Nitric oxide in the control of renal hemodynamics and excretory function

AJH

2001; 14:74S– 82S

Nitric Oxide in the Control of Renal Hemodynamics and Excretory Function Dewan S.A. Majid and L. Gabriel Navar Experimental evidence has now been amassed to indicate that inhibition of nitric oxide (NO) synthase reduces total or regional renal blood flow by approximately 25 to 30% and markedly increases the renal vascular resistance, demonstrating that basal release of NO helps to maintain the relatively low vascular resistance that is characteristic for the kidney. It has been demonstrated that intraarterial administration of NO synthase inhibitors causes marked reductions in sodium excretion without changes in filtered load and suppressed the arterial pressure-induced natriuretic responses in the kidney. We also demonstrated that a constant rate infusion of a NO donor in dogs pretreated with a NOS inhibitor resulted in increases in sodium excretion but failed to restore the slope of the relation between arterial pressure and sodium excretion, suggesting that an alteration in intrarenal NO production rate

T

he importance of various intrarenal paracrine systems and their interactive contributions to the regulation of renal hemodynamics and renal function has received increased attention in recent years.1 Among these paracrine agents, nitric oxide (NO), initially identified as endothelium-derived relaxing factor, has been implicated in many physiologic processes that influence both acute and long-term control of kidney function.1– 8 There is now substantial evidence that the endothelial, epithelial, and other cells in the kidney can generate NO, which interacts with vascular smooth muscle, mesangial, juxtaglomerular, and tubular cells to regulate vascular and tubular function.1–3,5,9

during changes in arterial pressure is involved in the mediation of pressure natriuresis. Further experiments in dogs performed in our laboratory have confirmed that there is a direct relationship between changes in arterial pressure and intrarenal NO activity measured using NOsensitive microelectrodes in the renal tissue. These arterial pressure-induced changes in intrarenal NO activity were seen positively correlated with the changes in urinary excretion rates of sodium. Collectively, these data suggest that acute changes in arterial pressure alter intrarenal NO production, which inhibits tubular sodium reabsorption to manifest the phenomenon of pressure natriuresis. Am J Hypertens 2001;14:74S– 82S © 2001 American Journal of Hypertension, Ltd. Key Words: Renal autoregulation, pressure natriuresis, renal regional blood flow.

Nitric oxide is synthesized from the amino acid L-arginine in endothelial as well as other cell types by the action of an NO synthase (NOS).10 NOS exists in three isoforms of which two forms are constitutive and the other is an inducible form. These isoforms are heme-containing enzymes that catalyze

the oxidation of L-arginine to NO and L-citrulline. NOS I or neuronal NOS and NOS III or endothelial NOS are constitutively present and are dependent on calcium and calmodulin for activation.11 An inducible NOS (NOS II) is usually expressed primarily after transcriptional induction, which seems less dependent on calcium for its activation because of its very high affinity to bind with calmodulin with which it forms a constitutive subunit.12 Studies have now demonstrated that all these isoforms are expressed in various locations in the kidney.9 The concentrations of both NOS I and NOS III are generally higher in renal medulla than in the cortex.9,13 Table 1 provides the localization of NOS isoforms in the kidney. Generally, the endothelia of the renal vasculature and also some tubular epithelial cells express NOS III.14,15 NOS I is expressed in macula densa cells and also in lesser quantities in efferent arterioles.14 The inducible NOS II is expressed in vascular smooth muscle, mesangial, medullary interstitial cells, as well as in tubular epithelial cells.2,9,16 Because NOS reacts directly with L-arginine, the formation and release of NO can be competitively inhibited by structural analogs of L-arginine such as N-monometh-

Received February 26, 2001. Accepted March 6, 2001. From the Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana. The experimental work conducted by the authors was supported by grants from the National Heart Lung and Blood Institute (HL 18426, HL

51306), Louisiana Education Quality Support Funds and National Kidney Foundation. Address correspondence and reprint requests to Dr. Dewan S.A. Majid, Department of Physiology, SL39, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112.

NO Formation in the Kidney

0895-7061/01/$20.00 PII S0895-7061(01)02073-8

© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

AJH–June 2001–VOL. 14, NO. 6, PART 2

Table 1. ney

NITRIC OXIDE AND KIDNEY FUNCTION

Localization of NOS isoforms in the kidConstitutive

Endothelium Large vessels Afferent arterioles Efferent arterioles Glomerular capillaries Epithelium Macula densa Thick ascending limb Collecting duct Proximal tubule Vascular smooth muscle Mesangial cells Intrarenal neuron Medullary interstitial cells

Inducible

NOS III

NOS I

NOS II

⫹⫹⫹ ⫹⫹⫹ ⫹⫹

⫺ ⫺ ⫹

⫺ ⫺

⫹⫹⫹

⫺

⫺

⫺

⫹⫹⫹

⫺

⫺ ⫹ ⫺

⫹ ⫺ ⫺

⫹ ⫹ ⫹

⫺ ⫺ ⫺

⫺ ⫹ ⫹

⫹ ⫹⫹ ⫺

⫺

⫺

⫹

⫹ ⫽ present; ⫺ ⫽ absent; NOS ⫽ nitric oxide synthase.

