Renin- and non-renin–mediated antihypertensive actions of converting enzyme inhibitors

Kidney International, Vol. 25 (1984), pp. 969—983

NEPHROLOGY FORUM

Renin- and non-renin—mediated antihypertensive actions of converting enzyme inhibitors Principal discussant: RANDALL M. zusMAN Massachusetts General Hospital and Harvard Medical school, Boston, Massachusetts

impulse was palpated in the anterior axillary line, 5th intercostal space.

Carotid upstrokes were brisk. Jugular venous pressure was approximately 8 cm of water. Peripheral pulses were full and intact bilaterally. Abdominal examination revealed no organomegaly and no bruits were

Editors JORDAN J. COHEN JOHN T. HARRINGTON JEROME P. KASSIRER

heard. No evidence of peripheral edema, cyanosis, or clubbing was found. The patient's blood pressure initially was controlled with intravenous nitroprusside. A gradual transition to oral therapy with hydralazine, 50

NlcoLAos E. MAmAs

mg every 6 hours; furosemide, 20 mg twice daily; propranolol, 20 mg every 6 hours; and alpha-methyldopa, 500mg every 6 hours, resulted in a reduction in his blood pressure to 130/90 mm Hg. Prior to discharge from the hospital, urine collection revealed the catecholamine excretion to be within normal limits. A random plasma renin activity was 0.3 ngl

Mnnaging Editor CHERYL J. ZUSMAN

mllhr, and the plasma aldosterone concentration was 66 pg/mI. At discharge the patient's BUN was 22 mg/dl. serum creatinine was 2.0 mg/dl, and sodium and potassium concentrations were normal. The

Michael Reese Hospital and Medical Center University of Chicago Prilzker School of Medicine

patient was returned to the care of his private physician. One month following discharge, the patient's blood pressure was 174/ 112 mm Hg. Hydralazine and alpha-methyldopa administration was discontinued, propranolol was increased to 40 mg every 6 hours, and minoxidil, 5 mg twice daily, was added to his drug regimen. His blood pressure fell to 150/80 mm Hg, and he continued to do well without evidence of congestive heart failure. One year following the initial hospitalization, the patient developed musculoskeletal pain thought to be secondary to degenerative joint disease. He was given indomethacin, 50mg orally three times daily, which relieved his pain. One month later, follow-up examination disclosed a blood pressure of 210/140 mm Hg. The minoxidil dose was raised progressively to 10 mg orally four times daily, but the increase produced no significant effect. Alpha-methyldo-

and

New England Medical Center Tufts University School of Medicine

Case presentation A 41-year-old black man was admitted to the Massachusetts General Hospital (MGH) because of shortness of breath. The patient had been hypertensive for 10 years. and had been treated with propranolol, 40mg orally three times daily. On the day of admission, he became acutely

short of breath, but he denied chest pain and other cardiovascular symptoms. Blood pressure at the time of admission was 200/100 mm

Hg. His bean rate was 150 beats/mm, and the electrocardiogram revealed global ST-segment and T-wave changes consistent with diffuse myocardial ischemia. Measurement of blood gases obtained while the patient was breathing room air revealed a Pa02 of 64 mm Hg, PaCO2 of 91 mm Hg. and pH of 7.05. Physical examination disclosed rales in both

lung fields to the apices; the chest x-ray revealed bilateral alveolar pulmonary edema. The patient was intubated and given 100% oxygen. His blood pressure fell to 120/70mm Hg and his heart rate decreased to

50 beats/mm. A second electrocardiogram revealed complete heart block and acute right bundle-branch block. Treatment with intravenous epinephrine. atropine, morphine sulfate, and furosemide resulted in an improvement in pulmonary function, resumption of sinus rhythm, and a prompt diuresis. The blood pressure rose to 200/120 mm Hg, and the heart rate increased to 110 beats/mi Funduscopic examination revealed arteriolar narrowing but no hemorrhages or exudates. Examination of the chest revealed normal breath sounds bilaterally; no rales or rhonchi were present. Cardiac examination revealed normal first and

second heart sounds; a loud summation gallop was heard, but there

were no murmurs, rubs, heaves, or thrills. The point of maximal

pa, 500 mg twice daily, was restarted; it also was ineffective. The patient's regimen eventually consisted of minoxidil, 10 mg three times daily; alpha-methyldopa, 500 mg twice daily; furosemide, 40 mg twice daily; captopril, 100 mg three times daily; and propranolol, 40 mg four times daily. On this regimen, the blood pressure remained at 180/110 mm Hg, and the patient returned for further evaluation. He was admitted to the MGH Clinical Research Center and was given a 10 mEq sodium diet. Minoxidil, alpha-methyldopa, captopril. propranolol, and indomethacin were discontinued, but the patient continued to receive 40mg of furosemide daily. Urinary sodium excretion fell to less than 10 mEq/day. The BUN and creatinine concentrations were 14 and 1.1 mg/dl, respectively; serum sodium concentration was 137 mEq/liter, and potassium concentration was 4.4 mEq/Iiter. Plasma renin activity was 0.2 ng/ml/hr in the supine position and 1.1 ng/ml/hr after 3 hours in the upright position. The administration of 75 mg of captopril orally lowered the blood pressure from 160/120mm Hg to 120/90mm Hg

Presentation of the Forum is made possible by grants from Smith Kline

& French Laboratories, CIBA Pharmaceutical Company, GEIGY Pharmaceuticals, and E. R. Squibb & Sons.

© 1984 by the International Society of Nephrology

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Nephrology Forum

in the supine position, and from 170/125 to 100/65 in the upright position (Fig. 1). The patient was discharged on a regimen of furosemide, 40 mg twice daily, and captopril, 50 mg three times daily. His blood pressure has remained approximately 130/75 mm Hg and he is asymptomatic.

Captoprii, mg 50 25

70

Cardiac Unit, Massachusetts General Hospital, and Assistant

Professor of Medicine, Harvard Medical School, Boston,

S

Mass.): The patient presented for discussion today provides an opportunity for us to examine the therapeutic utility of inhibi-

causes increased aldosterone production and secondary sodium retention. Because both vasoconstriction and sodium retention increase blood pressure, considerable attention has been directed toward the development of a clinically useful inhibitor of the renin-angiotensin cascade. As shown in Figure 2, three steps in

the generation of angiotensin II or its cellular action can be attacked [1]. Renin, a proteolytic enzyme produced principally by the juxtaglomerular apparatus, cleaves angiotensinogen, a polypeptide synthesized by the liver, to produce angiotensin I, which has no vasopressor activity. The angiotensin converting enzyme, located principally within the pulmonary circulation [21, then removes two amino acids from the angiotensin I molecule and forms the octapeptide angiotensin 11; the latter compound, through interaction with its receptor, constricts

150

0,—

130

tors of the renin-angiotensin cascade. I will focus on the

vasoconstriction. It also stimulates the adrenal gland and

Supine

1.0

DR. RANDALL M. ZUSMAN (Director, Hypertension Division,

Renin-angiotensin cascade Angiotensin II stimulates vascular smooth muscle and causes

I

110

Discussion

mechanism of action of the converting enzyme inhibitors and will present evidence for a prostaglandin-dependent, non-reninmediated, antihypertensive effect of captopril, an orally active converting enzyme inhibitor. Before discussing these issues, however, I would like to review the present understanding of the renin-angiotensin system.

