Changes in mean arterial pressure predict degranulation of renomedullary interstitial cells

1. Renomedullary interstitial cells (RMIC) are characterized by numerous intracellular granules thought to contain renal medullary antihypertensive substances. However, the nature of the trigger for RMIC degranulation remains to be elucidated. The present study examines the effects of acute alterations in mean arterial pressure (MAP) and medullary blood flow (MBF) on RMIC granulation. 2. Basal MAP and MBF in anaesthetized Sprague-Dawley rats (n = 4/group) were altered by intravenous infusions of vasoactive agents, including angiotensin II alone or with a nitric oxide (NO) synthase inhibitor (N-omega-nitro-l-arginine) or NO donor (sodium nitroprusside), noradrenaline and by carotid artery clamping. Following these treatments, kidneys were examined by electron microscopy and the absolute volume of granules in the renal medulla was calculated using unbiased stereological methods. 3. Acute increases in MAP, regardless of the treatment causing the increase, were associated with a reduction in the absolute volume of granules in the range of 42-67%. Regression analysis revealed that only increases in MAP, but not MBF, strongly predict RMIC degranulation. 4. Despite previous reports that changes in MBF activate renomedullary antihypertensive activity, we conclude that the change in MAP is an important determinant of the activity of the blood pressure-lowering mechanism of the renal medulla, with the assumption that the medullary lipids mediate the antihypertensive property of the renal medulla.     

Role of renal medullary oxidative and/or carbonyl stress in salt-sensitive hypertension and diabetes

1. Salt-sensitive hypertension is commonly associated with diabetes, obesity and chronic kidney disease. The present review focuses on renal mechanisms involved in the development of this type of hypertension. 2. The renal medullary circulation plays an important role in the development of salt-sensitive hypertension. In vivo animal studies have demonstrated that the balance between nitric oxide (NO) and reactive oxygen species (ROS) in the renal medulla is an important element of salt-sensitive hypertension. The medullary thick ascending limb (mTAL) in the outer medulla is an important source of NO and ROS production and we have explored the mechanisms that stimulate their production, as well as the effects of NO superoxide and hydrogen peroxide on mTAL tubular sodium reabsorption and the regulation of medullary blood flow. 3. Angiotensin II-stimulated NO produced in the mTAL is able to diffuse from the renal mTAL to the surrounding vasa recta capillaries, providing a mechanism by which to increase medullary blood flow and counteract the direct vasoconstrictor effects of angiotensin II. Enhanced oxidative stress attenuates NO diffusion in this region. 4. Carbonyl stress, like oxidative stress, can also play an important role in the pathogenesis of chronic kidney disease, such as insulin resistance, salt-sensitive hypertension and renal vascular complications. 5. Despite the large number of studies undertaken in this area, there is as yet no drug available that directly targets renal ROS. Oxidative and/or carbonyl stress may be the next target of drug discovery to protect against salt-sensitive hypertension and associated end-organ damage.     

NITRIC OXIDE IN THE MEDIATION OF PRESSURE NATRIURESIS

1. Recent studies have indicated that nitric oxide (NO) production in the kidney contributes to the regulation of renal haemodynamics and excretory function. Inhibition of nitric oxide synthase (NOS) reduces renal blood flow by approximately 25% and markedly reduces sodium excretion without reductions in filtered load. In particular, inhibition of NO synthesis markedly suppresses the slope of the arterial pressure-mediated response in sodium excretion. 2. Further studies have shown that constant intrarenal infusion of a NO donor in dogs treated with a NOS inhibitor produced diuretic and natriuretic responses but failed to restore the slope of the pressure-induced natriuretic response. These data indicate that an alteration in intrarenal NO activity, rather than the simple presence of NO during changes in arterial pressure is required for full expression of pressure natriuretic responses. 3. In support of the hypothesis that NO is involved in the mediation of pressure natriuresis, we also recently demonstrated a direct relationship between changes in arterial pressure and urinary excretion rate of sodium as well as nitrate and nitrite (a marker for endogenous NO activity) in the presence of efficient autoregulation of cortical and medullary blood flow. 4. The direct inhibitory actions of NO on tubular sodium reabsorption have also been observed in cultured tubular cells as well as isolated, perfused cortical collecting duct segments. 5. Thus, the collective data suggest that acute changes in arterial pressure induce changes in intrarenal NO production, which may directly alter tubular reabsorptive function to manifest the phenomenon of pressure natriuresis.     