yl-L-arginine (L-NMMA) and nitro-L-arginine (NLA).10 Endothelial NOS can be stimulated by agents such as acetylcholine (Ach), bradykinin, and ATP, as well as flow-induced sheer stress on the vessel wall.4,10 Agonist agents such as Ach and bradykinin have long been known to exert marked renal vasodilation.1,17,18 Because of the short half-life and the labile nature of NO, studies evaluating the in vivo effects of endogenous NO in the kidney have been conducted primarily by pharmacologic inter-

75S

ventions with agents that can stimulate its release as well as those that can competitively block its formation.

NO and Renal Vascular Resistance and Blood Flow It is now well established that tonic release of NO plays an important role in maintaining normal vascular tone in the kidney, which is known to have substantially lower vascular resistance than most other organs or vascular beds. Intrarenal NO helps to maintain the normally low renal vascular resistance (RVR), being responsible for up to one-third of the normal renal blood flow (RBF).1,19 –22 The contribution of endogenously released NO to the basal level of RVR has been assessed from the responses to L-arginine analogs that inhibit NO synthesis. In response to inhibition of NO synthesis, there is an increase of 30% to 50% in RVR and a decrease of 25% to 40% in RBF in anesthetized as well as in conscious animals.8,17,19 –21,23–27 In experiments conducted in our laboratory,21,22,24,28,29 intraarterial administration of NLA at a rate of 50 ␮g/kg/min for 30 min in anesthetized dogs resulted in an increase of 48% in RVR and a decrease of 28% in RBF. Fig. 1 shows the average renal responses to NOS inhibition in anesthetized dogs collated from several studies from our laboratory. The responses to NOS inhibition have been shown to be reversed by the administration of NO substrate, L-arginine substantiating that the responses to NLA were due to inhibition of endogenous NO formation and release.21 Renal cortical blood flow (CBF) measurements in dogs and rats, measured by laser-Doppler flowmetry (LDF) with a surface probe,24,30 as well as blood flow in single cortical capillaries in rats measured with fluorescent videomicroscopy,31 have shown similar decreases in re-

FIG. 1. Summary of the relative renal responses to intraarterial infusion of nitro-L-arginine in anesthetized dogs. Data collected from several studies (Refs. 21, 22, 24, 28, 67). RVR ⫽ renal vascular resistance; RBF, CBF, MBF ⫽ renal, cortical, medullary blood flow; GFR ⫽ glomerular filtration rate; U ⫽ urine flow; UNaV ⫽ sodium excretion; FENa ⫽ fractional sodium excretion; UKV ⫽ potassium excretion.

76S

NITRIC OXIDE AND KIDNEY FUNCTION

AJH–June 2001–VOL. 14, NO. 6, PART 2

FIG. 2. Summary of renal autoregulatory behavior of RBF, CBF and MBF in response to nitro-L-arginine (NLA) and to the NO donor s-nitroso-n-acetylpenicillamine (SNAP) (E control; F NLA; ‚ NLA⫹SNAP). RAP ⫽ renal arterial pressure; other abbreviations as in Fig. 1. (Data derived from Refs. 22 and 38.)

sponse to NOS inhibition with L-arginine analogs. In further studies, LDF with needle probes was used to assess renal CBF and medullary blood flow (MBF) responses to NOS inhibition in dogs.29,32 These studies demonstrated that blockade of NO synthesis in the kidney by NLA administration resulted in reductions in both CBF (26%) and MBF (25%), which were very similar to the reductions in total RBF (24%). However, studies performed in rats have suggested that NO may exert a greater influence on the medullary circulation than on the cortical circulation.33 Comparison of the responses to NOS inhibition of blood flow and vascular resistances in other vascular beds such as femoral, coronary, and brain have shown that the renal vasculature is more dependent on endogenous NO than other organs to maintain normal perfusion of the organ.34,35 Collectively, the data generated in various species provide clear evidence that basal release of NO helps to maintain the relatively low RVR that is characteristic for the renal circulation. Several studies have evaluated the direct effects of elevated intrarenal NO levels using nitrovasodilators, also known as NO donor compounds. Among the commonly used nitrovasodilators, s-nitrosothiols are potent vasodilators and have been used to mimic the actions of endogenously formed NO.10,36 To evaluate the unique and specific actions of NO on RBF and RVR, experiments were performed in which s-nitroso-n-acetlypenicillamine (SNAP), an s-nitrosothiol compound, was administered intraarterially in anesthetized dogs, which were pretreated with NLA to inhibit endogenous NO release.22 Administration of SNAP at a dose of 2 ␮g/kg/ min to NLA-treated dogs elicited renal vasodilator responses and restored RBF and RVR to values existing before NOS inhibition, confirming the specificity of the vascular actions of NO in the kidney.

