show faster outward Na+/K+/CI-cotransport (COT) in erythrocytes than do Milan normotensive strain (MNS) rats (Ferrari et ul., 1987), so there is a smaller volume of erythrocytes with a lower sodium content in MHS rats (Ferrari et ul., 1987). Abnormal Na+/K+COT function in a group of patients with essential hypertension was also reported (Garay et al., 1983). Na+/K+/CI-COT is also present in the vesicles of the thick

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Makoto Katori and Masataka Majima

ascending limb of Henle's loop (Ferrandi et al., 1990; Ferrari et d., 1992). Isolated kidney cells and tubular cells in the kidney cortex also show increased Na+/K+/CI- COT and sodium transport across their plasma membranes (Parenti et al., 1986,1991; Ferrari etal., 1987; Ferrandi et al., 1990). MHS rats show a greater diuretic and natriuretic response to the selective COT inhibitor furosemide (Salvati et al., 1990), and in the isolated perfused kidney, a generalized increase in tubular reabsorption is observed (Salvati et al., 1984, 1987). Compared with normotensive rats and with normal COT hypertensive rats, high-COT hypertensive rats had lower fractional uric acid excretion and plasma renin activity with similar glomerular filtration rates and urinary sodium and potassium excretion levels (Cusi et al., 1993). The differences in erythrocyte function are genetically determined within the stem cells and are associated with hypertension in Fz hybrid rats (Bianchi et al., 1985). In the MHS rat model, since the difference in membrane ion transport disappeared after elimination of the membrane skeleton, some of the components of this skeleton may have been involved (Ferrari et al., 1991).Thus, adducin is identified as the only cytoskeleton component that could be associated with membrane ion transport differences (Salardi et al., 1986). On comparison of control subjects with hypertensive patients by testing the allele-disease association relative to the marker genotype, these researchers concluded that a polymorphism within the a-adducin gene may affect BP in humans (Casari et al., 1995). Adducin is a heterodimer formed of a and p subunits that promotes the assembly of actin with spectrin. The amino acid phenylalanine at 316 of the a subunit in MNS rats is replaced with tyrosine in MHS rats; in the p subunit, MHS rats are always homozygous for arginine at position 529, while in MNS rats either arginine or glutamine occurs. The arginine-glutamine heterozygotes showed lower BP than did any of the homozygotes (Bianchi et al., 1994). Although erythrocyte outward Naf/K'/C1- COT is high and is genetically associated with hypertension in MHS rats, it is low in SHR and normal in Sabra hypertensive and Dahl salt-sensitive rats. Approximately 75% of essential hypertensives fall into the lower COT and 25% into the higher in erythrocytes. Even if adducin is associated with outward Na+/K+COT in the erythrocyte membrane, further explanation is required of how inward Na+/K+/Cl-COT in the tubular cells of the ascending limb of Henle's loop and outward Nat/Kc/C1- COT in the erythrocytes can both be also associated with adducin. Furthermore, in SHRs and in mutant BN-Ka rats under sodium loading, the sodium content of the erythrocytes is greater than that in normotensive WKY rats and normal BN-Ki rats. Therefore, the possibility that two point mutations of the adducin molecule might be related to other dysfunction of the kidney cannot be excluded. In summary, patients with essential hypertension and either genetically or experimentally hypertensive animal models may excrete less urinary kallikrein, although careful differentiation of the effects of kidney injuries is

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necessary. Failure of kinin generation in the renal collecting ducts precludes the excretion of excess sodium and the accumulation of sodium in CSF and the cells, probably including vascular smooth muscle, thus increasing sympathetic tone and arteriolar sensitivity to vasoconstrictive substances and, finally, causing hypertension. Therefore, the possible role of the renal kallikrein-kinin system is evident. The involvement of genetic factors located in the kidney in the development of hypertension is evident on the basis of both animal studies and human epidemiologic studies. The genetic factors are unknown but might be related to renal kallikrein excretion.