Molecular mechanisms and therapeutic strategies of chronic renal injury: physiological role of angiotensin II-induced oxidative stress in renal medulla

Renal medullary circulation has now been found to play a fundamental role in regulating long-term blood pressure control and fluid balance. Elevation of superoxide or reduction of nitric oxide (NO) in renal medulla decreases medullary blood flow and Na excretion, resulting in sustained hypertension. Angiotensin II (Ang II)-induced interaction of superoxide and NO was determined in thin tissue strips isolated from the renal outer medullary region of Sprague-Dawley rats using fluorescent microscopy techniques. Ang II can induce diffusion of NO, but not superoxide, from the medullary thick ascending limb (mTAL) to the surrounded vasa recta. However, when NO is reduced by the NO scavenger carboxy-PTIO, Ang II can induce superoxide diffusion from mTAL to vasa recta pericytes. Therefore, the physiological action of oxidative stress in renal medullary region is demonstrated as balance of superoxide and NO diffusion ("tubulo-vascular cross-talk"). These results explain how chronically hypoxic medulla can maintain blood flow. In other studies using chronically instrumented rats, we found that nearly 70% of Ang II-induced medullary renal injury was dependent on pressure determined by servo-control of renal perfusion pressure, whereas 30% of the injury was non-hemodynamic. We conclude that oxidative stress within the renal medulla can induce hypertension and also make the kidney functionally more vulnerable to the effects of Ang II.     

NITRIC OXIDE, THE KIDNEY AND HYPERTENSION

1. According to the renal body fluid feedback mechanism for long-term control, persistent hypertension can only occur as a result of a reduction in renal sodium excretory function or a hypertensive shift in the pressure natriuresis relationship. Although an abnormal relationship between renal perfusion pressure and renal sodium excretion has been identified in every type of hypertension where it has been sought, factors responsible for this effect are still unclear. 2. Nitric oxide (NO) is produced within the kidney and plays an important role in the control of many intrarenal processes that regulate the renal response to changes in perfusion pressure and, thus, help determine systemic vascular volume and blood pressure. Numerous studies have shown that long-term inhibition of NO synthesis results in a chronic hypertensive shift in renal pressure natriuresis. 3. Recent studies have shown that certain animal models of genetic hypertension and forms of human hypertension areas are associated with a decrease in NO synthesis. Reductions in NO synthesis reduce renal sodium excretory function, not only through direct actions on the renal vasculature, but through modulation of other vasoconstrictor processes and through direct and indirect alterations in tubular sodium transport. 4. The causes and consequences of the disregulation of NO in hypertension and other renal disease processes remain an important area of investigation.     

Renomedullary interstitial cells: a target for endocrine and paracrine actions of vasoactive peptides in the renal medulla