NO and RBF Autoregulation The autoregulatory adjustments in the renal vasculature that occurs in response to changes in arterial pressure are associated with changes in blood flow velocity through the small arteries and arterioles. Because the entire preglo-

merular arteriolar vasculature changes dimensions in response to changes in arterial pressure,1,37 there would be sustained sheer stress-induced alterations in NO release, which could modulate renal vascular tone.10 As the diameters of preglomerular vessels decrease in response to increases in arterial pressure, the blood flows at an increased velocity thus causing increased shear stress on the vessel wall leading to increases in NO synthesis.29,32 Several studies in dogs and rats have been performed to determine how NO might contribute to renal autoregulatory behavior.19 –22,24 There is now general agreement that NOS inhibition does not interfere with the ability of the kidney to autoregulate RBF in response to alterations in renal arterial pressure (RAP); however, there is suppression of the autoregulation plateau due to the decrease in basal RBF during NOS inhibition.19 –21 In experiments conducted in anesthetized dogs in our laboratory,22 RBF and RVR responses to stepwise reductions in RAP were evaluated before, after NOS inhibition, and during administration of the NO donor SNAP. As illustrated in Fig. 2, autoregulatory efficiency of RBF remained intact during both NOS inhibition and after NO replacement with SNAP. Most reports in both anesthetized and unanesthetized animals have reported similar results. Studies using LDF in anesthetized dogs have shown that autoregulatory efficiency of CBF remains highly efficient during intrarenal infusion of NOS inhibitors.24,29,38 There are mixed reports with regard to MBF. It has been reported that an impaired autoregulatory efficiency of papillary blood flow in volume-expanded rats, measured by LDF, could be restored by administering the NOS inhibitors.39 This finding indicates that an enhancement of NO production during volume expansion in rats may be responsible for impairment of autoregulatory efficiency in MBF, which was not observed in euvolumic rats.40,41 Studies in dogs have indicated, however, that MBF maintains efficient autoregulatory responses under conditions of euvolumic and volume expansion.42,43 Collectively, the data indicate that intrarenal NO activity does not influence normal autoregulatory efficiency of RBF but does affect the plateau of autoregulation. Although increases in RAP

AJH–June 2001–VOL. 14, NO. 6, PART 2

cause increased NO release from the vascular endothelium due to increased sheer stress, the amount released is apparently not sufficiently powerful to counteract the autoregulatory mechanism.

Renal Microvascular Actions of NO Studies involving direct assessment of renal microvascular responses to NOS inhibition in rats and rabbits have demonstrated that tonically released NO regulates both preand postglomerular vascular resistance.26,44 – 48 Results from both in vivo micropuncture experiments and in vitro studies have consistently demonstrated decreases in the vessel diameter and increases in vascular resistance in the afferent arterioles; the efferent arteriolar responses have been more variable. Using a perfused isolated rabbit afferent arteriole– glomerulus preparation, Ito and Ren48 reported no change in efferent arteriolar diameter during arteriolar microperfusion of NOS inhibitors. Similar to this finding, Deng and Baylis46 reported that intraarterial infusion of NOS inhibition did not cause detectable increases in efferent arteriolar resistance, glomerular pressure, or glomerular flow, although systemic infusion of NOS inhibitors did cause efferent arteriolar constriction. However, studies using the in vitro blood-perfused juxtamedullary nephron preparation demonstrated that both afferent and efferent arteriolar diameters in rat kidneys decreased equally by about 15% to 18% after superfusion of renal tissue with 0.1 to 1 mmol/L NLA.45,49 Similar observations were also reported in several other studies.44,47,50 Decreases in glomerular flow and associated increases in resistance of afferent and efferent arterioles were also noted during systemic administration of L-arginine analogs in in vivo micropuncture studies.26,51 In addition, inhibition of NOS I activity by the specific inhibitor smethyl-L-thiocitrulline (L-SMTC) in an in vitro juxtamedullary nephron preparation in rats elicited decreases in efferent and afferent arteriolar diameter by about 15%.49 Thus, on balance, the results support the conclusion that intrarenal NO contributes to the regulation of vascular tone of both preglomerular and efferent arterioles.