IV. New Approaches to Drugs against Development of Hypertension Once a diagnosis of hypertension has been established, control of the high BP of the patients with drugs may not be difficult. However, no drugs for preventing the development of hypertension are available, because the mechanisms of development of hypertension have not been fully clarified. Once the gene(s) responsible for the induction of hypertension are discovered, gene therapy might be possible. Nevertheless, if reduced excretion of urinary kallikrein is a cause of hypertension, increasing the kinin concentration in the renal collecting ducts may be a reliable strategy for exploring the development of new drugs against hypertension. The simplest way is to inhibit the degradation of kinin in the renal collecting ducts. An alternative strategy is to accelerate secretion of renal kallikrein from the renal connecting tubules.

A. Inhibition of Kinin Degradation in Urine 1. Renal Kininase lnhibiton

According to the aforementioned results (Section I.B.4), the major kininases in urine collected from the rat ureter are CPY-like endopeptidase and NEP (Kuribayashi et al., 1993). In human urine, these two peptidases are also major kininases, but the contribution of kininases is dependent on the pH of the urine; therefore, NEP is more active at a neutral pH, whereas CPY is active at both neutral and acidic pH values, as demonstrated by the effects of inhibitors on each enzyme (Saito et al., 1996). Therefore, the urinary p H must be fixed when the contribution of urinary kininases is examined. In the renal collecting ducts, the contribution of individual enzymes is dependent on the urinary pH. a. Inhibitors of CPY-like hdopeptidase As described in Section I.B.4, ebelactone B, which is isolated from the culture medium of Actinomycetes,

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selectively inhibits the activity of CPY in rat urine as well as that of CPY from yeast without inhibiting carboxypeptidases A and B or other kininases in the plasma and urine (Majima et al., 1994a).Administration of ebelactone B to anesthetized rats caused diuresis and natriuresis in parallel with increased secretion of urinary kinin. The diuresis and natriuresis are blocked by HOE 140 (Fig. 16) (Majima et al., 1994a). In DOCA-salt hypertension in normal BN-Ki rats, subcutaneous infusion of lisinopril for 1 week from 8 weeks of age does not reduce SBP, since renin has been suppressed in this model. In contrast, the high BP of the normal BN-Ki rat is suppressed by subcutaneous infusion of ebelactone B (Fig. 17)(Majima et al., 1995b). The urinary sodium excretion of the rats was increased, and the urine volume was slightly increased. Mutant kininogen-deficient BN-Ka rats developed hypertension rapidly on DOCA-salt treatment, and their SBPs leveled off 2 weeks after the start of the treatment (at 9 wk of age), but neither ebelactone B nor lisinopril had any effect, since no kinin was generated in the urine (Majima et al., 1995b).Poststatin, which is also isolated from the fermentation broth of S. viridochvomogenes MH534-30F3, inhibits all kininase activities in rat urine (Majima et al., 1993a). Poststatin treatment of rats with DOCA-salt hypertension also reduced the high BP during this treatment (Majima et al., 1994b). These data indicate that increased level of kinin in the tubular lumen, not in the perivascular space, reduced the SBP, since CPY is responsible only for the degradation of kinin in the tubular lumen of the kidney but not in plasma of the peritubular space. b. Inhibitors of Neutral Endopeptidase NEP is another major kininase in rat urine (Kuribayashi et al., 1993) but is also reported to be a proteinase for the hydrolysis of ANP and enkephalins (Erdos and Skidgel, 1989) and significantly contributes to the extrarenal metabolism of ANP (Chiu et al., 1991).NEP is also present in the pig kidney microvillar membrane (Stephenson and Kenny, 1987)and in the glomeruli and brush borders of the proximal tubules of the kidney (Shima et al., 1988). It is responsible for 68% of the total kininase activity in rat urine (Ura et al., 1987). Many inhibitors of NEP have been developed that increase the endogenous ANP plasma levels in normal volunteers and in experimental animals (Gros et al., 1989; Jardine et al., 1990; Lecomte et al., 1990; Shepperson et al., 1991) or in congestive heart failure models (Northridge et al., 1990; Tikkanen et al., 1990) and in cirrhotic patients with ascites (Dussaule et al., 1991) in association with an increase in urine volume and mean urinary sodium excretion. NEP does not contribute to kinin hydrolysis in the plasma (Ishida et al., 1989). It is of interest to know whether an NEP inhibitor suppresses the SBP in hypertensive models and hypertensive patients. NEP inhibitors (candoxatrilat, or its prodrug candoxatril, and SCH 34826) reduced the SBP of onekidney DOCA-salt hypertensive rats by 30 to 40% (Stephenson and Kenny,