1. The renal medulla plays an important role in regulating body sodium and fluid balance and blood pressure homeostasis through its unique structural relationships and interactions between renomedullary interstitial cells (RMIC), renal tubules and medullary vasculature. 2. Several endocrine and/or paracrine factors, including angiotensin (Ang)II, endothelin (ET), bradykinin (BK), atrial natriuretic peptide (ANP) and vasopressin (AVP), are implicated in the regulation of renal medullary function and blood pressure by acting on RMIC, tubules and medullary blood vessels. 3. Renomedullary interstitial cells express multiple vasoactive peptide receptors (AT1, ETA, ETB, BK B2, NPRA and NPRB and V1a) in culture and in tissue. 4. In cultured RMIC, AngII, ET, BK, ANP and AVP act on their respective receptors to induce various cellular responses, including contraction, prostaglandin synthesis, cell proliferation and/or extracellular matrix synthesis. 5. Infusion of vasoactive peptides or their antagonists systemically or directly into the medullary interstitium modulates medullary blood flow, sodium excretion and urine osmolarity. 6. Overall, expression of multiple vasoactive peptide receptors in RMIC, which respond to various vasoactive peptides and paracrine factors in vitro and in vivo, supports the hypothesis that RMIC may be an important paracrine target of various vasoactive peptides in the regulation of renal medullary function and long-term blood pressure homeostasis.     

Altered renal medullary blood flow: A key factor or a parallel event in control of sodium excretion and blood pressure?

In the context of the ongoing debate on the mechanism of blood pressure (BP) regulation and pathophysiology of arterial hypertension (“renocentric” vs “neural” concepts), attention is focused on the putative regulatory role of changes in renal medullary blood flow (MBF). Experimental evidence is analysed with regard to the question whether an elevation of BP and renal perfusion pressure (RPP) is likely to increase MBF due to its impaired autoregulation. It is concluded that such increases have been clearly documented only in rats with extracellular fluid volume expansion. A possible translation of this finding to BP regulation in health and hypertension in humans may only be a matter of speculation. Within the “renocentric” theory, the key event leading to restoration of initial BP level is pressure natriuresis. Its relation to elevation of renal interstitial hydrostatic pressure and to the phenomenon of “wash-out” of renal medullary solutes by increasing MBF is discussed. We also assessed the validity of data supporting the putative mechanism of short-term restoration of elevated BP owing to the release of a vasodilator lipid (medullipin) by the medulla. The structure of the proposed medullary lipid is still undefined, and there is no sound evidence on its mediatory role in lowering elevated BP level. In conclusion, MBF change can hardly be regarded as a crucial event in the regulation of BP: it can be involved in the control of sodium excretion and BP only in some circumstances, although its contributory role cannot be excluded.     

DOI, a 5-HT2 receptor agonist, induces renal vasodilation via nitric oxide in anesthetized dogs

We have previously reported that (+/-)-1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, induced renal vasodilation in anesthetized dogs. The present study was designed to investigate whether DOI-induced renal vasodilation might be mediated by increased nitric oxide (NO) release/production in renal tissue. The experiments were performed in anesthetized dogs. A 23-gauge needle was inserted into the left renal artery for infusion of drug solutions. Renal blood flow was measured with an electromagnetic flowmeter. The microdialysis probes were implanted into the renal cortex to collect the dialysate for measurement of guanosine 3',5'-cyclic monophosphate (cGMP) and nitrite/nitrate (NO2/NO3) concentration. Intrarenal infusion of DOI at a rate of 5 microg/kg/min resulted in a significant increase, by 30 +/- 4%, in renal blood flow, indicating renal vasodilation. The renal interstitial concentrations of NO2/NO3 and cGMP also increased by 70 +/- 6% and 60 +/- 6%, respectively. These changes induced by DOI were completely abolished by the intrarenal pretreatment with N(w)-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor, 100 microg/kg/min) or sarpogrelate (100 microg/kg/min, a highly selective 5-HT2 receptor antagonist). DOI infusion increased urine volume and urinary excretion of Na+, which were also blocked by L-NAME or sarpogrelate. These results suggest that DOI caused renal vasodilation due to increased NO release/production by stimulation of 5-HT2 receptors in the kidney. The natriuretic effect of DOI might also be related to increased intrarenal NO production.     