NO and Glomerular Filtration Rate Although administration of NOS inhibitors consistently results in significant reductions in RBF, the glomerular filtration rate (GFR) responses have been less consistent. Several experiments conducted in dogs as well as in humans showed that GFR is well maintained during treatment with NOS inhibitors (Fig. 1).7,8,21,22,24,25,27–29,32,42 However, other studies report reductions in GFR in response to NOS inhibition.23,26,52 The decreases in GFR are comparatively less than the decreases in RBF leading to increases in filtration fraction during NOS inhibition. It seems that the reductions in GFR in response to NOS inhibition depends on the dose as well as the routes of administration of NOS inhibitors used. Systemic infusion

NITRIC OXIDE AND KIDNEY FUNCTION

77S

of NOS inhibitors have consistently caused substantial increases in arterial pressure, which may have an indirect effect on kidney function as it was shown that a lower systemic dose (1 ␮g/kg/min), which had minimal effects on arterial pressure, did not cause significant changes in GFR.53 It was also observed that if the renal perfusion pressure was not allowed to increase during treatment of NOS inhibition by the use of an aortic snare, there were greater decreases in GFR.54,55 However, studies in conscious rats and dogs demonstrated that NOS inhibition resulted in no change or only slight reductions in GFR depending on the dose and duration.19,56

NO and Tubuloglomerular Feedback Responses Several studies have indicated that NO may also be an important modulator of tubuloglomerular feedback (TGF) responsiveness.49,57,58 Studies in which NOS inhibitors were infused intravenously or microperfused into the interstitium or into the tubular segments encompassing the macula densa cells have shown that local NO production can attenuate TGF-mediated vasoconstriction of the afferent arterioles.57,58 Using the doubly perfused isolated glomerular segment with macula densa attached, Ito and Ren48 demonstrated that addition of an NOS inhibitor to the macula densa perfusate led to afferent arteriolar constriction only when the tubules were perfused with isotonic Krebs-Ringer’s solution but not when perfused with a hypotonic solution. Furthermore, Wilcox and Welch59 reported that the TGF response is enhanced by NOS blockade during high salt but not in low salt intake rats. Blockade of macula densa reabsorption by furosemide was also shown to abolish the enhancement of TGF responsiveness by NOS inhibition.59 Thus, it is generally thought that increased macula densa NaCl is associated with increased NO synthesis and solute reabsorption by the macula densa cells and the increased NO release partially counteracts the vasoconstrictor stimuli mediating TGF responses. NO is not the mediator of the TGF mechanism but serves to modulate the responsiveness. Recently, Ichihara et al49 demonstrated in the blood-perfused rat juxtamedullary nephron preparations that superfusion with the specific neuronal NOS inhibitor L-SMTC decreased afferent and efferent arteriolar diameters, but only under conditions of maintained tubular flow to the macula densa, as these decreases in arterial diameters were prevented during interruption of distal volume delivery by papillectomy. Afferent, but not efferent, arteriolar vasoconstrictor responses to L-SMTC were also enhanced during increases in volume delivery to the macula densa segment by the use of acetazolamide and this effect was completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor NLA were not significantly attenuated by papillectomy. These findings indicate that neuronal NOS in the macula densa exerts a modulating influence on TGF-mediated

78S

NITRIC OXIDE AND KIDNEY FUNCTION

adjustments in afferent arteriolar tone. Recent studies suggest that NO, produced in the macula densa by the action of neuronal NOS (NOS I) and not endothelial NO, serves as an important modulator of TGF responsiveness by stimulating soluble guanylate cyclase generating cGMP and activating cGMP-dependent protein kinase within the macula densa cells.60

NO Influences on Water and Electrolyte Excretion The results from many studies have implicated intrarenal NO as an important regulator of water and sodium excretion by the kidney.2,3,5–7 NOS inhibitors, when administered intrarenally, elicit substantial reductions in urine flow and in sodium and potassium excretion, suggesting that basal release of NO helps to maintain normal excretory function of the kidney.17,21,22,24,25,28 Fig. 1 illustrates the average responses to NOS inhibitors on renal excretory function in anesthetized dogs observed in experiments performed in our laboratory. Administration of a NO donor compound directly into the kidney reversed the effects of NLA and caused increases in urine flow and in sodium excretion confirming that NO serves as a diuretic and natriuretic agent.22,38 These effects are not consistently associated with significant reductions in GFR, indicating that NO exerts a tubular effect to inhibit epithelial transport. It is also possible that the effects of NOS inhibitors or NO donors on tubular reabsorptive function are mediated indirectly by the associated changes in peritubular hemodynamics or interstitial pressure.8,38,39 A direct effect is supported further by in vitro studies performed in cultured cortical collecting duct cells and in isolated perfused collecting duct segments,5 demonstrating that NO exerts a direct inhibitory effect on epithelial transport mechanisms. Interestingly, it has also been reported that systemic doses of NO inhibitors in rats induce diuretic and natriuretic responses.23,61,62 Although the reasons for these contrasting findings remain unclear, one explanation is that natriuretic and diuretic responses during systemic NOS inhibition may be mediated by other factors associated with the concomitant increases in systemic arterial pressure, reflex inhibition of sympathetic nerve activity to the kidney, and release of humoral agents from extrarenal tissues.61,62

NO and Pressure Natriuresis Nitric oxide has been strongly implicated in mediating the progressive increases in sodium excretion that occur in response to increases in RAP, which is known to occur even under conditions where RBF and GFR autoregulatory efficiency are essentially perfect.63,64 It was previously suggested that some humoral factor capable of detecting altered preglomerular arterial pressure and transmitting signals to the tubules could play a role in this RAP-induced natriuretic responses.63 During recent years, the hypothesis that NO serves as this humoral agent re-