,

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pudre

90 70

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diminishes the physiologic effect of angiotensin II in vivo and theoretically should decrease blood pressure in experimental models of hypertension and in patients with renin-dependent hypertension. Renin antibodies. Renin has been purified from dog [3], hog [4, 5], and human [6] kidney. Using purified renin as an antigen, Haber and coworkers raised antibodies against the catalytic site

of the enzyme; these antibodies serve as a probe for the investigation of the role of renin in normal cardiovascular homeostasis and in experimental models of hypertension [7]. Dzau and colleagues demonstrated that such antibodies specifi-

cally prevent an increase in blood pressure in response to injections of purified canine renin but do not prevent the increase in blood pressure induced by angiotensin I or angiotensin II [8]. Similarly, these investigators showed that the injec-

tion of renin-specific antibody reduces the blood pressure in sodium-depleted dogs, thus demonstrating that maintenance of blood pressure in this pathophysiologic state is renin dependent [7, 8]. Because the antibody is specific for renin, no significant hemodynamic response to antibody injection occurs in animals given a high-salt diet; under these conditions, the role of renin

180

240

300

Time, minutes Fig. 1. Effect of capiopril on the blood pressure iviih subject in the

position. The patient was receiving a diet containing 10 mEq sodium and 100 mEq potassium per 24-hour period. Blood pressure in

Supine

the upright position fell from 170/125 mm Hg prior to captopril administration to a nadir of 100/65 mm Hg.

[iotensinoe1J Renin

Angiotensin I __________J I

[

Converting enzyme

Angiotensin Ii

I

Renin antibody Pepstatin Substrate analogs Snake venom Peptides

_ )Pyr-Trp-Pro-Arg-ProGin-lie-Pro-Pro) D-3-mercapto-2-methyi propanoylL-prohne

Angiotensin Ii analogs (Sar-Arg-Vai-Tyr-lieHis-Pro-Ala)

smooth muscle and stimulates aldosterone biosynthesis. Inhibi-

tion of the renin-angiotensinogen reaction, blockade of the angiotensin II receptor, or inhibition of converting enzyme

120

igiotensin Ii

1

receptor activatioJ Fig. 2. The renin-angiorensin cascade and its inhibitors. (Adapted from

Ref. I.)

in maintaining blood pressure is minimal. The administration of renin-specific antibody to dogs with acute renovascular hypertension promptly eliminates renin from the peripheral circulation and restores normal blood pressure. The redevelopment of hypertension within 24 to 36 hours following antibody injection

coincides with the gradual metabolism of the renin-specific antibody and the reappearance of renin activity in the peripheral circulation [7, 8]. Recently monoclonal, antihuman, reninspecific antibodies have been isolated using cell fusion techniques [9]. These antibodies do not bind non-renin proteolytic enzymes and proteins, are species specific, and do not crossreact with mouse, dog, bovine, or rat renin. Because they are directed toward the catalytic site, these highly potent antibodies are specific tools for physiologic studies in subhuman primates

and in humans. In much the same way that digitalis-specific antibodies are used in the treatment of digitalis toxicity, renin-

971

A ntihypertensive actions of converting enzyme inhibitors

B 100 100 80

60

40 120

120

100

100

80 0 0 60

a 00

Fig. 3. Effect on blood pressure of infusion of a renin inhibitory peptide into normal volunteers on a JO mEq sodiuml24 hr diet in the supine (A) and upright (B) positions. (Reproduced from Ref. 14.)

0

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specific antibodies might become clinically valuable tools for the treatment of accelerated or malignant hypertension in the

Clinical investigation of the renin inhibitory peptide extended these experimental findings. When we administered the peptide

future [91.

to sodium-depleted humans, we observed a more complex hemodynamic response [14]. While the subjects were in the

Renin inhibitory peptides. Another method of inhibiting renin activity is the use of a specific competitive inhibitor, based on the structure of angiotensinogen. Since Skeggs and colleagues

reported that an octapeptide was the shortest peptide capable both of serving as a substrate for renin and of functioning as a competitive inhibitor of the renin-angiotensinogen reaction [10, 11], a number of analogues have been synthesized that exhibit stronger inhibitory properties than those of this original octapeptide. Renin normally cleaves a leucine-leucine bond in angiotensinogen. Burton and coworkers reported that the substitution of phenylalanine for these leucine residues yielded a molecule that served as a poor substrate for renin's proteolytic activity, and which prevented its reaction with angiotensinogen by competitive inhibition. The addition of a proline residue at the amino terminus and a lysine residue at the carboxy terminus of this molecule produced a peptide with inhibitory properties

supine position, intravenous administration at rates up to 1 mgI kglmin reduced blood pressure only moderately. When these

individuals stood up, blood pressure fell to zero (Fig. 3). In addition, in contrast to the tachycardia that usually accompaflies vasodilation in sodium-depleted subjects, the nadir of the blood pressure response frequently occurred in association with a marked sinus bradycardia. These findings suggest activation of the parasympathetic nervous system by the renin inhibitory peptide.

In a preliminary study, we determined the effect on blood pressure of giving the renin inhibitory peptide to one subject after administration of a high-salt diet (200 mEq/day). Because plasma renin activity is known to be suppressed under these conditions, we anticipated a minimal hypotensive response to inhibition of the renin-angiotensin cascade. Strikingly, the

in vivo [121.

subject's blood pressure fell markedly in both supine and

Is this renin inhibitory peptide effective in experimental models of hypertension? Its intravenous injection caused a

upright positions, and the decrease again was associated with bradycardia (Fig. 4). In the supine position, blood pressure fell from 118/68 to 66/0 mm Hg; in the upright position, blood pressure decreased from 105/80 mm Hg to an undetectable value. During renin inhibitory peptide infusion, the plasma renin activity of this one subject increased. This finding suggests that effective blockade of the generation of angiotensin II occurred with release of the negative feedback pathways that normally suppress renin release. In contrast to the fall in plasma aldosterone concentration that frequently accompanies the inhibition of the renin-angiotensin system with other substances, however, plasma aldosterone concentration increased during renin inhibitory peptide infusion.

reduction in blood pressure in sodium-depleted M. fasicularis

monkeys that was not observed following injection of the peptide into normotensive, sodium-replete animals [12]. Because peptide infusion blocked the pressor response to purified human renin but not to angiotensin I or angiotensin II in these animals, the investigators concluded that this renin inhibitory

peptide had no effect on the converting enzyme, but that its hemodynamic response was specific for inhibition of the reninangiotensinogen reaction. In a separate study, administration of

this renin inhibitory peptide in a monkey model of acute renovascular hypertension promptly lowered blood pressure, presumably because of inhibition of the renin-angiotensinogen reaction [131.

These data suggest that, although designed as a specific inhibitor of the renin-angiotensinogen reaction, the renin inhibi-

972 972

Nephro!ogyForum Forum Nephrology Renin inhibitory inhibitory peptide, peptide, Renin

Renin inhibitory inhibitory peptide, peptide, Renin

mg kg mm mgkg/min

mg kgmmn mg/kg/mm 0.25

0.25

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120

100-

100 a,

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Fig. 4. Effect on blood pressure of a renin

inhibitory peptide into a normal volunteer on a 200 mEq/sodium/24 hr diet. (Reproduced

20

20 F

-30 0 30

I I __________

90

150

Time, Time, minutes minutes

210

0

from Ref. 14.) —30 0 30

90

150

210

minutes Time, Time. minutes

tory peptide has multiple mechanisms of action. In addition to angiotensin II molecule yields the highly competitive receptor inhibiting peripheral renin activity, the peptide might inhibit antagonist, saralasin [18]. Administration of this peptide to renin within the blood vessel wall, brain, or other sites. If so, a experimental animals with acute renovascular hypertension and previously unrecognized role for these tissue renins in the to patients with high-renin hypertension significantly reduces regulation of cardiovascular homeostasis will be unmasked. blood pressure. In low-renin states, however, saralasin posThe peptide might produce parasympathetic stimulation that sesses angiotensin II agonistic activity and increases blood

results in sinus bradycardia, venous dilation, and a fall in pressure [19]. The clinical utility of this compound thus is cardiac output. Alternately, it might interact with another limited to the identification of renin-dependent states, and even system and release vasodilating substances. Finally, the peptide

here its lack of specificity has prevented its widespread adop-

might activate cardiac reflexes such as the Bezold-Jarisch tion as a diagnostic tool. reflex, which results in peripheral vasodilation, bradycardia, and hypotension.