Dilator and constrictor response of renal vasculature during acute renal hypotension in anesthetized goats. Role of nitric oxide

The relative role of NO derived from endothelium NO synthase (eNOS) and neuronal NO synthase (nNOS) in renovascular reactivity during renal hypotension is unknown. To examine this issue, we recorded the effects of unspecific inhibitor of NO synthase N(w)-nitro-L-arginine methyl esther (L-NAME) and inhibitor of nNOS 7-nitroindazole monosodium salt (7-NINA) on renal vasodilator and vasoconstrictor responses in anesthetized goats during renal hypotension by constricting the abdominal aorta. Intrarenal administration of L-NAME and hypotension, either untreated or treated with L-NAME, decreased resting renal blood flow, and the increases in renal blood flow by acetylcholine but not those by sodium nitroprusside were tempered, and the decreases by norepinephrine and angiotensin II were augmented. Intraperitoneal administration of 7-NINA did not affect, and 7-NINA+hypotension decreased renal blood flow, and under these conditions the increases in renal blood flow by acetylcholine and sodium nitroprusside were not modified, and the decreases by norepinephrine and angiotensin II were slightly (during 7-NINA) or consistently augmented (7-NINA+hypotension). Therefore, NO derived from eNOS plays a significant role, while that derived from nNOS plays a little role, if any, to regulate renal blood flow and to mediate acetylcholine-induced vasodilation, as well to modulate renal vasoconstriction by norepinephrine and angiotensin II.     

Renal medullary interstitial infusion is a flawed technique for examining vasodilator mechanisms in anesthetized rabbits

INTRODUCTION: In rats, medullary interstitial (IMI) infusion is a useful technique for selective delivery of pharmacological agents to the renal medulla, in both acute and chronic experimental settings. We examined the feasibility of using this technique for delivery of vasodilators in rabbits, since this larger species would provide a number of advantages, particularly in long-term studies of circulatory control. METHODS: Rabbits were anesthetized with pentobarbitone and artificially ventilated. Catheters were placed in a side branch of the renal artery and/or the renal medullary interstitium. Renal blood flow (RBF) was determined by transit-time ultrasound flowmetry, and blood flow in the cortex and medulla was estimated by laser Doppler flowmetry. RESULTS: Pilot studies showed that renal arterial (IRA) infusions of bradykinin (10-300 ng/kg/min) and adenosine (1-10 ng/kg/min) produced only transient renal vasodilatation. IRA infusions of methylamine hexamethylene methylamine (MAHMA) NONOate (100-1000 ng/kg/min) and acetylcholine (10-250 ng/kg/min) produced dose-dependent and sustained increases in RBF and reductions in arterial pressure at the highest doses. However, IMI infusion of the same doses did not consistently increase medullary laser Doppler flux (MLDF). After IRA MAHMA NONOate and IMI acetylcholine, RBF fell to below its resting level. IRA boluses of acetylcholine (10-1250 ng/kg), bradykinin (2-250 ng/kg), and MAHMA NONOate (100-3000 ng/kg) dose-dependently increased RBF and CLDF and MLDF. DISCUSSION: We had previously validated the IMI infusion technique for intramedullary delivery of vasoconstrictors in rabbits. Our present results indicate that this technique has limited application for delivery of vasodilator agents, in part because counterregulatory vasoconstrictor mechanisms are activated.     

INTRARENAL BLOOD FLOW: MICROVASCULAR ANATOMY AND THE REGULATION OF MEDULLARY PERFUSION

1. The microcirculation of the kidney is arranged in a manner that facilitates separation of blood flow to the cortex, outer medulla and inner medulla. 2. Resistance vessels in the renal vascular circuit include arcuate and interlobular arteries, glomerular afferent and efferent arterioles and descending vasa recta. 3. Vasoactive hormones that regulate smooth muscle cells of the renal circulation can originate outside the kidney (e.g. vasopressin), can be generated from nearby regions within the kidney (e.g. kinins, endothelins, adenosine) or they can be synthesized by adjacent endothelial cells (e.g. nitric oxide, prostacyclin, endothelins). 4. Vasoactive hormones released into the renal inner medullary microcirculation may be trapped by countercurrent exchange to act upon descending vasa recta within outer medullary vascular bundles. 5. Countercurrent blood flow within the renal medulla creates a hypoxic environment. Relative control of inner versus outer medullary blood flow may play a role to abrogate the hypoxia that arises from O₂ consumption by the thick ascending limb of Henle. 6. Cortical blood flow is autoregulated. In contrast, the extent of autoregulation of medullary blood flow appears to be influenced by the volume status of the animal. Lack of medullary autoregulation during volume expansion may be part of fundamental processes that regulate salt and water excretion.     

