Inhibition Of Renin Release Research Articles

Sodium reduces renin secretion less in natriuretic peptide C receptor deficient mice

The impact of the natriuretic peptide C receptor (NPR-C) on renin secretion was assessed in mice possessing normal or mutated (nonfunctional) NPR-C’s. Heterozygous mice with a mutation of the NPR-C were bred to obtain either wild type, heterozygote or homozygote (NPR-C deficient) mice. The mice were tested at 2 months of age. Half of the mice of each genotype drank 0.9% saline and the other half drank tap water. After five days of saline or water consumption, the mice were anesthetized with pentobarbital sodium and 150 μl of blood were withdrawn from the inferior vena cava. Wild type control mice exhibited a decrease in renin activity from 2062 ± 364 to 1518 ± 178 ng angiotensin I/ml/hr after saline exposure. The decrease in heterozygotes was from 1663 ± 201 to 1366 ± 128, whereas homozygote (deficient) mice experienced a change from 2070 ± 284 to 1951 ± 314. The difference between renin activity while drinking water and saline averaged 544 ng angiotensin I/ml/hr in wildtype mice, 297 in heterozygote mice and 119 in homozygote mice. Thus, a linear relationship existed between the number of functional NPR-C copies and the ability of saline consumption to suppress renin secretion. Prior studies have identified the natriuretic peptide A receptor as the functional natriuretic peptide receptor suppressing renin release. These data suggest an involvement of the NPR-C as well. (This study was supported by the Minnesota Medical Foundation.)

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

A different vision of the osmolar regulation of renin secretion

in this issue, the proverbial question of osmotic regulation of renin secretion is revisited by Kurtz and Schweda ([9][1]) with rather surprising, yet apparently definitive, results. Since the development of osmotic diuretics, there has been much interest in whether renin secretion by the kidney is

Membrane potential and cation channels in rat juxtaglomerular cells.

The relationship between membrane potential and cation channels in juxtaglomerular (JG) cells is not well understood. Here we review electrophysiological and molecular studies of JG cells demonstrating the presence of large voltage-sensitive, calcium-activated potassium channels (BK(Ca)) of the ZERO splice variant, which is also activated by cAMP. These channels explain the hyperpolarization, which has been observed after stimulation of renin release with cAMP. In addition, there is now evidence that JG cells express functional L-type voltage-dependent calcium channels (Ca(v) 1.2), which in situations with strong depolarization lead to calcium influx and inhibition of renin release. In most in vivo situations the membrane potential is probably protected against depolarization by the BK(Ca) channels.

Cellular mechanism of renin release.

In this review we aim to give a comprehensive overview over the current knowledge of the cellular control of renin release. We hereby focus on the inhibitory effects of calcium on the exocytosis of renin. After a short introduction into general aspects of the regulation of renin release, including a brief summary on the role of the second messengers cAMP and cGMP, we will discuss parts of the literature on the effects of calcium on the renin system together with recent studies from our laboratory, investigating putative calcium influx and extrusion pathways of juxtaglomerular cells. Finally, as the precise mechanisms by which calcium inhibits the exocytosis of renin are far from being understood, we will present some hypotheses on the intracellular events being involved in the suppression of renin release by calcium.

Mechanisms for macula densa cell release of renin

The juxtaglomerular apparatus in the kidney is important in controlling extracellular fluid volume and renin release. The fluid load to the distal tubule is first sensed at the macula densa site via the entry of NaCl, through a Na, K, 2Cl co-transport mechanism. The next step is unclear, but there is recent evidence of an increased macula densa cell calcium concentration with a reduction in fluid load to the macula densa. An increase in macula densa cell calcium could activate phospholipase A2 to release arachidonic acid, the rate-limiting step in the formation of prostaglandins. Recent evidence suggests that the prostaglandin formed is PGE2, a potent stimulator for renin release. Recent evidence has also shown that adenosine has an important function in the juxtaglomerular apparatus. It stimulates calcium release in afferent arteriolar smooth muscle cells, leading to contraction of the afferent arteriole as part of the tubuloglomerular feedback mechanism, and inhibits renin release. Thus, renin release from the afferent arteriole is mediated partly through formation of PGE2, and partly through the reduction of adenosine formation that inhibits renin production.