Other investigators also have explored the hemodynamic effects of renin-specific inhibitors. Szelke and coworkers synthesized a renin-specific inhibitor that reduces blood pressure in sodium-depleted conscious dogs [15]. In vitro, this substance inhibits the proteolytic activity of human, canine, and rat renin, but its effect on blood pressure homeostasis in human subjects

has not been tested. Similarly, Boger and colleagues have developed a highly potent renin inhibitor through substitution of

a statine (a chemical amino acid analogue) residue in the angiotensinogen peptide sequence [161. Administration of this material to sodium-depleted dogs also decreased blood pressure and, like the administration of the previously described renin inhibitory peptide to normal volunteers [14], reduced heart rate instead of producing tachycardia [17]. These studies lend credence to the suggestion that although renin inhibitory peptides were synthesized as specific inhibitors of the renin-angiotensinogen reaction, they might have multiple mechanisms of action,

either dependent or independent of the renin-angiotensin cascade.

Angiotensin II receptor antagonists A similar multiplicity of activity characterizes the action of angiotensin analogues, competitive antagonists of the angiotensin II receptor. The substitution of sarcosine and alanine for the naturally occurring amino acids at positions one and eight in the

Converting enzyme inhibition The importance of the angiotensin converting enzyme was first recognized by Skeggs and colleagues, who found that the product of the reaction of crudely purified porcine renin with equine angiotensinogen was a mixture of two peptide hormones [20]. Subsequent study revealed that production of the second hormone, later shown to be angiotensin II, was due to contamination of the angiotensinogen substrate by an enzyme that released a dipeptide from the carboxy terminus of angiotensin I [21, 22]. Both angiotensins had vasopressor properties following intravenous infusion. But Helmer, using a superfusion assay system measuring rabbit aortic strip contraction, later identified

angiotensin II as the biologically active moiety [22]. The vasopressor response to angiotensin I infusion therefore was attributable to its conversion to angiotensin II. Ng and Vane demonstrated that angiotensin I was converted to angiotensin II during passage through the pulmonary circulation [23, 241. Their work suggested that a pulmonary enzyme in intimate contact with the blood as it passed through the pulmonary circulation accounted for the rapid metabolism of the precursor peptide to angiotensin II. Subsequent studies have demonstrated that the converting enzyme is a component of the vascular endothelium of many tissues and that its localization on the luminal surface of the plasma membrane is ideally suited for its function [21. Because of the parallelism of proteolytic deactivation and activation of bradykinin and angiotensin I, respective-

973

Antihypertensive ac/ions of converting enzyme inhibitors

ly, during transit through the pulmonary circulation, it was suggested that the same protein, the angiotensin converting enzyme, might be responsible for the catalysis of both reactions

[25]. In 1968 Bakhte reported that bradykinin potentiating factor, a mixture of polypeptides isolated from venom of the snake Bothrops jararaca, inhibited the conversion of angiotensin Ito angiotensin II by canine pulmonary tissue [26]. Ferreira previously had demonstrated that this peptide mixture potentiated the action of bradykinin on smooth muscle by inhibiting

kininase activity and kinin degradation [27]. After purifying individual peptides from the snake venom, Ferreira and colleagues confirmed that the substances could inhibit both angiotensin converting activity and bradykininase activity of a pulmonary homogenate [28, 29]. The first angiotensin converting enzyme inhibitor studied in humans was a synthetic nonapeptide then known as SQ20881

and later named teprotide. Teprotide blocked the vasopressor response to intravenous infusions of angiotensin I, and effectively reduced blood pressure in patients with elevated plasma renin activity [30]. Because of teprotide's short duration of action and its limitation to parenteral administration, however, its clinical utility is limited. Studies with synthetic substrates and inhibitors of angiotensin converting enzyme led to the conclusion that the angiotensin converting enzyme was a carboxypeptidase similar to pancreatic carboxypeptidase A [31]. Additional studies revealed that the angiotensin converting enzyme is a zinc-containing metallopro-

tein, also similar to carboxypeptidase A [32]. It therefore was assumed that the site and mechanism of action of the angiotensin converting enzyme would be similar to those of the pancreatic enzyme [33]. In 1973 Byers and Wolfenden reported that d2-benzylsuccinic acid was a potent competitive inhibitor of carboxypeptidase A. This competitive activity was thought to be secondary to the simultaneous and stereospecific interaction of the inhibitor with three substrate binding sites at the active

site of the carboxypeptidase enzyme [34]. Reasoning that similar stereospecificity might characterize the active site of angiotensin converting enzyme, Cushman and colleagues undertook a sequential analysis of compounds that might serve as orally active converting enzyme inhibitors. These investigators demonstrated that an analogue of proline, D-3-mercapto-2methyl-propanoyl-l-proline, was a highly specific inhibitor of the converting enzyme in vitro [35]. The alpha-methyl group and the carboxyl groups of proline later were shown to interact with hydrophobic sites of the angiotensin converting enzyme.

Bradykinin

Angiotensinogen

I Renin

+ Angiotensin I

I

Angiotensin converting enzyme Captopril

Angiotensin II

I

i.-

———

Inactive peptides

Aldosterone Fig. 5. Theoretical mechanism of action of captopril. Inhibition of the angiotensin converting enzyme (kininase II) was theorized to result in a

fall in plasma angiotensin II and aldosterone concentration and a rise in plasma bradykinin concentration. (Reproduced from Ref. 37.)

renin-independent models of hypertension, the efficacy of captopril can only be explained by a non-renin—mediated antihyper-

tensive activity. It is my view that the non-renin—mediated activity of captopril is accounted for by captopril's stimulation of arachidonic acid release and a consequent increase in synthe-

sis of vasodilatory prostaglandins. The following discussion outlines the evidence that captopril has antihypertensive properties that are not mediated by renin and that prostaglandins account for those properties. The theoretical mechanism of action of a converting enzyme

inhibitor is represented in Figure 5 [37]. Inhibition of the converting enzyme by captopril decreases generation of angio-

tensin II from angiotensin I. The decrease in angiotensin II diminishes vasoconstrictor activity and decreases adrenal aldosterone biosynthesis. The consequent decrease in vasoconstrictor activity (and in theory, a sodium diuresis) thus lowers blood pressure. Because angiotensin II participates in a negative-feedback loop that inhibits renin release by the juxtaglo-

merular apparatus, the fall in angiotensin II concentration produces a reflex increase in renin activity and an increased concentration of angiotensin I. Because of the inhibition of the converting enzyme, however, this increase in angiotensin I concentration cannot elevate plasma angiotensin H concentration. In addition, because the converting enzyme is responsible

marked inhibitory properties of the molecule [36]. This new

for the destruction of bradykinin, the accumulation of increased concentrations of the vasodilator bradykinin reduces peripheral vascular resistance and lowers systemic blood pressure. Many clinical and laboratory studies have confirmed that the administration of teprotide or captopril significantly decreases plasma

proline analogue, originally known as SQ14225 and later named

angiotensin II concentration, plasma aldosterone concentra-

captopril, was found to be a potent competitive inhibitor of

tion, and blood pressure. Systemic vascular resistance falls and

converting enzyme activity.

cardiac output is maintained or increased, consistent with a reduction in the vasoconstrictor effects of angiotensin II [38].