AJH–June 2001–VOL. 14, NO. 6, PART 2

sponsible for the arterial pressure-induced changes in sodium excretion has received growing support. Initial studies as well as others demonstrated that NOS inhibition caused marked attenuation of the relationship between arterial pressure and sodium excretion.22,24,28,32 We also observed that a constant rate intrarenal infusion of an NO donor agent in dogs pretreated with NOS inhibitors failed to restore the slope of the pressure–natriuresis relationship, although it caused increased sodium excretion. These findings consequently led to the suggestion that an alteration in intrarenal NO activity during changes in RAP, rather than just the presence of NO, is directly involved in mediating pressure–natriuresis. To examine possible alterations in renal NO activity during changes in RAP, experiments were conducted in anesthetized dogs evaluating the changes in urinary excretion rate of NO metabolites, nitrate and nitrite (NOX), at different levels of RAP.28 Changes in urinary excretion rates of nitrate and nitrite provide an index of the changes in endogenous formation of NO provided other exogenous factors such as dietary intake of nitrates and nitrites are maintained constant.65 As shown in Fig. 3 in response to acute changes in RAP, we observed a positive correlation between RAP and the changes in urinary NOX excretion rate.28 These changes in urinary NOX excretion also showed a positive correlation with urinary sodium excretion.28 To provide a more direct measure of intrarenal NO, we examined the changes in renal tissue NO activity during changes in RAP using an NO selective electrode inserted into the tissues of renal cortical and medullary regions.29,32 These data are summarized in Fig. 4 and show that acute reductions in RAP induce concomitant decreases in intrarenal NO activity. This direct relationship was observed in the presence of efficient autoregulation of cortical and MBF, as determined by single fiber laser-Doppler needle probes.29,32 The changes in tissue NO activity in response to acute changes in RAP were strongly correlated with the concomitant changes in urinary excretion rate of NOX.29,32 These findings demonstrate that intrarenal NO activity is altered by changes in RAP and support the hypothesis that NO is involved in the mediation of pressure natriuretic responses. On the basis of well-known evidence that flowinduced shear stress stimulates the release of NO from the vascular endothelium, it seems likely that alterations in shear stress occurring as a consequence of the changes in resistance of the preglomerular vessels during changes in RAP induce alterations in the release on NO.4,66 As shown in Fig. 5, increases in NO production during increases in RAP would boost prevailing tissue NO levels, which in turn would mediate natriuretic responses by either influencing tubular transport directly or possibly altering the intrarenal hemodynamic environment. Increases in intrarenal NO activity during raises in RAP may partly influence tubular transport by eliciting concomitant increases in renal interstitial hydrostatic pressure (RIHP).8 We have recently demonstrated that intrarenal NO is linked with

AJH–June 2001–VOL. 14, NO. 6, PART 2

NITRIC OXIDE AND KIDNEY FUNCTION

79S

FIG. 3. Summary of changes in fractional sodium excretion (FENA) and urinary nitrate/nitrite excretion (UNOXV) in response to change in renal arterial pressure (RAP) during control conditions (E), during infusion of NLA (F), and during concomitant infusion of NLA and SNAP (‚). (Data derived from Refs. 29 and 38.)

changes in RIHP that occur in response to alterations in RAP.38 As mentioned earlier, it has also been shown that NO exerts a direct inhibitory effect on epithelial transport mechanisms.5 To examine the tubular sites responsive to changes in RAP, we also examined the possible role of distal nephron sodium entry pathways in mediating pressure natriuresis. The two major sodium transport pathways in the distal nephron were blocked using pharmacologic agents.67 We observed that blockade of apical sodium entry pathways in the distal nephron by intraarterial infusion of amiloride and bendroflumethiazide caused a marked attenuation of the pressure natriuretic responses particularly at higher pressure levels.67 These findings suggest that the distal nephron sodium entry pathways,

FIG. 4. Changes in cortical and medullary tissue nitric oxide (NO) activity (assessed using nitric oxide electrode) in response to changes in renal arterial pressure (RAP) (E cortex; F medulla). (Data derived from Refs. 29 and 32.)

which have been shown to be responsive to NO, are principally involved in mediating arterial pressure-induced changes in urinary sodium excretion. The source of enhanced NO production in the kidney during increases in RAP has not yet been determined. However, because increases in RAP caused changes in blood flow velocity and sheer stress in the preglomerular vessels, it is reasonable to assume that renal endothelial NOS in preglomerular arterioles is responsible for enhanced NO production rate. There are abundant close contacts between afferent arterioles and distal tubules68 and it is possible that the NO released during increases in RAP would have a relatively short linear diffusion pathway from the preglomerular arterioles to the tubular segments. Thus, as shown in Fig. 5, it is reasonable to propose that enhancement of renal tissue NO levels in response to acute increases in RAP may directly inhibit distal tubular sodium transport leading to an increase in sodium excretion. In addition, collecting duct cells also contain substantial quantities of NOS9,15 and it is possible that NO formed in collecting duct cells affect tubular sodium transport directly. The link between the changes in RAP and direct effects on NO production by tubular NOS is unclear, but tubular NO may alter the magnitude of the pressure natriuresis phenomenon. As mentioned earlier, macula densa cells contain neuronal NOS, which has been shown to play a role in modulating tubuloglomerular feedback responses.9,15,57,59 Thus, it is also possible that signals from preglomerular vessels due to changes in RAP cause an enhancement of NO release from the macula densa that may travel downstream to the distal segment causing alterations in the sodium reabsorption rate.