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FIGURE 16 Effects of ( A ) ebelactone B (EB) on urinary kinin levels, (B) urine volumes, ( C )urinary sodium levels, and (D) urinary potassium levels in anesthetized SD rats. EB (3 mgkg) was administered intraduodenally. Urine samples for 15 minutes were collected 15 minutes before EB (Pre) and 1 hr after EB (Post). HOE 140, a BK Bz antagonist (BK-A) was infused (3 mg/kg/hr) intravenously from 15 minutes before EB for 75 minutes. Each value represents the mean 2 SEM from 4 animals. The “post” value was compared with the “pre” value in each group of animals (paired t-test. * p < 0.05, * * * p < 0.001). From Majima eta!., 1994a, with permission.

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FIGURE 17 Effects of ebelactone B and IisinoDril on the develoDmenta1 stage of DOCA-salt hypertension. Values (SBP) are means (5SEM) of the ._ number ( n )of rats. After uninephrectomy at 7 weeks of age, DOCA (5 m&g s.c.) was administered once for 1 week. From 8 weeks of age, ebelactone B (5, 15 mgkglday) or lisinopril (5 mg/kg/day) was administered (s.c.) for 1 week to DOCA-salt-treated normal BN-Ki rats and kininogen-deficient BNKa rats. Values from rats receiving ebelactone B or lisinopril were compared with those of rats receiving vehicle at the same time period. * p < 0.05. From Majima et al., 1995b, with permission. Reprinted from European Journal of Pharmacology, 284, by Majima et al., Ebelactone B, an inhibitor of urinary carboxypeptidase Y-like kininase, prevents the development of deoxycorticosterone acetate-salt hypertension in rats, 1-1 1, 1995 with kind permission of Elsevier Science-NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam, The Netherlands. ~~~

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1987; Sybertz etal., 1990; Seymour et al., 1990).However, a direct relationship between plasma ANP levels and the antihypertensive effect is not always present, so the reduction of BP by this inhibitor in DOCA-salt hypertensive rats is unlikely to be due to increased plasma ANP levels (Sybertz, 1991), although the reduction of BP by an NEP inhibitor is abolished by pretreatment with ANP antiserum (Sybertz et al., 1991). The effects of NEP inhibitors may also be influenced by the activity of the ANP c receptors (Chiu et al., 1991). Thiorphan, an NEP inhibitor, increased the plasma and urinary ANP levels with increased sodium excretion in SHRs, but the degree of natriuresis was much greater than that expected from the rise of the plasma ANP level (Cavero et al., 1990; Hirata et al., 1991), indicating that tubular ANP may play some direct role in natriuresis at the distal nephron or that inhibition of NEP may result in natriuresis through inhibition of cleavage by NEP of other peptides, such as BK in the kidney. The same was true in Dahl salt-sensitive rats (Suzuki et al., 1992). Analysis by reversed-phase high-performance liquid chromatography revealed that @-recombinant ANP(1-28) in the plasma of Dahl saltsensitive rats is degraded to a-recombinant ANP(1-25)in the urine, and candoxatril, an ANP inhibitor, inhibits this degradation (Suzuki et al., 1992), indicating the presence of NEP in the kidney (Kenny and Stephenson, 1980; Roques et al., 1980). Indeed, NEP is found in high concentrations in the kidney, liver, and lung (Ronco et al., 1988). The natriuresis by ANP was completely abolished by a BK antagonist (Smits et al., 1990), but it is reported that no BK antagonist contributes to the antihypertensive response to NEP inhibition (Sybertz et al., 1989, 1991; Sybertz, 1991). Infusion of anesthetized normotensive rats with an NEP inhibitor, UK 73967, significantly decreased NEP activity and increased the kinin, urine volume, and urinary sodium excretion levels but did not induce a significant increase in plasma ANP. Simultaneous administration of HOE 140 eliminated the increases in urine volume and urinary sodium excretion caused by UK 73967 (Ura et al., 1994). These results indicate that NEP may play some role in the kidney, so that its inhibition induces natriuresis, probably through inhibition of kinin degradation, which supports the hypothesis that NEP contributes to kinin degradation in rat urine as one of the major kininases (Kuribayashi et al., 1993). In clinical studies with NEP inhibitors in hypertensive patients, the results were not always consistent in relation to the role of ANP. Candoxatril also increased the plasma ANP levels in hypertensive patients in a sodium concentration-related manner. Urinary sodium excretion was increased up to 6 hr after drug administration, but no difference from normotensive subjects was observed in urinary cGMP excretion (Sagnella et al., 1992). In contrast, SCH 42495 increased the plasma cGMP level in positive correlation with an increase in the plasma ANP level (Ogihara et al., 1994). A 28-day course of treatment of essential hypertensive patients with candoxatril did