Role of angiotensin II AT1 receptor blockers in the treatment of arterial hypertension.

Hypertension is a very common condition and the most important risk factor for the occurrence of cardiovascular events. The hyperactivity of the renin-angiotensin-aldosterone system is considered a cardiovascular risk factor in subjects with essential hypertension. The intrinsic vascular abnormality in which the renin-angiotensin-aldosterone system is clearly the milieu for the development of the pathologic changes in blood vessel walls is one of the causes of the establishment of hypertension. Many drugs with different mechanisms of action have been used for the treatment of hypertension and its vascular complications. Nevertheless, the utilities of many drugs are limited by their adverse effects. Continuous research in the search for new pharmacological agents for the treatment of hypertension has led to the development of angiotensin II receptor type AT1 blockers. The most important functions mediated by AT1 receptors include: vasoconstriction, induction of the production and release of aldosterone, renal reabsorption of sodium, cardiac cellular growth, proliferation of vascular smooth muscle, increase of peripheral noradrenergic action and the central activity of the sympathetic nervous system, stimulation of vasopressin release, and inhibition of renin release from the kidney. The angiotensin II receptor type AT1 blockers inhibit the interaction of angiotensin II with its AT1 receptor. These agents lower blood pressure without producing cough as a side effect since, unlike the angiotensin-converting enzyme inhibitors they do not influence the levels of bradykinin or substance P. Hence, these drugs are suitable for the treatment of hypertensive patients who require therapy with a drug blocking the effect of angiotensin-converting enzyme but cannot use angiotensin-converting enzyme inhibitors due to cough as a side effect.

Effect of beta blockade ( carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure

Beta blockers are known to suppress renin release in hypertension and in patients taking angiotensin-converting enzyme (ACE) inhibitors. This study sought to explore the effect of additional β blockade on neurohumoral modulation in patients with severe heart failure (HF) who received ACE inhibitors. Forty-nine patients with chronic HF who received ACE inhibitors were given metoprolol 50 mg or carvedilol 25 mg twice daily after a 4-week dose titration period in addition to standard therapy in a prospective trial. Samples of plasma renin activity (PRA), aldosterone, aminoterminal B-type natriuretic peptide (N-BNP), and atrial natriuretic peptide (ANP) were taken at baseline and at 4, 12, and 52 weeks after starting therapy. Treatment with either β blocker significantly lowered PRA at 4 weeks compared with baseline (−2.0 ± 0.6 nmol/L/hour, p = 0.006), but at 12 weeks, PRA had reduced to –1.1 ± 0.6 nmol/L/hour (p = 0.08), but at 52 weeks, it was not significantly different from baseline (+1.05 ± 0.6 nmol/L/hour, p = 0.13). Aldosterone levels did not change significantly from baseline at 4 or 12 weeks, although there was a nonsignificant trend for lower levels at 52 weeks (baseline 232 ± 154 pmol/L, 52 weeks 192 ± 100 pmol/L, p = 0.09). There was significant reduction in N-BNP and ANP together with an improvement in symptom and left ventricular systolic function at 1-year follow-up. These results indicate that the suppressive effect of β blockers on PRA in patients with HF taking ACE inhibitors is temporary, and that there is no significant effect on serum aldosterone levels.

Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension

Acute hypertension inhibits proximal tubule (PT) sodium reabsorption. The resultant increase in NaCl delivery to the macula densa suppresses renin release. We tested whether the sustained pressure-induced inhibition of PT sodium reabsorption requires a renin-mediated decrease in ANG II levels. Plasma ANG II concentration of anesthesized Sprague-Dawley rats was clamped by simultaneous infusion of the ANG I-converting enzyme inhibitor captopril (12 microg/min) and ANG II (20 ng. kg(-1). min(-1)). Blood pressure was increased 50 mmHg for 20 min by arterial constriction +/- ANG II clamp or by sham operation. This acute hypertension increased urine output and endogenous Li(+) clearance, and these responses were blunted 40-50% in ANG II clamped rats. Acute hypertension provoked a rapid redistribution of Na(+)/H(+) exchanger isoform 3 (NHE3) out of apical brush-border membranes (21 +/- 4% decrease of total NHE3 abundance) to endosomal/lysosomal membranes (16 +/- 6% increase of total). In ANG II-clamped rats, acute hypertension also provoked disappearance of NHE3 from the apical membranes (27 +/- 2% decrease of total), but NHE3 was shifted to membranes enriched in intermicrovillar cleft and dense apical tubules (step 1) rather than endosomal/lysosomal membranes (step 2). This difference was independently confirmed by confocal analysis. In contrast, the pressure-induced redistribution of Na(+)-P(i) cotransporter type 2 was not altered by ANG II clamp. We conclude that the responses to acute hypertension, including diuresis and redistribution of PT NHE3 into intracellular membranes, require a responsive renin-angiotensin system and that the responses may be induced by the sustained increase in NaCl delivery to the macula densa during acute hypertension.

Nitric oxide modulates and adenosine mediates the tubuloglomerular feedback mechanism.

The tubuloglomerular feedback (TGF) mechanism is an important regulator of the glomerular filtration rate (GFR) and urine excretion rate. It operates by sensing the distal delivery of fluid at the macula densa site and adjusting the tone of the glomerular arterioles to control GFR. We found evidence that nitric oxide is an important modulator of the setting of the sensitivity of the TGF mechanism. Studies on adenosine A1 receptor deficient mice have shown that these animals lack the TGF response and have an increased renin release. These findings show the important role of adenosine as a mediator of the signal for the TGF mechanism and as an inhibitor of renin release.

Manipulation of the renin-angiotensin system.

Since the initial description of angiotensin II–mediated hypertension >40 years ago, basic and clinical investigations of the renin-angiotensin system (RAS) have resulted in a broader understanding of cardiovascular pathophysiology and significant advances in therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are now widely prescribed for the treatment of hypertension and left ventricular (LV) dysfunction; more recently, the aldosterone receptor antagonist, spironolactone, has proven beneficial in severe heart failure. This article will focus on our current understanding of the RAS and how pharmacological manipulation of this system can improve clinical outcomes in patients with cardiovascular disease. ### Pathophysiological Rationale for RAS Manipulation Renin is released by juxtuloglomerular cells in the kidney in response to renal hypoperfusion, decreased sodium delivery, and sympathetic activation (Figure 1). Angiotensinogen produced by the liver is cleaved by renin to yield the inactive decapeptide angiotensin I. Circulating angiotensin I is, in turn, converted to angiotensin II in the lungs by the action of ACE. ACE, or kininase II, also plays a key role in the kallikrein-kinin system by cleaving bradykinin to inactive peptides. In addition to the hormonal effects of circulating angiotensin II, all of the necessary components of the RAS exist in several organs and tissues, including the heart, kidneys, and vasculature. Figure 1. Pathophysiology of the RAS. SMC indicates smooth muscle cell. Angiotensin II exerts its actions in target organs and tissues by binding to both angiotensin II type 1 and 2 (AT1 and AT2) receptors, although adverse effects in humans seem to be mediated primarily by the AT1 receptor (Figure 1). In the kidney, angiotensin II causes sodium and water retention and efferent arteriolar vasoconstriction. Constriction of the systemic vasculature by angiotensin II causes hypertension, whereas coronary vasoconstriction may cause myocardial ischemia and arrhythmias. Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine …

Prostaglandin I(2)/E(2) ratios in unilateral renovascular hypertension of different severities.