Conclusion Recent developments have provided substantial evidence demonstrating the important role of NO in the regulation

80S

NITRIC OXIDE AND KIDNEY FUNCTION

AJH–June 2001–VOL. 14, NO. 6, PART 2

FIG. 5. Nitric oxide hypothesis as the mediator for arterial pressure-induced changes in sodium excretion.

of renal function. Nitric oxide helps to maintain the normally low RVR necessary to ensure adequate perfusion of the kidney. Nearly one-third to one-fourth of total RBF is dependent on an intact NO influence. Nitric oxide regulates both pre- and postglomerular vascular resistances. However, the basic autoregulatory mechanism is not dependent on an intact NO system, although NOS blockade does decrease the absolute RBF. There is also substantial evidence that NO is an important local regulator of tubular reabsorptive function and serves as a major mediator of arterial pressure-induced natriuretic responses in the kidney.

9.

10.

11.

12. 13.

Acknowledgment We are grateful to Debbie Olavarrieta for excellent secretarial assistance.

14.

References

15.

1.

2.

3.

4. 5. 6. 7. 8.

Navar LG, Inscho EW, Majid DSA, Imig JD, Harrison-Bernard LM, Mitchell KD: Paracrine regulation of the renal microcirculation. Physiol Rev 1996;76:425–536. Kone BC, Baylis C: Biosynthesis and homeostatic roles of nitric oxide in the normal kidney (Review). Am J Physiol 1997;272:F561– F578. Mattson DL, Lu S, Cowley AW Jr: Role of nitric oxide in the control of the renal medullary circulation. Clin Exp Pharmacol Physiol 1997;24:587–590. Furchgott RF, Vanhoutte PM: Endothelium-derived relaxing and contracting factors. FASEB J 1989;3:2007–2018. Stoos BA, Garvin JL: Actions of nitric oxide on renal epithelial transport. Clin Exp Pharmacol Physiol 1997;24:591–594. Raij L: Nitric oxide and the kidney. Circ 1993;87(suppl V):V-26 – V-29. Manning RD, Hu L: Nitric oxide regulates renal hemodynamics and urinary sodium excretion in dogs. Hypertension 1997;23:619 – 625. Granger JP, Alberola AM, Salazar FJ, Nakamura T: Control of renal hemodynamics during intrarenal and systemic blockade of nitric

16.

17.

18.

19.

20.

oxide synthesis in conscious dogs. J Cardiovasc Pharmacol 1992; 20(suppl 12):S160 –S162. Star RA: Intrarenal localization of nitric oxide synthase isoforms and solubel guanylyl cyclase. Clin Exp Pharmacol Physiol 1997;24: 607– 610. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109 – 142. Lamas S, Marsden PA, Li GK, Tempst P, Michel T: Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA 1992;89:6348 – 6352. Cooke JP, Dzau VJ: Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 1997;48:489 –509. Chin SY, Pandey KN, Shi S-J, Kobori H, Moreno C, Navar LG: Increased activity and protein expression of calcium-dependent nitric oxide synthases in the renal cortex of angiotensin II-infused hypertensive rats. Am J Physiol-Renal Physiol 1999;277:F797– F804. Bachmann S, Bosse HM, Mundel P: Topography of nitric oxide synthesis by localizing constitutive NO synthases in mammalian kidney. Am J Physiol Renal Physiol 1995;268:F885–F898. Ujiie K, Drewett JG, Yuen PST, Star RA: Differential expression of mRNA for guanylyl cyclase-linked endothelium-derived relaxing factor receptor subunits in rat kidney. J Clin Invest 1993;91:730 – 734. Bachmann S, Mundel P: Nitric oxide in the kidney: synthesis, localization, and function (Review). Am J Kidney Dis 1994;24:112– 129. Lahera V, Salom MG, Fiksen-Olsen MJ, Romero JC: Mediatory role of endothelium-derived nitric oxide in renal vasodilatory and excretory effects of bradykinin. Am J Hypertens 1991;4:260 –262. Lahera V, Salom MG, Fiksen-Olsen MJ, Raij L, Romero JC: Effects of NG-monomethyl-l-arginine and l-arginine on acetylcholine renal response. Hypertension 1990;15:659 – 663. Baumann JE, Persson PB, Ehmke H, Nafz B, Kirchheim HR: Role of endothelium-derived relaxing factor in renal autoregulation in conscious dogs. Am J Physiol-Renal Physiol 1992;263:F208 –F213. Beierwaltes WH, Sigmon DH, Carretero OA: Endothelium modulates renal blood flow but not autoregulation. Am J Physiol-Renal Physiol 1992;262:F943–F949.