The mercapto substitution on the beta carbon resulted in specific interaction with the zinc atom, which is a crucial portion of the catalytic site of the enzyme, and accounts for the

Based on the foregoing discussion of the synthesis of the converting enzyme inhibitor captopril and the properties of the converting enzyme as both the activator of angiotensin II and the deactivator of bradykinin, it was assumed that the response

of animals and humans to captopril could be explained by changes in the levels of angiotensin II and bradykinin. However, this assumption cannot explain many of the responses to captopril in normal and hypertensive animals and humans. In

The acute response to converting enzyme inhibition appears to correlate closely with the pretreatment plasma renin activity, and the response thus is consistent with the theoretical mechanism of action of these compounds that I have outlined [39]. Captopril's effect on the kinin system. Although theoretically expected to increase plasma kinin levels, converting enzyme inhibition could not be consistently proved to alter circulating

974

Nephrology Forum

kinin concentration. Occasional studies have reported an elevation in plasma kinin concentration [40—45], but most investigators have failed to demonstrate any significant increase [46—56]. Kinins are local mediators rather than circulating substances,

lease. In contrast, Textor and coworkers reported that chronic angiotensin II infusion in conscious rats prevented any hemodynamic response to converting enzyme inhibition. These investi-

gators concluded that neither bradykinin nor vasodilator hor-

and many enzymes other than the angiotensin converting mones contributed to the long-term antihypertensive activity of enzyme can inactivate them through kininase activity. Therefore, a failure to demonstrate an increase in circulating kinin concentration is not totally unexpected. Carretaro and colleagues examined the role of kinins in the acute and chronic hypotensive effect of converting enzyme inhibitors, using spe-

captopril [61]. Additional studies by Muirhead and associates revealed that

administration of captopril significantly decreases blood pressure in spontaneously hypertensive rats, an experimental model in which the hypertension is thought to be independent of the cific antikinin antibodies that block the depressor effect of renin-angiotensin system [62]. The decrease in peripheral vasexogenously administered bradykinin. Because the administra- cular resistance in these studies also suggests a non-renin— tion of antikinin antibodies had no effect on the hypotensive mediated antihypertensive activity of captopril. If captopril's antihypertensive activity were solely due to the response to captopril in sodium-depleted rats, the authors concluded that the antihypertensive activity of captopril in this antagonism of the generation of angiotensin II by renin in the model could be attributed solely to its inhibition of the renin- peripheral circulation, bilateral nephrectomy would be expectangiotensin cascade. Administration of the antikinin antibodies ed to totally eliminate any hemodynamic response to the in the spontaneously hypertensive rat or in 2-kidney, 1-clip administration of this converting enzyme inhibitor. Leslie and hypertensive rats significantly attenuated the decrease in blood coworkers reported that captopril failed to reduce the blood pressure following captopril administration, however [57]. Al- pressure of 5 anephric patients. These authors concluded that if though a consistent change in plasma kinin levels has not been captopril had an angiotensin-independent antihypertensive acfound, the possibility that tissue kinins accessible to the anti- tivity, this action would depend on the presence of functional kinin antibodies played a role in the antihypertensive activity of renal tissue [63]. Man ln't Veld, however, reported that the captopril cannot be excluded by such studies. volume status of anephric patients dramatically affected the Non-renin—mediazed hypotensive effect of converting enzyme hemodynamic response to captopril. Salt- and water-repleted inhibition. In addition to the possible role of kinins in the patients showed no response to captopril prior to hemodialysis. antihypertensive activity of captopril, additional evidence for a Following hemodialysis and relative salt and water depletion, non-renin—mediated antihypertensive activity of captopril was however, captopril significantly reduced blood pressure 164, obtained in studies involving experimental animals and normo- 65]. tensive and antihypertensive humans. Marks and coworkers The relative activities of saralasin and captopril in early and reported that captopril decreased blood pressure by 15% in late Goldblatt 2-kidney, 1-clip hypertension were studied by normal rats. Following nephrectomy, the blood pressure of the Thurston and colleagues, They found that in the early phase of animals fell by 30%; however, the administration of captopril hypertension, both saralasin and captopril reduced blood presproduced a further 10% drop in blood pressure despite the sure significantly. In the chronic phase of hypertension, howevabsence of renin in the peripheral circulation. In animals with er, only captopril evoked a statistically significant decrease in early Goldblatt 2-kidney, 1-clip hypertension (a model known to blood pressure, again suggesting that captopril has an antihybe renin dependent), captopril produced a 50% decrease in pertensive effect independent of the renin-angiotensin system. blood pressure that was associated with marked elevations in They further found that in salt-loaded or salt-restricted animals, plasma renin activity. On the other hand, in rats with late 2- or those with chronic 2-kidney Goldblatt hypertension, teprokidney, I-clip hypertension (a model of hypertension thought tide produced a reduction in blood pressure beyond that obnot to depend on the renin-angiotensin system), captopril also served following angiotensin receptor blockade with saralasin produced a substantial drop in blood pressure. In addition, in [66]. An additional approach to the study of a possible non-renin— animals made hypertensive by the chronic administration of deoxycorticosterone and a high-salt diet, captopril reduced mediated antihypertensive activity of captopril was reported by blood pressure by 20 mm Hg. These rats have markedly Tree and Morton. Investigating the blood pressure of sodiumsuppressed plasma renin activity and represent an experimental loaded dogs as a function of the plasma angiotensin II concenmodel of volume-expansion, low-renin hypertension [58]. tration before and after captopril administration, they found Moreover, in salt-depleted rats in which the endogenous renin- that a higher concentration of angiotensin II was required to angiotensin system has been blocked by infusion of the compet- produce the same blood pressure in dogs that had received itive angiotensin II antagonist saralasin, captopril further re- captopril than in those animals that had not [67]. In a similar study, Swartz and coworkers found that following infusion of duces blood pressure [59]. Muirhead and colleagues reported that the administration of teprotide, the plasma angiotensin II level had to be raised by a captopril to rats receiving exogenous angiotensin Ii and high- mean value of 45 pg/mI above the control plasma angiotensin II salt diets significantly decreased blood pressure [60]. The concentration to maintain the same blood pressure. Because an reduction of blood pressure in this experimental model could increase in plasma bradykinin levels following converting ennot be explained on the basis of a reduction in plasma angioten- zyme inhibition was found in this study, the authors suggested sin II concentration, as the exogenous administration of angio- that one or more other factors, perhaps bradykinin, was respontensin II maintained a high level of this vasoconstrictor poly- sible for the greater-than-expected hypotensive response to peptide in the peripheral circulation, raised the blood pressure converting enzyme inhibition based on the fall in angiotensin II to hypertensive levels, and suppressed endogenous renin re- concentration [45]. Crantz and colleagues reported that capto-