Differences between prostaglandins I(2) and E(2) in their renal synthesis and pathophysiological roles were investigated in unilateral renovascular hypertension of different severities in 18 patients: 6 with mild stenosis (<75% of the diameter) of the renal artery, 7 with moderate stenosis (75% to 90%), and 5 with severe stenosis (>90%). Before and after aspirin administration (10 mg/kg), renal venous and aortic plasma was assayed for 6-ketoprostaglandin F(1alpha) (instead of prostaglandin I(2)), prostaglandin E(2), and renin activity. In mild or moderate stenosis, the mean 6-ketoprostaglandin F(1alpha) level in renal venous plasma from the stenotic side was not different from that from the normal side or from aortic plasma. Prostaglandin E(2) levels and renin activity in such patients were higher on the stenotic side than on the normal side and higher in venous than in aortic plasma. Aspirin inhibited prostaglandin E(2) synthesis and suppressed renin release from stenotic kidneys and lowered blood pressure as the renin activity decreased in patients with mild or moderate stenosis. In severe stenosis, levels of 6-ketoprostaglandin F(1alpha) and prostaglandin E(2) were higher on the stenotic side than on the normal side and higher in venous than in aortic plasma. Aspirin inhibited the synthesis of both prostaglandins and suppressed renin release from the stenotic kidney. In patients with unilateral renovascular hypertension with mild or moderate stenosis of the renal artery, prostaglandin E(2), rather than I(2), seems to contribute to further acceleration of renin release. Prostaglandin I(2) may increase and participate in further renin release when the stenosis is severe.

Neural mechanisms subserving central angiotensinergic influences on plasma renin in sheep.

The mechanisms and brain regions subserving the suppression of plasma renin concentration caused by intracerebroventricular (ICV) infusion of angiotensin II were studied in sodium-depleted sheep. Infusion of angiotensin II (3 microg/h for 1 hour) into the lateral ventricle reduced plasma renin from 4.3+/-0.4 to 1.6+/-0.2 pmol angiotensin I/mL per hour at 1 hour after the commencement of infusion. This change persisted for at least another 90 minutes and was blocked by concomitant ICV infusion of the AT(1) antagonist losartan (1 mg/h). Arterial pressure did not change, but plasma vasopressin secretion was increased. ICV infusion of losartan (1 mg/h) significantly increased plasma renin in sodium-depleted sheep. The reduction of plasma renin concentration in response to either ICV angiotensin II or hypertonic NaCl (0.75 mol/L at 1 mL/h) and the increase in response to ICV losartan was prevented in sheep in which the lamina terminalis of the brain had been ablated. Lesions in the median eminence (MEL), which blocked the increased plasma vasopressin levels, did not prevent suppression of plasma renin in response to ICV angiotensin II. However, bilateral renal denervation largely blocked this inhibition of plasma renin concentration but not the increased plasma renin resulting from ICV infusion of losartan in sodium-depleted sheep. The results show that AT(1) receptors, probably located in the lamina terminalis, mediate a central inhibitory influence of angiotensin II on renin secretion. This inhibition of renin release is probably due to a reduction in activity of renal sympathetic nerves innervating the juxtaglomerular apparatus of the kidney.

Endothelin-B Receptors Play an Important Role in Modulating Chronic Pressure-Natriuresis and Blood Pressure Regulation in Response to Changes in Dietary Sodium Intake.