Effects of nitric oxide synthase inhibition with or without cyclooxygenase-2 inhibition on resting haemodynamics and responses to exendin-4

BACKGROUND AND PURPOSE: Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation. Here we measured the effects of acute cyclooxygenase-2 inhibition (with parecoxib), alone and in combination with NOS inhibition (with NG-nitro-L-arginine methyl ester (L-NAME)), on resting cardiovascular variables and on responses to the glucagon-like peptide 1 agonist, exendin-4, which causes regionally-selective vasoconstriction and vasodilatation. EXPERIMENTAL APPROACH: Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious, freely moving state. L-NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle, and exendin-4 was given 60 min after the onset of L-NAME infusion. KEY RESULTS: Parecoxib had no effect on resting cardiovascular variables or on responses to L-NAME. Exendin-4 caused a pressor response accompanied by tachycardia, mesenteric vasoconstriction and hindquarters vasodilatation. Parecoxib did not affect haemodynamic responses to exendin-4, but L-NAME inhibited its hindquarters vasodilator and tachycardic effects. When combined, L-NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response. CONCLUSIONS AND IMPLICATIONS: Cyclooxygenase-2-derived products do not affect basal haemodynamic status in conscious normotensive rats, or influence the NO system acutely. The inhibitory effects of L-NAME on the hindquarters vasodilator and tachycardic effects of exendin-4 are consistent with a previous study that showed those events to be beta-adrenoceptor mediated. The additional effect of parecoxib on responses to exendin-4 in the presence of L-NAME, is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced.     

INTERACTION OF VASOPRESSIN, ANGIOTENSIN AND α-ADRENERGIC SYSTEM IN SODIUM DEPLETION IN THE RAT

1. The role of vasopressin in cardiovascular adaptation to sodium depletion was examined in rats after 6 days on a low sodium diet. Studies were performed after selective or combined blockade with d(CH2)5 Tyr(Me)AVP (AVPA), enalaprilat (CEI) and phentolamine (PHENTOL). AVPA alone had no effect on systemic haemodynamics or regional blood flow distribution. After CEI or PHENTOL pretreatment, AVPA led to significant falls in peripheral resistance and increases in cardiac output and renal blood flow. In sodium depletion, endogenous vasopressin acts as a vasoconstrictor hormone, particularly in the kidney, when either the renin-angiotensin or alpha-adrenergic system is inhibited.     

RENAL HAEMODYNAMIC AND EXCRETORY RESPONSES TO BRADYKININ IN ANAESTHETIZED DOGS

1. Effects of bradykinin (BK) on renal haemodynamics and urine formation were examined in anaesthetized dogs. 2. Renal arterial infusion of BK at doses of 5 or 50 ng/kg per min produced dose-dependent increases in renal blood flow (RBF), without affecting systemic arterial pressure or glomerular filtration rate. There were also significant and dose-dependent increases in urine flow (UF), urinary excretion of sodium (UNaV) and fractional excretion of sodium (FENa) and decreases in urine osmolality during BK infusion. 3. Renal haemodynamic and excretory responses to the BK infusion were completely abolished by the simultaneous administration of Hoe 140 (icatibant, 100 ng/kg per min intrarenally), a selective BK B2-receptor antagonist. 4. In the presence of NG-nitro-L-arginine (NOARG; 40 micrograms/kg per min intrarenally), a nitric oxide (NO) synthase inhibitor, BK-induced renal vasodilative and natriuretic effects were markedly attenuated, although responses of UF and urine osmolality to BK remained unchanged. The water diuretic effect of BK was abolished in dogs given both NOARG and ibuprofen (12.5 mg/kg bolus injection plus 12.5 mg/kg per h of sustained infusion intravenously), a cyclooxygenase inhibitor. 5. These results clearly indicate that renal haemodynamic and excretory responses to BK were mediated exclusively by the B2-receptor. Renal vasodilative and natriuretic responses are mainly linked to NO generation, while both NO and prostaglandin biosynthesis are involved in the BK-induced water diuresis.     