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not induce either a fall in supine BP or the urinary excretion of more cGMP than was excreted by placebo-treated patients (Bevan et al., 1992). In saltloaded volunteers, SCH 34826 (400-600 mg) significantly increased the urinary excretion of sodium, cGMP, and ANP without causing changes in the cGMP or ANP levels in the plasma, suggesting that ANP has specific renal effects in normal individuals after sodium loading (Burnier et al., 1990). In low-renin essential hypertensive patients, SCH 34826 (400 mg 4 times a day) significantly reduced supine systolic and diastolic BPs, but the urinary excretion of sodium and the urine volume were not altered (Kosoglou et al., 1990). It is likely that in human subjects, NEP inhibitors may induce natriuresis and diuresis by the inhibition of NEP in the kidney, probably by inhibiting kinin degradation in the renal tubules. The effects of ANP inhibitors should be examined under salt loading and at neutral pH in urine, since the renal kallikrein-kinin system plays its role only when sodium is prone to being accumulated in the body. The inconsistency of the beneficial effects of NFP inhibitors may be partly due to unawareness of this function of the renal kallikrein-kinin system.

6. Acceleration of Secretion of Renal Kallikrein If the urinary excretion of renal kallikrein is reduced in patients with essential hypertension and in hypertensive models, one treatment strategy is to accelerate the excretion of renal kallikrein and raise the kinin concentrations in the renal cortical collecting duct. No drugs that have such effects are known, and their development is becoming a matter of urgency. Nevertheless, stimuli to accelerate the secretion of kallikrein in experimental animals are known (see Section II.B) and include sodium deprivation, DOCA or aldosterone administration, and potassium intake. Of these, sodium deprivation and sodium-retaining steroid hormones are unlikely to be used as medical intervention. However, potassium administration can be useful for accelerating the secretion of renal kallikrein. Clinical trials may be expected. Nevertheless, at present it is hard to decide which stimuli can be used as medical interventions for acceleration of urinary kallikrein secretion. Vasopressin may be used as a releaser of urinary kallikrein (Section II.B.4), but more precise experimentation may be necessary before use of this peptide hormone is recommended. Oxytocin could also be added as another such experimental accelerator (Section ILB.4). It may be true that oxytocin plays a physiological role in both males and females, in addition to its induction of uterine contractions of labor in females, since the serum level of oxytocin in males (1.80 2 0.07 mU/ml) is the same as that in nonpregnant females (1.71 ? 0.07 mU/ml) (Amico et al., 1981). These results were confirmed by Leake et al., (1981). As shown in Figure 18, intravenous infusion of oxytocin under pentobarbital anesthesia in SD-strain male rats increases the urine volume and urinary sodium excretion as well