Antihvpertensive actions of converting enzyme inhibitors

pril elicited a greater drop in blood pressure in a group of patients with normal renin, essential hypertension than did teprotide. Unlike the response to teprotide, captopril administration was not associated with an increase in plasma kinin

concentration [46]. Finally, in a study of 26 hypertensive patients, Fagard and coworkers reported that captopril had a greater antihypertensive effect than did saralasin [68]. Their findings again suggested a non-renin—mediated antihypertensive

activity for this orally active converting enzyme inhibitor. Prostaglandin synthesis and the non-renin—mediated antihypertensive effect of converting enzyme inhibitors. Vinci and coworkers published the first study suggesting that the nonrenin—mediated antihypertensive activity of converting enzyme

inhibitors was due to prostaglandin release. They infused teprotide at a rate sufficient to lower blood pressure by 10 mm Hg in subjects with mild essential hypertension. The concentra-

tion of prostaglandin E in arterial blood, as measured by radioimmunoassay, increased threefold during teprotide infusion [69]. The authors also observed the anticipated rise in plasma renin activity and angiotensin I concentration as well as a fall in plasma angiotensin II and aldosterone concentrations. Plasma arterial bradykinin concentration remained unchanged during teprotide infusion. Swartz and coworkers subsequently reported the effect of captopril on the prostaglandin system in normal subjects on both high- and low-sodium diets. Captopril induced a significant increase in the excretion of the 13,14dihydro-15-keto metabolite of prostaglandin E2. No changes in plasma levels of 6-keto prostaglandin F2a, the major metabolite of prostacyclin, or thromboxane B2, the major metabolite of thromboxane A2, were observed. The depressor response to captopril correlated closely with the change in urinary prostaglandin E2 metabolite excretion, but did not correlate with changes in plasma angiotensin II and kinin levels [70]. Abe and coworkers reported an increase in urinary prostaglandin E excretion following captopril administration in patients with essential hypertension. Administration of a prostaglandin synthesis inhibitor to these same patients abolished the

antihypertensive activity of captopril [71]. Moore and colleagues reported an increase in the urinary excretion of the prostaglandin E2 metabolite following captopril administration in 31 sodium-restricted patients with essential hypertension. In

18 of these patients, the administration of indomethacin or aspirin was associated with decreased prostaglandin E2 excre-

tion and a significant blunting of the depressor response to captopril [72]. Similarly, Silberbauer et al [73], Ogihara et al [74], Witzgall et al [75], and Goldstone et al [76] have demon-

975

inhibitors on captopril's hemodynamic response, suggest that captopril has major prostaglandin-mediated antihypertensive activity. In-vivo studies have shown that captopril-stimulated prostaglandin biosynthesis and release play an important role in the hypotensive response to this compound. The prostaglandinmediated vasodilation is particularly important in the hypotensive response to captopril in experimental animals or in humans

with a low plasma renin activity. But what is the cellular mechanism by which captopril stimulates prostaglandin biosynthesis? I will now review the cellular regulation of arachidonic

acid release and prostaglandin biosynthesis, and describe our studies on the effect of captopril on prostaglandin biosynthesis. The chemical pathways leading to prostaglandin biosynthesis have been exquisitely elucidated in numerous laboratories [78]. Prostaglandins are derived from arachidonic acid, a polyunsaturated fatty acid stored within the phospholipid storage pool of every cell in the body. Activation of a phospholipase—predomi-

nantly phospholipase A2, but phospholipase C in some tissues—results in the release of arachidonic acid, which subsequently is converted to the precursor prostaglandin G2 by the cyclooxygenase enzyme. The cyclooxygenase enzyme, sensitive to the inhibitory effects of nonsteroidal antiinflammatory drugs, is specifically acetylated by aspirin, thus rendering the enzyme permanently incapable of catalyzing arachidonic acid metabolism. Prostaglandin G2 is converted to prostaglandin E2

or prostaglandin F2a by peroxidation and isomerization, to thromboxane A2 by thromboxane synthetase, or to prostacyclin by prostacyclin synthetase. Prostaglandin E2 is a potent vasodilator, but because it is rapidly metabolized in a single passage through the pulmonary vasculature, it probably does not play a significant role as a vasodilating hormone [79]. However, it has significant effects on adenylcyclase and cyclic AMP metabo-

lism, and it probably is important in the regulation of local hormonal action [37]. Prostaglandin F2a, in contrast to prostaglandin E2, is a potent vasoconstrictor. Like PGE2, however, it

is rapidly metabolized by the pulmonary circulation, and it probably does not function as a circulating vasoconstricting hormone. The production of prostaglandin E2 and prostaglandin F2 locally might have a significant effect on individual vascular beds. Thromboxane A,, a strikingly potent vasoconstrictor [80] predominantly synthesized in the platelet, is a potent stimulant of platelet aggregation [81]. Although thromboxane A2 can be synthesized by other tissues, it probably is not a vasoconstrict-

ing hormone. Prostacyclin, a potent vasodilating substance produced predominantly by the vascular endothelium [82],

strated that the administration of a prostaglandin synthesis inhibitor blunts the hemodynamic response to captopril in hypertensive and normal subjects. Finally, Provoost reported that aspirin and indomethacin diminished the hemodynamic

causes vasodilation and inhibition of platelet aggregation. Because prostacyclin is stable in aqueous solution and has a half-

response to captopril administration in rats [77]. This series of studies led to the conclusion that the antihypertensive activity of captopril is not solely related to its inhibition of the renin-angiotensin cascade. Nor is there consistent evidence to suggest that an increase in plasma kinin concentration

[83].

plays an important role in the reduction in blood pressure following captopril administration. The accumulated studies of captopril's effect in models of low-renin hypertension, as well as the evidence for an increase in plasma and urinary prostaglandins, and the inhibitory effect of prostaglandin synthesis

life in biologic systems of up to 5 minutes, it might be an important circulating vasodilator or antiaggregating substance Although the biochemistry of prostaglandin biosynthesis has

been well elucidated, the study of the regulation of cellular prostaglandin biosynthesis has been limited by the lack of a model system in which the controlling factors affecting prostaglandin production could be identified. Neither whole-organ perfusion nor tissue slices provide sufficient control for such experimental studies, especially when an individual organ can have multiple prostaglandin biosynthetic sites, and the function of one cellular system might affect prostaglandin biosynthesis

976

Nephrology Forum

Table 1. Effect of captopril on basal and hormone-stimulated PGE2 synthesis and arachidonic acid release by renomedullary interstitial cells in tissue cultures

5

Arachidonic

'A

4

0 A)

acid release

PGE2 synthesis

'q)

fmoleIg of

protein per hour

protein per hour

42 4

0.3 2.4

0.1

Captopril (7.5 M)

0.4

3425

269b

Bradykinin (20 nM) Captopril + bradykinin

3.0 8.1

0.6b 0.8c

3428

427'

21629

668c

Control 2

ng/rig of

'A

0

Each value represents the mean SEM, N = 8. (Reproduced from Ref. 37). b

Mean SEM, N=6 0

0

2

5

10

20

50

p < 0.01 versus control. P < 0.01 versus control, captopril, or bradykinin.

100

Captopril, pm Fig. 6. Effect of captopril on prostaglandin E2 biosynthesis by rabbit renomedullary interstitial cells in tissue culture. (Reproduced from Ref. 37.)

by a second cell type within that same organ. In no tissue is this more apparent than in the kidney, where a minimum of 5 cell

types—the vascular endothelium, the mesangial cells of the glomerulus, the epithelial cells of Bowman's capsule, the renomedullary interstitial cells, and the epithelial cells of the collecting tubule—can produce prostaglandins [37].

captopril stimulates prostaglandin biosynthesis through activation of the phospholipase and through an increase in the rate of release of the precursor fatty acid leading to prostaglandin E2 biosynthesis. In similar studies, captopril increased prostacydin biosynthesis from aortic vascular endothelium (LEVINE L, personal communication) and increased prostacyclin and prostaglandin E2 biosynthesis by isolated renal glomeruli [88].