AJH–June 2001–VOL. 14, NO. 6, PART 2

21. Majid DSA, Navar LG: Suppression of blood flow autoregulation plateau during nitric oxide blockade in canine kidney. Am J PhysiolRenal Physiol 1992;262:F40 –F46. 22. Majid DSA, Williams A, Kadowitz PJ, Navar LG: Renal responses to intra-arterial administration of nitric oxide donor in dogs. Hypertension 1993;22:535–541. 23. Baylis C, Harton P, Engels K: Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol 1990;1:875– 881. 24. Majid DSA, Williams A, Navar LG: Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anesthetized dogs. Am J Physiol-Renal Physiol 1993;264:F79 –F87. 25. Salom MG, Lahera V, Miranda-Guardiola F, Romero JC: Blockade of pressure natriuresis induced by inhibition of renal synthesis of nitric oxide in dogs. Am J Physiol-Renal Physiol 1992;262:F718 – F722. 26. Denton KM, Anderson WP: Intrarenal haemodynamic and glomerular responses to inhibition of nitric oxide formation in rabbits. J Physiol 1994;475:159 –167. 27. Bech JN, Nielsen CB, Pedrsen EB: Effects of systemic NO synthesis inhibition on RPF, GFR, UNa, and vasoactive hormones in healthy humans. Am J Physiol-Renal Physiol 1996;270:F845–F851. 28. Majid DSA, Godfrey M, Grisham MB, Navar LG: Relation between pressure natriuresis and urinary excretion of nitrate/nitrite in anesthetized dogs. Hypertension 1995;25(part 2):860 – 865. 29. Majid DSA, Said KE, Omoro SA: Responses to acute changes in arterial pressure on renal medullary nitric oxide activity in dogs. Hypertension 1999;34:832– 836. 30. Chen C, Mitchell KD, Navar LG: Role of endothelium-derived nitric oxide in the renal hemodynamic response to amino acid infusion. Am J Physiol Regulatory Integrative Comp Physiol 1992; 263:R510 –R516. 31. Lockhart JC, Larson TS, Knox FG: Perfusion pressure and volume status determine the microvascular response of the rat kidney to NG-monomethyl-L-arginine. Circ Res 1994;75:829 – 835. 32. Majid DSA, Omoro SA, Chin SY, Navar LG: Intrarenal nitric oxide activity and pressure natriuresis in anesthetized dogs. Hypertension 1998;32:266 –272. 33. Mattson DL, Lu S, Cowley AW Jr: Role of nitric oxide in the control of the renal medullary circulation. Clin Exp Pharmacol Physiol 1997;24:587–590. 34. Sonntag M, Deussen A, Schrader J: Role of nitric oxide in local blood flow control in the anaesthetized dog. Pflu¨gers Arch 1992; 420:194 –199. 35. Sigmon DH, Carretero OA, Beierwaltes WH: Renal versus femoral hemodynamic response to endothelium-derived relaxing factor synthesis inhibition. J Vasc Res 1993;30:218 –223. 36. Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739 –749. 37. Carmines PK, Inscho EW, Gensure RC: Arterial pressure effects on preglomerular microvasculature of juxtamedullary nephrons. Am J Physiol-Renal Physiol 1990;258:F94 –F102. 38. Majid DSA, Said KE, Omoro SA, Navar LG: Nitric oxide dependency of arterial pressure induced changes in renal interstitial hydrostatic pressure in dogs. Cir Res 2001;88:347–351. 39. Fenoy FJ, Ferrer P, Carbonell L, Garcı´a-Salom M: Role of nitric oxide on papillary blood flow and pressure natriuresis. Hypertension 1995;25:408 – 414. 40. Roman RJ, Cowley AW Jr, Garcia-Estan J, Lombard JH: Pressurediuresis in volume-expanded rats: cortical and medullary hemodynamics. Hypertension 1988;12:168 –176. 41. Mattson DL, Lu S, Roman RJ, Cowley AW Jr: Relationship between

NITRIC OXIDE AND KIDNEY FUNCTION

42. 43.

44. 45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56. 57.

58.

59.

60.

61.