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FIGURE 18 Effect of Hoe 140, a bradykinin B,-agonist, on the increases in urine volume (A) and urinary excretions of active kallikrein (B), sodium (C),chloride (D),potassium (E) and creatinine (F) induced by intravenous infusion of oxytocin (OT). O T was infused at the rate of 30 nmofig/30 min, and Hoe 140 was infused a t the rate of 4.5 mg/kg/90 min as shown in the scale below. The value represents the means ? S.E.M. Each value of the Hoe 140-treated group (W) was compared with that of the Hoe 140 non-treated group (OT-infused group: 0 )('P < 0.05, **P < 0.01) or the vehcle-infused group (0)(IP < 0.05, ssp < 0.01, IsrP < 0.001) at the same time period. In the urinary kallikrein analysis, the values during infusion of O T were compared with that at the time of 15 min (#P < 0.05, "P < 0.01). 0: n = 6 for A and B, n = 5 for C-E, n = 4 for F, W: n = 5 for A-F, 0: n = 5 for A-E, n = 4 for F. From Adachi et al., 1995, with permission.

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as kallikrein secretion (Adachi et al., 1995). The increases in sodium and chloride excretion and urine volume due to oxytocin were markedly reduced by infusion of HOE 140 (Fig. 1 8 ) or the kallikrein inhibitor aprotinin. Thus, oxytocin may be a candidate as a urinary kallikrein releaser, although its natriuretic activity is not potent. In summary, if it is true that the reduced function of the renal kallikreinkinin system is a cause of hypertension at the early developmental stage through sodium accumulation in the body, increasing the kinin concentrations in the renal collecting ducts may be a novel way to prevent the development of hypertension. Since the main kininases in urine are CPY and NEP, the inhibitors of the urinary kininases may become novel antihypertensive drugs. Another strategy could be to accelerate the secretion of renal kallikrein from the connecting tubules. Agents that might serve this purpose are not known but may be discovered in the near future.

V. Conclusion It is clear that the distal tubules are equipped with a full complement of the tissue kallikrein-kinin system from the connecting tubules to the inner medullary collecting ducts. The major role of this system may be to inhibit sodium reabsorption in the collecting ducts through BK Bl receptors, but this system works effectively in situations in which excess sodium enters the body or in conditions that favor sodium accumulation in the body, as demonstrated by a series of experiments with kininogen-deficient BN-Ka rats. Therefore, past results should be reevaluated on this basis. It has not been fully confirmed that patients with essential hypertension, genetically hypertensive animals, or experimentally induced hypertensive models excrete less urinary kallikrein, since the reduced excretion of urinary kallikrein due to renal injuries obscures the conclusion. Nevertheless, several indirect findings, including results from kininogen-deficient BN-Ka rats, strongly suggest that reduced function of the renal kallikrein-kinin system plus excess sodium ingestion or aldosterone release may trigger the development of hypertension, at least in sodium-sensitive hypertension. In this context, development of new types of drugs that increase the kinin concentrations in the renal collecting ducts, either by inhibition of kinin degradation or by acceleration of secretion of renal kallikrein from the connecting tubules, may be required to prevent hypertension. Acknowledgments The authors express deep appreciation both for the contributions of the staff and the technicians of the Department of Pharmacology, Kitasato University School of Medicine, in

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performing the experiments o n kininogen-deficient BN-Ka rats, and for those of the technicians in the Animal Facilities of Kitasato University School of Medicine for carrying out the difficult work of breeding the mutant BN-Ka rats. The authors also appreciate the work of Mr. Chris W. P. Reynolds in reviewing the English of the manuscript.