Using the in-vitro renomedullary interstitial cell system, it has been possible to elucidate the mechanism by which convert-

ing enzyme inhibition, prostaglandins, and bradykinin interact in a way that might explain the captopril-related antihypertensive response. Previous studies have demonstrated that potenti-

The development of a technique for the isolation of reno-

ation of bradykinin following captopril administration was secondary to the stimulation of prostaglandin biosynthesis,

medullary interstitial cells in tissue culture provided an opportunity for the study of the regulation of cellular prostaglandin

particularly in the kidney [89]. Mullane and Moncada reported increased prostacyclin release following bradykinin administra-

biosynthesis [841. Previous studies in our laboratory have

tion in beagles [90]. The administration of a prostaglandin synthesis inhibitor markedly attenuated the potentiation of bradykinin following captopril administration. Both captopril

shown that this cell line makes significant quantities of prostain tissue culture. The addition of vasoacglandins E2 and tive peptides such as angiotensin II, vasopressin, and importantly, bradykinin, causes an increase in prostaglandin synthe-

sis [85]. Incubation of these cells with radioactively labeled arachidonic acid allows for identification of the endogenous

and bradykinin independently stimulated arachidonic acid release and prostaglandin biosynthesis by renomedutlary interstitial cells in tissue culture [37]. However, incubation of cells in

the simultaneous presence of captopril and bradykinin in-

arachidonic acid storage pool. Subsequent stimulation by vasoactive peptides activates the phospholipase and releases arachidonic acid from the phospholipid fraction; the arachidonic acid subsequently is converted to prostaglandins [68]. This prosta-

creased prostaglandin biosynthesis and arachidonic acid re-

glandin synthetic response to angiotensin II stimulation has

pril and bradykinin is particularly noteworthy in view of the

been studied in detail, and the interaction of angiotensin II with

data of Vinci et al [69]. In addition to the increase in prostaglandin biosynthesis observed following converting enzyme inhibition with teprotide, Vinci and coworkers found that the reduc-

its receptor, the binding characteristics of this receptor, the stimulation of phospholipase activity, and the release of arachi-

lease; these alterations exceeded the additive effects of the two agents' independent effects (Table 1). The augmented prostaglandin synthesis in response to capto-

donic acid and subsequent conversion to prostaglandin E2

tion in blood pressure correlated with the increase in arterial

demonstrate parallel dose-response curves and receptor binding kinetics [871.

blood prostaglandin concentration of their patients; these same

Using renomedullary interstitial cell tissue culture, we found that captopril produced up to a 30-fold stimulation of prostaglandin biosynthesis (Fig. 6). Half-maximal stimulation of prostaglandin biosynthesis occurred at a captopril concentration of approximately 8 M. This concentration is similar to the plasma level of drug achieved following administration of captopril to normotensive or hypertensive subjects. When we investigated the effect of captopril on the release of radiolabeled arachidonic acid, we found that captopril significantly increased arachidonic

acid release (Table 1). Thus, like the vasoactive peptides,

patients were found to have significantly increased urinary kinin excretion. A small number of hemodynamic nonresponders failed to demonstrate the increase in prostaglandins

and urinary kinin. An increase in urinary kinin excretion was observed by Olsen and Arrigoni-Martelli following captopril administration and blood pressure reduction in normal conscious dogs [91].

Mechanism of action of captopril: Summary

A summary of the proposed mechanism of action of captopnl is shown in Figure 7. Inhibition of the angiotensin converting

977

Antihypertensive actions of converting enzyme inhibitors Angiotensinogen Renin

Angiotensin I

Inactive peptides , Arachidonic acidstorage pool

CAPTOPRIL- -

Kinins (Tissue vs. plasma)

/

Angiotensin converting enzyme

CAPTOPRIL

\Angiotensin II

1Phospholipase Arachidonic acid

Blood pressure

y, lung)—/

Cyclooxygenase

PGE2

PG Endoperoxides

Fig. 7. Biochemical effects of angiotensin converting enzyme inhibition following captopril administration.

enzyme in the pulmonary circulation reduces the rate of conversion of angiotensin Ito angiotensin H. The fall in angiotensin II concentration and the concomitant decrease in plasma aldosterone concentration cause decreased vasoconstriction and a loss

of sodium that lead to a drop in blood pressure. This effect is predominant in the sodium-depleted state and in models of high-

renin hypertension. Although the angiotensin converting enzyme is also responsible for destruction of bradykinin, no consistent and significant change in plasma bradykinin concentrations can be documented, probably because of the multiple other enzymes with kininase activity that are not affected by captopril. Nonetheless, under certain circumstances the administration of an antikinin antibody attenuates the antihypertensive response following captopril administration. The lack of a significant increase in plasma kinin concentrations, yet the sensitivity under certain conditions to the effects of antikinin antibodies, might point to the importance of tissue rather than plasma kinins in this antihypertensive mechanism. In particular, augmented kinin formation by the kidney, as reflected by the increase in urinary kinin excretion following converting enzyme inhibition in humans and experimental animals, might reflect the inhibition of kinin destruction in tissue systems as opposed to in the plasma. Finally, captopril directly stimulates prostaglandin biosynthesis by renal and vascular endothelium and raises the arterial concentration of vasodilating prostaglandins. This increase in prostaglandin biosynthesis might accrue from the direct effects of captopril or from the accentuation of the stimulation of prostaglandin biosynthesis by bradykinin. The vasodilation due to increased arterial prostaglandin concentrations is the major reason for the antihypertensive activity of captopril in the sodium-replete state and in models of lowrenin hypertension. The mechanism of the synergistic effect of captopril and bradykinin on cellular prostaglandin biosynthesis remains unknown. Although peptide hormone-stimulated prostaglandin biosynthesis depends on increased calcium influx following receptor activation [92], captopril-stimulated prostaglandin bio-

synthesis does not appear to be a calcium-dependent process (ZUSMAN R, unpublished observations). It is possible, howev-

Sodium retention

PGl

(Lung, blood vessel endothelium)

er, that captopril and bradykinin interact so as to result in a greater-than-additive increase in prostaglandin biosynthesis.

The interaction of the converting enzyme inhibitors and

prostaglandin biosynthesis might account in part for the reversible renal failure in patients with bilateral renal artery stenosis

and in patients with renal artery stenosis in a solitary kidney [94—97]. With normal renal vasculature, administration of a converting enzyme inhibitor augments renal blood flow because

of decreased vascular resistance of the preglomerular renal arteriole [98, 99]; the decrease in preglomerular renal arteriolar resistance may be the result of an increase in the concentration of vasodilator prostaglandins in the arterial blood. The postglomerular efferent arterial vasculature simultaneously dilates because of diminished angiotensin Il-mediated vasoconstriction [100, 1011. Under normal conditions, the net effect of the fall in afferent as well as efferent arteriolar resistance is an increase in glomerular filtration rate. With significant renal artery stenosis, however, maximal poststenotic renal afferent arteriole vasodila-

tion is present prior to captopril administration. Because the stenosis is a fixed and structural obstruction to renal blood flow, and because of maximal afferent arteriolar dilation due to the decreased renal perfusion pressure, angiotensin converting enzyme inhibition decreases intrarenal angiotensin II concentration and markedly dilates the efferent arteriole. In patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney, the reduction of efferent arteriolar resistance reduces glomerular filtration pressure, filtration fraction, and glomerular filtration rate, and induces a deterioration of renal function. Finally, the patient presented today demonstrates the clinical significance of the interaction of captopril, the bradykinin system, and prostaglandins. This patient had low-renin, essential hypertension. His low plasma renin activity would have suggested that his clinical response to converting enzyme inhibition would be minimal. Nonetheless, following sodium restriction, captopril strikingly reduced his blood pressure in both the supine and upright positions. A significant component of the reduction of blood pressure in patients such as the one

presented today no doubt results from the stimulation of

978

Nephrology Forum

prostaglandin biosynthesis by this unique compound. The dete-

rioration of blood pressure control in this patient following therapy with indomethacin for musculoskeletal pain reflects the potential clinical significance of the relationship between con-