81S

renal perfusion pressure and blood flow in different regions of the kidney. Am J Physiol Reg Integ Comp Physiol 1993;264:R578 –R583. Majid DSA, Godfrey M, Navar LG: Pressure natriuresis and renal medullary blood flow in dogs. Hypertension 1997;29:1051–1057. Majid DSA, Godfrey M, Omoro S: Pressure natriuresis and autoregulation of inner medullary blood flow in canine kidney. Hypertension 1997;29(part 2):210 –215. Imig JD, Roman RJ: Nitric oxide modulates vascular tone in preglomerular arterioles. Hypertension 1992;19:770 –774. Ohishi K, Carmines PK, Inscho EW, Navar LG: EDRF–angiotensin II interactions in rat juxtamedullary afferent and efferent arterioles. Am J Physiol-Renal Physiol 1992;263:F900 –F906. Deng A, Baylis C: Locally produced EDRF controls preglomerular resistance and ultrafiltration coefficient. Am J Physiol-Renal Physiol 1993;264:F212–F215. Edwards RM, Trizna W: Modulation of glomerular arteriolar tone by nitric oxide synthase inhibitors. J Am Soc Nephrol 1993;4:1127– 1132. Ito S, Ren Y: Evidence for the role of nitric oxide in macula densa control of glomerular hemodynamics. J Clin Invest 1993;92:1093– 1098. Ichihara A, Inscho EW, Imig JD, Navar LG: Neuronal nitric oxide synthase modulates rat renal microvascular function. Am J Physiol Renal Physiol 1998;274:F516 –F524. Hoffend J, Cavarape A, Endlich K, Steinhausen M: Influence of endothelium-derived relaxing factor on renal microvessels and pressure-dependent vasodilation. Am J Physiol-Renal Physiol 1993;265: F285–F292. Baylis C, Mitruka B, Deng A: Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992;90:278 –281. Johnson RA, Freeman RH: Pressure natriuresis in rats during blockade of the L-arginine/nitric oxide pathway. Hypertension 1992;19: 333–338. Lahera V, Salom MG, Miranda-Guardiola F, Moncada S, Romero JC: Effects of Ng-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol-Renal Physiol 1991;261:F1033– F1037. Welch WJ, Wilcox CS, Aisaka K, Gross SS, Griffith OW, Fontoura BMA, Maack T, Levi R: Nitric oxide synthesis from L-arginine modulates renal vascular resistance in isolated perfused and intact rat kidneys (abst). J Cardiovasc Pharmacol 1991;17(suppl 3):S165– S168. Takenaka T, Mitchell KD, Navar LG: Contribution of angiotensin II to renal hemodynamic and excretory responses to nitric oxide synthesis inhibition in the rat. J Am Soc Nephrol 1993;4:1046 –1053. Hu L, Manning RD Jr, Brands MW: Long-term cardiovascular role of nitric oxide in conscious rats. Hypertension 1994;23:185–194. Wilcox CS, Welch WJ, Murad F, Gross SS, Taylor G, Levi R, Schmidt HHHW: Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci 1992;89:11993– 11997. Thorup C, Persson AEG: Inhibition of locally produced nitric oxide resets tubuloglomerular feedback mechanism. Am J Physiol-Renal Physiol 1994;267:F606 –F611. Wilcox CS, Welch WJ: TGF and nitric oxide: effects of salt intake and salt-sensitive hypertension. Kidney Int 1996;49(suppl 55):S-9 – S-13. Ren Y, Garvin JL, Carretero OA: Role of macula densa nitric oxide and cGMP in the regulation of tubuloglomerular feedback. Kidney Int 2000;58:2053–2060. Gabbai FB, Thomason SC, Peterson O, Wead L, Malvey K, Blantz RC: Glomerular and tubular interactions between renal adrenergic activity and nitric oxide. Am J Physiol-Renal Physiol 1995;268: F1004 –F1008.

82S

NITRIC OXIDE AND KIDNEY FUNCTION

62. Khraibi AA: Role of renal nerves in natriuresis of L-NMMA infusion in SHR and WKY rats. Am J Physiol-Renal Physiol 1995;269: F17–F21. 63. Navar LG, Paul RV, Carmines PK, Chou C-L, Marsh DJ: Intrarenal mechanisms mediating pressure natriuresis: role of angiotensin and prostaglandins. Fed Proc 1986;45:2885–2891. 64. Cowley AW Jr: Long-term control of arterial blood pressure. Physiol Rev 1992;72:231–300. 65. Grisham MB, Johnson GG, Gautreaux MD, Berg RD: Measurement of nitrate and nitrite in extracellular fluids: a window to systemic nitric oxide metabolism, in Abelson JN, Simon MI (eds): Methods:

AJH–June 2001–VOL. 14, NO. 6, PART 2

A Companion to Methods in Enzymology. New York, Academic Press, 1995, pp 84 –90. 66. Kuchan MJ, Frangos JA: Role of calcium and calmodulin in flowinduced nitric oxide production in endothelial cells. Am J PhysiolCell Physiol 1994;266:C628 –C636. 67. Majid DSA, Navar LG: Blockade of distal nephron sodium transport attenuates pressure natriuresis in dogs. Hypertension 1994;23(part 2):1040 –1045. 68. Dorup J, Morsing P, Rasch R: Tubule-tubule and tubule-arteriole contacts in rat kidney distal nephrons. Lab Invest 1992;67:761–769.