References Abe, K., Seino, M., Otsuka, Y., and Yoshinaga, K. (1977). Urinary kallikrein excretion and sodium metabolism in human hypertension. In Chemistry and Biology of the KallikreinKinin System in Health and Disease. (J. J. Pisano and K. F. Austen, eds.), pp. 411-414. Washington, Fogarty International Center Proc., Washington, DC. Abe, K., Yasujima, M., Irokawa, N., Seino, M., Chiba, S., Sakurai, Y., Sato, M., Imai, Y., Saito, K., Ito, T., Haruyama, T., Otsuka, Y., and Yoshinaga, K. (1978). The role of intrarenal vasoactive substances in the pathogenesis of essential hypertension. Clin. Sci. Mol. Med. 55, 363s-366s. Abelous, J. E., and Bardier, E. (1909).Les substance hypotensive de I’urine humaine normale. Crit.Rev. SOC. Biol. 66, 511. Adachi, K., Majima, M., Katori, M., and Nishijima, M. (1995).Oxytocin-induced natriuresis mediated by the renal kallikrein-kinin system in anesthetized male rats.]pn. /. Pharmacol. 67, 243-252. Ader, J.-L., Pollock, D. M., Butterfield, M. I., and Arendshorst, W. J. (1985). Abnormalities in kallikrein excretion in spontaneously hypertensive rats. Am. 1. Physiol. 248, F396F403. Ader, J.-L., Tran-Van, T., and Praddaude, F. (1987). Reduced urinary kallikrein activity in rats developing spontaneous hypertension. Am. 1. Physiol. 252, F964-F969. Adetuyibi, A,, and Mills, I. H. (1972). Relation between urinary kallikrein and renal function, hypertension, and excretion of sodium and water in man. Lancet ii, 203-207. Alla, S. A., Buschko, J., Qitterer, U., Maidhof, A,, Haasemann, M., Breipohl, G., Knolle, J., and Mueller-Esterl, W. (1993).Structural features of the human bradykinin Bz receptor probed by agonist, antagonists and anti-iodotypic antibodies. /. Biol. Chem. 268, 1727717285. Alla, S. A., Qitterer, U., Grigoriev, S., Maidhof, A., Haasemann, M., Jarnagin, K., and MuellerEsterl, W. (1996).Extracellular domains of the bradykinin Bz receptor involved in ligand binding and agonist sensing defined by anti-peptide antibodies. 1.Biol. Chem. 271, 17481755. Amico, J. A., Seif, S. M., and Robinson, A. G. (1981).Oxytocin in human plasma: Correlation with neurophysin and stimulation with estrogen.]. Clin.Endocrinol. Metab. 52,988-993. Arbeit, L. A,, and Serra, S. R. (1985).Decreased total and active urinary kallikrein in normotensive Dahl salt susceptible rats. Kidney Int. 28, 440-446. August, J. T., Nelson, D. H., and Thorn, G. W. (1958).Response of normal subjects to large amounts of aldosterone. I . Clin. Invest. 38, 1549-1555. Balment, R. J., Brimble, M. J., and Forsling, M. L. (1980). Release of oxytocin induced by salt loading and its influence on renal excretion in the male rat. /. Physiol. (Lond.) 308, 439-449. Balment, R. J., Brimble, M . J., Forsling, M. L., and Musabayane, C. T. (1986).The influence of neurohypophysial hormones o n renal function in the acutely hypophysectomized rat. I. Phy5iOl. (Lond.) 3381, 439-451. Barraclough, M. A., and Mills, I. H. (1965).Effects of bradykinin on renal function. Clin. Sci. 28, 199-206.