25 Activation of the ET B receptor by endothelin (ET-1) has been shown to inhibit renal tubule transport, dilate renal microcirculatory vessels, and inhibit renin release. The purpose of this study was to determine the role of ET and ET B receptors in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake. To test whether the renal production of ET is enhanced in response to elevation in Na intake, the effects of a low (0.4%), normal (1.0%), or high (8%) Na diet on 24hr urinary excretion of ET-1 and mRNA expression of preproendothelin (ribonuclease protection assay) were determined. Increasing Na intake from low to normal levels had no effect on urinary ET-1 excretion or renal expression of preproendothelin. In contrast, increasing Na intake from normal to high levels resulted in significant increases in urinary excretion of ET-1 (7223±968 vs 2127±167 pg/24hrs) and expression of preproendothelin (42.3±6.7 vs 25.4±1.8 densitometric units) in the renal medulla. To test whether ET B receptors play an important role in modulating arterial pressure in response to changes in Na intake, the relationship between arterial pressure and sodium excretion was determined in control rats and in ETB receptor antagonist-treated rats (A-192621, 30mg/kg/day for 7 days). Long-term ET B receptor blockade resulted in a significant rightward shift in the chronic pressure-natriuresis relationship. In control rats on a normal and high Na intake, AP was 122±3 and 132±3mmHg, respectively. In contrast, AP in ETB receptor antagonist-treated rats on a normal and high Na intake was 144±2 and 171±12mmHg, respectively. In summary, we report that the renal endothelin system is upregulated in response to increases in sodium intake. Blockade of the ET B receptors results in significant hypertension that is salt-sensitive. These results indicate that endothelin via ET B receptors plays an important role in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake.

Endothelin-B Receptors Play an Important Role in Modulating Chronic Pressure-Natriuresis and Blood Pressure Regulation in Response to Changes in Dietary Sodium Intake.

25 Activation of the ET B receptor by endothelin (ET-1) has been shown to inhibit renal tubule transport, dilate renal microcirculatory vessels, and inhibit renin release. The purpose of this study was to determine the role of ET and ET B receptors in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake. To test whether the renal production of ET is enhanced in response to elevation in Na intake, the effects of a low (0.4%), normal (1.0%), or high (8%) Na diet on 24hr urinary excretion of ET-1 and mRNA expression of preproendothelin (ribonuclease protection assay) were determined. Increasing Na intake from low to normal levels had no effect on urinary ET-1 excretion or renal expression of preproendothelin. In contrast, increasing Na intake from normal to high levels resulted in significant increases in urinary excretion of ET-1 (7223±968 vs 2127±167 pg/24hrs) and expression of preproendothelin (42.3±6.7 vs 25.4±1.8 densitometric units) in the renal medulla. To test whether ET B receptors play an important role in modulating arterial pressure in response to changes in Na intake, the relationship between arterial pressure and sodium excretion was determined in control rats and in ETB receptor antagonist-treated rats (A-192621, 30mg/kg/day for 7 days). Long-term ET B receptor blockade resulted in a significant rightward shift in the chronic pressure-natriuresis relationship. In control rats on a normal and high Na intake, AP was 122±3 and 132±3mmHg, respectively. In contrast, AP in ETB receptor antagonist-treated rats on a normal and high Na intake was 144±2 and 171±12mmHg, respectively. In summary, we report that the renal endothelin system is upregulated in response to increases in sodium intake. Blockade of the ET B receptors results in significant hypertension that is salt-sensitive. These results indicate that endothelin via ET B receptors plays an important role in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake.

Different patterns of renal prostaglandins I2 and E2 in patients with essential hypertension with low to normal or high renin activity

Differences in renal synthesis between prostaglandins I2 and E2, and the relationships of the amounts synthesized to renin release were investigated in patients with essential hypertension. Of 12 inpatients, six had low to normal plasma renin activity and six had high renin activity. Before and 30 min after intravenous injection of aspirin D,L-lysine (18 mg/kg), abdominal aortic and renal venous plasma was sampled and assayed for renin activity, 6-ketoprostaglandin F1alpha (as an index of prostaglandin I2), and prostaglandin E2. In patients with low to normal renin activity, mean +/- SD plasma levels of 6-keto-prostaglandin F1alpha were lower in the right and left renal veins (3.6 +/- 1.4 and 4.1 +/- 1.5 pg/ml, respectively) than in the aorta (5.5 +/- 2.0 pg/ml), but in the other patients, the levels in these veins (7.0 +/- 2.4 and 6.5 +/- 1.5 pg/ml) were higher than in the aorta (5.4 +/- 0.9 pg/ml). Plasma prostaglandin E2 levels in both veins were higher than in the aorta in both groups and, at each site, the levels were similar in the two groups. Aspirin suppressed renin release in the patients with high renin activity. In patients with essential hypertension with low to normal renin activity, either less prostaglandin I2 than prostaglandin E2 is produced in the kidney or else more is metabolized there, and in such patients with high renin activity, the renal synthesis of prostaglandin I2, more than that of prostaglandin E2, seems to be related to the increased renin release.