DR. ZUSMAN: Doses as low as 25 or 50 mg inhibit the converting enzyme, reduce angiotensin II concentration, and reduce blood pressure [106]. DR. COHEN: Are those doses also effective in increasing

verting enzyme inhibitors and nonsteroidal antiinflammatory prostaglandins? drugs as well as the possibility of an adverse clinical response in patients simultaneously treated with these substances.

of captopril in their study and demonstrated an increase in

Questions and answers

prostaglandin synthesis [70]. DR. RICHARD KOPELMAN (General Medicine Division,

DR. JOHN T. HARRINGTON: Does captopril have a residual

DR. ZUSMAN: Yes, Swartz and coworkers used a single dose

NEMC): You mentioned that the decrease in blood pressure caused by converting enzyme inhibition is not accompanied by

antihypertensive effect that is not explained on the basis of a reflex tachycardia. What are your views on the reason for this interference with an effect on angiotensin II, bradykinin, or phenomenon? prostaglandins?

DR. ZUSMAN: Although there is limited information on this

such a residual effect would issue, evidence indicates that captopril potentiates arterial require a relatively complex experiment that could make use of baroreflexes, and thus prevents a reflex tachycardia after blood currently available techniques. The first step would be elimina- pressure reduction [107]. tion of the effects of the renin system by administering the DR. COHEN: Steroid hormones are known to inhibit phosphorenin-specific antibody, then eliminating the prostaglandin sys- lipase activity and thereby diminish prostaglandin production. tem by administering a large dose of nonsteroidal antiinflamma- Is there any evidence suggesting that the hypertensive effect of tory drug, and finally administering a maximal dose of a steroids might relate to this action? converting enzyme inhibitor. It would be of particular interest DR. ZUSMAN: One of the problems with ascribing a homeoto compare the effects of captopril and a non-sulthydryl— static role for prostaglandins in the regulation of blood pressure containing converting enzyme inhibitor such as MK-421 to is that despite the large number of patients who take nonsteroidassess the relative potency of those two agents under these al antiinflammatory drugs, blood pressure rises in only the conditions. That study has not been done, but it is something occasional patient. I think a similar relationship is true for we are contemplating as we attempt to evaluate the antihyper- patients who receive steroids. I doubt that the increase in blood tensive effect of the renin inhibitory peptide currently under pressure in patients receiving steroid hormones is related to investigation in my laboratory. We will try to dissect the renin- prostaglandin inhibition; hypertension in these patients probaand non-renin—mediated effects of our peptide using the antire- bly develops because of increased sensitivity to vasoconstrictor nm antibody, and hopefully we will have some information hormones, increased plasma renin activity, and/or an increase along those lines in the future. in intravascular volume. DR. NIc0LA0s E. MADIAS: As you know, vasopressin has DR. HARRINGTON: Has verapamil been used to treat high been implicated in the pathogenesis of several models of blood pressure in the unusual patient with indomethacin-inhypertension. Moreover, angiotensin II stimulates vasopressin duced hypertension? What would you predict would happen if secretion. Are there any data regarding changes in vasopressin verapamil were used, and by what mechanism might it act? levels following administration of captopril? DR. ZUSMAN: I don't know of any patients treated with DR. ZUSMAN: Captopril decreased urinary vasopressin excre- verapamil in that setting. It is possible that in hypertensive tion in spontaneously hypertensive rats [102], and in patients patients verapamil produces vasodilation and reduces blood with essential [103, 104] and renovascular hypertension [104]. pressure via blockade of the voltage-dependent calcium chanHowever, in Brattleboro strain vasopressin-deficient rats cap- nels and the resultant vascular smooth muscle relaxation [108]. DR. ANDREW LEVEY (Division of Nephrology, NEMC): Intopril reduced blood pressure [105]. Thus the antihypertensive activity of captopril does not appear to depend on the reduction vitro studies with captopril analogues having no su1flydryI of antidiuretic hormone concentration. group inhibit converting enzyme and do not increase prostaDR. JORDAN J. COHEN: You indicated that angiotensin II as glandin synthesis. Are these agents effective in lowering blood well as captopril stimulate prostaglandin activity. This raises pressure in non-renin—dependent hypertension? If so, doesn't the possibility that increased angiotensin I levels might be this suggest that at least part of the antihypertensive effect of responsible for the effect of captopril on this system. Does captopnl under these circumstances is simply the result of angiotensin I have any effect on prostaglandins? converting enzyme inhibition? DR. ZUSMAN: The increase in angiotensin I concentration DR. ZUSMAN: Both captopril and MK-421, the non-sulihyfollowing captopril administration is probably three- or four- dryl—containing converting enzyme inhibitor, lower the blood fold. But the concentration of angiotensin I required to produce pressure of the spontaneously hypertensive rat [109]; this equivalent stimulation of prostaglandin biosynthesis is approxi- finding suggests that renin does play an important role in the mately 100 to 1000 times higher than the concentration of pathogenesis of this model of hypertension. Unlike captopril, angiotensin H having an equivalent effect. The increase in MK-421 does not lower the blood pressure of rats with DOCADR. ZUSMAN: Demonstrating

prostaglandin biosynthesis therefore cannot be explained on the basis of a small increase in angiotensin I concentration. DR. COHEN: Are the doses of captopril currently used the

minimum doses for effective inhibition of angiotensin II production?

salt hypertension [109] or rats made hypertensive by the prolonged intravenous infusion of angiotensin II [110]. These findings, once again, suggest a non-renin—mediated antihyper-

tensive activity of captopril, which I believe is due to the

stimulation of prostaglandin biosynthesis; this activity is not

979

Antihypertensive actions of converting enzyme inhibitors

shared by the other, non-sulfhydryl—containing, converting enzyme inhibitors. Again, one way in which to study the renin- and non-renin— mediated effects of these compounds would be to administer the

renin-speciflc antibody and give one or the other converting enzyme inhibitor, or give them sequentially and see whether you could elicit a greater maximum blood pressure fall with one than with the other. DR. LEVEY: Has the effect of these agents on bradykinin been studied? DR. ZUSMAN: The investigational compound MK-42l has no

consistent effect on plasma bradykinin levels (C. SWEET, personal communication). DR. MADIAS: What is the mechanism of the suppression of the initial hyperreninemia during chronic captopril administration? Also, are there any data suggesting that chronic captopril treatment might lead to the development of autonomous hyperreninemia, that is, hyperreninemia that will be sustained following discontinuation of captopril administration? DR. ZUSMAN: I am not aware of any evidence that autonomous hyperreninemia occurs. The drop in plasma renin activity

after the acute increase is, I think, secondary to volume expansion. Retention of sodium and water frequently occurs following the administration of vasodilators such as hydralazine, prazosin, captopril, or nifedipine. If hypertension recurs in a patient with suppression of renin activity after chronic captopril therapy, the patient will become sensitive once again to the effects of captopril following the administration of a diuretic. The patient exhibits an acute hyperreninemic response following initial captopril administration, and blood pressure drops; thereafter, the patient's intravascular volume increases, and renin is suppressed by a "volume-sensitive" mechanism; the administration of a diuretic at this point restores the renindependent mechanism of blood pressure homeostasis, and the patient's blood pressure decreases because of converting enzyme inhibition and increased prostaglandin biosynthesis. DR. MADIAS: Does captopril change the level of renin substrate? DR. ZUSMAN: Yes, the concentration of renin substrate can fall because of the increase in renin activity and the generation of angiotensin I [ill]. DR. COHEN: We now have a large array of antihypertensive

drugs available to choose from in planning treatment in an individual patient. Where do you place captopril in the overall scheme of things? DR. ZUSMAN: The concept of step therapy for hypertension is becoming less rigid as drugs with novel mechanisms of action

are becoming available. The original use of captopril was limited to the patient with severe or resistant hypertension because concerns existed about the drug's potential toxicity. Now that large numbers of patients have received captopril, however, it has become clear that these risks are minimal. For example, in the patient with normal renal function and without collagen vascular disease, the risk of neutropenia associated with captopril administration is no greater than that associated with the administration of other antihypertensive medications