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Bascands, J. L., Girolami, J.-P., Pecher, C., Moatti, J.-P., Manuel, Y., and SUC,J. M. (1987). Compared effects of a low and a high sodium diet on the renal and urinary concentration and activity of kallikrein in normal rats. J. Hypertens. 5, 311-315. Beierwalter, W. H., Arendshorst, W. J., and Klemmer, P. J. (1982). Electrolyte and water balance in young spontaneously hypertensive rats. Hypertension 4, 908-915. Berg, T., Bradshaw, R. A,, Carretero, 0. A., Chao, J., Chao, L., Clements, J. A., Fahnesto, Gauthier, F., MacDonald, R. J., Margolius, H. S., Morris, B. J., Richards, R. I., and Scicli, A. G. (1992). A common nomenclature for members of the tissue (glandular) kallikrein gene families.” Agents Actions 38, (Suppl.), 19-25. Berk, B. C., Vallega, G., Muslin, A. J., Gordon, H. M., Canessa, M., and Alexander, R. W. (1989). Spontaneously hypertensive rat vascular smooth muscle cells in culture exhibit increased growth and Na+/H+ exchange. J. Clin. Invest. 83, 822-829. Berry, T. D., Hasstedt, S . J., Hunt, S. C . , Wu, L. L., Smith, J. B., Ash, K. O., Kuida, H., and Williams, R. R. (1989).A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension 3, 3-8. Berry, C. A., and Rector, F. C. J. (1991). Renal transport of glucose, amino acids, sodium, chloride and water. In The Kidney. Vol. 1. (B. M. Brenner and F. C. J. Rector, eds.), pp. 250-251. W. B. Saunders, Philadelphia. Bevan, D. R., MacFarlane, N. A. A,, and Mills, I. H. (1974). The dependence of urinary kallikrein excretion on renal artery pressure. J. Physiol. (Lond.) 241, 34P-35P. Bevan, E. G., Connell, J. M. C., Doyle, J., Carmichael, H. A., Davies, D. L., Lorimer, A. R., and McInnes, G. T. (1992).Candoxatril, a neutral endopeptidase inhibitor: Efficacy and tolerability in essential hypertension. J. Hypertens. 10, 607-613. Bhoola, K. D., Figueroa, C. D., and Worthy, K. (1992). Bioregulation of kinins: Kallikreins, kininogens, and kininases. Pharmacol. Rev. 44, 1-80. Bianchi, G., Fox, U., and Imbasciati, E. (1974a).The development of a new strain of spontaneously hypertensive rats. Life Sci. 14, 339-347. Bianchi, G. P., Fox, U., Di Francesco, G. F., Giovanetti, M., and Bagetti, D. (1974b). Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin. Sci. Mol. Med. 47, 435-448. Bianchi, G. P., Baer, G., Fox, U., Duzzi, L., Pagetti, D., and Giovanetti, M. (1975). Changes in renin, water balance, and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ. Res. 36, 1-153-1-161. Bianchi, G., Ferrari, P., Trizio, D., Ferrandi, M., Torielli, L., Barber, B. R., and Poli, E. (1985). Red blood cell abnormalities and spontaneous hypertension in the rat. A genetically determined link. Hypertension 7, 319-325. Bianchi, G., Tripodi, G., Casari, G., Salardi, S., Barber, B. R., Garcia, R., Leoni, P., Torielli, L., Cusi, D., Ferrandi, M., Pinna, L. A., Baralle, F. E., and Ferrari, P. (1994). Two point mutations within the adducin genes are involved in blood pressure variation. Proc. Natl. Acad. Sci. USA 91,3999-4003, Blatter, L. A., Taha, Z., Mesaros, S., Sacklock, P. S., Wier, W. G., and Malinski, T. (1995). Simultaneous measurement of CaZt and nitric oxide in bradykinin-stimulated vascular endothelial cells. Circ. Res. 76, 922-924. Bonner, G., Rasher, W., Speck, G., Marin-Grez, J., and Gross, F. (1981).The renal kallikreinkinin system in Brattleboro rats with hereditary hypothalamic diabetes inspidus. Acta Endocrinol. 98, 35-42. Bonner, G., Schwertschlag, U., Martin-Grez, M., and Gross, F. (1983). Effect of changes in perfusion pressure on urinary kallikrein in the isolated perfused rat kidney. Renal Physiol. 6, 288-294. Bonner, G., Preis, S., Schunk, U., Toussaint, C., and Kaufmann, W. (1990). Hernodynamic effects of bradykinin on systemic and pulmonary circulation in healthy and hypertensive humans. J. Cardiovasc. Pharmacol. 15, (Suppl. 6), S46-S56.

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