Renal NO production and the development of hypertension.

The juxtaglomerular apparatus (JGA) has the very important functions of detecting the fluid flow rate to the distal tubule and thus controlling the glomerular filtration rate (GFR) (tubuloglomerular feedback mechanism [TGF]) and renin release from the afferent arteriole. In studies of the TGF it has been evident that the sensitivity of this mechanism can be reset. Volume expansion will reset it to a low sensitivity leading to a high GFR and urine excretion rate, while dehydration will sensitize the TGF mechanism, giving rise to a low GFR and low urine excretion rate. Furthermore, we have found that in animals that spontaneously develop hypertension there is initially a sensitization of the TGF, leading to a reduced GFR and urine excretion rate, with fluid volume retention in the body and a consequent rise in blood pressure. When the pressure is raised, the TGF characteristics are normalized. In the macula densa (MD) cells in the JGA, there is a large production of NO from neuronal NOS. This production continuously reduces TGF sensitivity and is apparently impaired in animals that spontaneously develop hypertension. When we added an nNOS inhibitor to the drinking water for several weeks while measuring blood pressure, we found an increase in blood pressure after 3-4 weeks of treatment. This effect was abolished by a high salt diet. From these investigations, it also appeared as if nNOS-derived NO inhibited renin release. Experiments have also indicated that NO may resensitize inhibited G-protein coupled purinergic receptors.

Renin Angiotensin System Antagonists and Anesthesia

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

Different role of angiotensin II type 1 and type 2 receptors in renin release by interaction of angiotensin II and renal sympathetic nerve

Background. Angiotensin II (Ang II) is involved in the direct inhibition of renin release from juxtaglomerular (JG) cells in the kidney as the negative feedback loop of the renin-angiotensin system. Ang II also modulates renin release via the sympathetic nervous system, since the renal sympathetic nerves stimulate renin release, and the interaction of the sympathetic nervous system with Ang II has been demonstrated to occur at multiple levels.

Chronic nitric oxide inhibition model six years on.

The discovery in 1987 that endothelium-derived nitric oxide (NO) mediates the vasodilatory effect of certain endothelium-dependent agonists1 2 inaugurated the current huge field of NO biology. It is now recognized that NO plays essential roles in many diverse physiological processes and in some pathophysiologic events. Development of these concepts has been based largely on evidence obtained by limiting NO biosynthesis. This review is centered on the cardiovascular and particularly the renal functional and structural consequences of chronic pharmacologic NO inhibition by l-arginine analogues. We devoted special attention to the mechanisms of hypertension and organ injury that occur under these circumstances, while appreciating the inherent limitations surrounding interpretation of this data. NO is made by the enzymatic action of several widely distributed NO synthases (NOS). In the presence of the substrates l-arginine and oxygen, as well as a number of essential cofactors, NO is produced in response to appropriate stimuli. The constitutively expressed NOS play a major role in the physiological control of vascular tone and kidney function.3 4 Vascular endothelial NOS (eNOS) and brain-type NOS (bNOS) are widely distributed throughout the kidney5 as well as the cardiovascular system and in strategic locations in the peripheral and central nervous system (CNS).6 7 Both eNOS and particularly bNOS are abundant in the kidney, glomeruli, and vasculature as well as in most segments of the tubule,3 5 and NOS activity in medulla is considerably greater than in cortex.8 NO generated within the kidney controls the glomerular filtration rate (GFR), total renal and medullary blood flow, pressure natriuresis, epithelial sodium transport, and production of various vasoactive factors including renin.3 4 5 eNOS is distributed throughout most parts of the arterial and venous circulation, although there is considerable heterogeneity in the extent to which NO controls …