[112]. I think captopril should be considered as first-step therapy in some patients, especially those who have contraindications to diuretics, those with borderline left-ventricular function, or those who have had side effects following administra-

Table 2. Costs of commonly used antihypertensive medications Drug

Total daily dose

Approximate cost per month

Hydrochlorothiazide

50 mg

$ 1.50

160 mg 80 mg 20 mg

11.50 13.00 15.00

1000 mg

13.00

Propranolol Nadolol Timolol

Alpha-methyldopa

150 mg

8.00

4 mg

11.00

Captopril

50 mg

16.00

K-Lyte KCI Elixir

25 mEq 20 mEq

12.00

Hydralazine Prazosin

2.50

Average costs are for the Boston metropolitan area. Costs may vary considerably in different locations.

tion of beta blockers or centrally acting sympatholytic agents. Now that it has been demonstrated that captopril can be used on a regimen of twice-daily doses [106], it is reasonable for us to

consider its use in patients who lead active lives. With this newly available information, we should not reserve captopril only for the patient with resistant or severe hypertension. DR. COHEN: Are you concerned about proteinuria associated with the use of this agent? DR. ZUSMAN: The incidence of proteinuria is most marked in

patients with preexisting renal failure and in those receiving doses greater than 150 mg/day. In patients with normal renal function who receive less than 150 mg/day, the incidence of

proteinuria is 0.2%; the incidence rises to 1% in patients receiving more than 150 mg/day. In patients with a history of renal disease, the incidence increases to 1% and 3.5% in patients receiving less than or greater than ISO mg/day, respectively [1131.

DR. HARRINGTON: Could you comment on the use of capto-

pril in pregnancy? What happens to uterine blood flow in experimental animals given converting enzyme inhibitors? DR. ZUSMAN: The administration of captopril to pregnant rabbits significantly reduced systemic blood pressure and uterine blood flow and was associated with a 90% fetal mortality rate [114]. Pregnancy is one of the few absolute contraindications to captopril administration. DR. COHEN: What about the cost of captopril? DR. ZUSMAN: Table 2 illustrates the costs of typical doses of antihypertensive medications for patients with mild to moderate

hypertension. In patients responding to low doses of a beta blocker, sympatholytic, vasodilator, or converting enzyme inhibitor, the costs are comparable. Hydrochlorothiazide, 50 mg daily, is considerably less expensive if a potassium supplement

is not required. In patients receiving double- or triple-drug therapy, the costs, of course, can exceed the costs of low-dose captopril therapy.

DR. LEVEY: What is a reasonable dose of captopril for

patients with renal insufficiency who are on dialysis? DR. ZUSMAN: Captopril is excreted by the kidneys. Therefore

the interval between doses should be increased in patients with

980

Nephrology Foru,n

progressively severe renal failure; in patients without functional a potassium supplement or a potassium-sparing diuretic. The

renal tissue the interval between doses can be as long as 120 simultaneous use of a converting enzyme inhibitor (which reduces plasma aldosterone concentration and thereby reduces hours [115]. DR. LEVEY: Plasma renin activity and urinary prostaglandin potassium excretion) and a potassium-sparing agent—amilorE2 excretion are both increased in numerous clinical circum- ide, spironolactone, or triamterene—can result in clinically stances, including congestive heart failure, volume depletion, significant hyperkalemia even in a patient with normal renal and cirrhosis. What is the link between them? For example, do function. In patients receiving captopril, these agents should be you think that the rise in angiotensin II levels stimulates renal used with care and close supervision. prostaglandin synthesis? Reprint requests to Dr. R. Zusman, Hypertension Division, Cardiac DR. ZUSMAN: Multiple factors affect urinary prostaglandin Unit, Massachusetts General Hospital. 15 Parkman Street, Boston, excretion; these include plasma potassium concentration, an- Massachusetts 02/14 giotensin II, antidiuretic hormone, and urine flow rate [116]. The disorders you have mentioned are all associated with an Acknowledgments increase in plasma angiotensin II and vasopressin concentraDr. Zusman is an Established Investigator of the American Heart tion, which may be the unifying factors. In patients with the Association. Original research described in this manuscript was suphepatorenal syndrome, however, urinary thromboxane, and not ported by the National Institutes of Health (HL 19259), the National PGE2 excretion, is increased; yet plasma renin activity is high Aeronautics and Space Administration, and a grant from R. J. Reynolds in these patients too [117]. A unifying hypothesis for the control of urinary prostaglandin excretion is not yet available.

mentioned that captopril increases prostaglandin synthesis through an increase in arachidonic acid

Industries, Inc.

References

DR. HARRINGTON: You

release. Why does it selectively increase the vasodilatory prostaglandins? DR. ZUSMAN: In renomedullary interstitial cells and vascular endothelial cells one finds a single predominant prostaglandin product: PGE, in the kidney and PGI2 in endothelium. The studies of the isolated renal glomeruli are hard to explain. Galler and coworkers reported the selective increased synthesis of the vasodilator prostaglandins, PGE2 and PG!,. Their results suggest that compartmentalization of prostacyclin synthetase and

of the endoperoxide isomerase and peroxidase leads to increased PGE2 and PGI2 biosynthesis only [88]. The increased arachidonic acid released after incubation with captopril would have to be directed toward these compartmentalized enzymes

selectively. I can think of no other explanation for this phenomenon.

DR. MADIAs: What is your assessment of the role of the decreased levels of aldosterone in the hypotensive effect of converting enzyme inhibition? Somewhat conflicting results

have been obtained in the dog [118, 119]. DR. ZUSMAN: The restoration of normal blood pressure levels by aldosterone administration in animals treated with captopril is inconsistent with our understanding of the role of aldosterone in blood pressure control. The results of Hall et al [118] directly

contradict those of McCaa and colleagues [40] but are more consistent with the primary role of angiotensin H rather than aldosterone in blood pressure control of sodium-depleted animals. In sodium-replete animals, even large doses of steroids

fail to prevent the hypotensive response to captopril; this response clearly is related to prostaglandin stimulation by captopril [1191. DR. VINCENT CANZANELLO (Renal Fellow, Division of Nephrology, NEMC): Hyperkalemia has been reported in patients with decreased glomerular filtration rates who are receiv-

ing captopril. Has hyperkalemia occurred in patients with essential hypertension and normal renal function, particularly when captopril is used without a potassium-sparing diuretic? DR. ZUSMAN: Abnormalities of serum potassium concentration are rare in patients who are receiving captopril with or without diuretics unless the patient is simultaneously receiving

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