EFFECTS OF FR139317 ON RENAL RESPONSES TO ACUTE NITRIC OXIDE BLOCKADE IN ANAESTHETIZED RATS

1. Effects of FR139317, an endothelin ET_A receptor antagonist, on renal haemodynamic and excretory responses to acute nitric oxide (NO) blockade were examined using anaesthetized rats. 2. Intrarenal arterial infusion of N^G-nitro-l -arginine (NOARG), the NO synthase inhibitor, at a rate of 40 μg/kg per min, produced a significant decrease in renal blood flow, with no change in systemic blood pressure. There were significant decreases in urine flow and urinary excretion of sodium during infusion of NOARG. In animals pretreated with FR139317, similar renal responses to the NOARG infusion were observed. 3. These results suggest that an action of endothelin-1 via ET_A receptors does not greatly contribute to the renal haemodynamic and excretory responses to acute blockade of renal NO production.     

PATHWAYS LINKING RENAL EXCRETION AND ARTERIAL PRESSURE WITH VASCULAR STRUCTURE AND FUNCTION

1. A brief review is presented which summarizes the role of the kidney in the long-term regulation of arterial pressure and the mechanism whereby changes in body fluid volume can influence the function and structure of the systemic vasculature. 2. Studies indicate that the kidney detects changes of arterial pressure via changes of medullary blood flow which in the volume expanded state is poorly autoregulated. Elevations of renal arterial pressure raise vasa recta capillary pressure and renal interstitial fluid pressure, which in turn reduces tubular reabsorption of sodium and water. 3. The sensitivity of the pressure-diuresis relationship is controlled by renal sympathetic nerve activity and a variety of hormone and autocrine systems. 4. Evidence is also reviewed which shows that small changes of blood volume (5%) resulting from reduced renal excretion can acutely and chronically result in 25% increases of total peripheral resistance and arterial pressure. 5. Short-term increases of vascular resistance are predicted by regional autoregulatory responses while long-term elevations of vascular resistance appear to result from the structural changes of large vessel hypertrophy and microvascular rarefaction within skeletal muscle.     

New concepts in endothelin control of sodium balance

1. Endothelin (ET)-1, which was originally found to be secreted by the vascular endothelium, is highly expressed in the kidney, particularly in the renal medulla. 2. Recent studies using genetic models have provided significant breakthroughs in the role of ET-1 in the kidney. For example, ET-1 in the medullary collecting duct physiologically regulates water and salt reabsorption, thereby controlling blood pressure. Surprisingly, to explain the blood pressure regulation both ET(A) and ET(B) receptors are necessary in collecting duct. In fact, we recently revealed that ET(A) receptor stimulation in the renal medulla was natriuretic and diuretic. 3. The expression and secretion of ET-1 in the renal medulla are regulated by multiple mechanisms, such as changes in osmolality, exaggerated renin-angiotensin system activity and hypoxia. The changes in the renal medullary ET system are likely to work as compensatory 'protective' natriuretic factors in response to high sodium exposure in the kidney. 4. In the present review, we focus on recent publications that describe our current knowledge of the functional role of renal medullary ET-1, including the recently characterized actions of ET(A) receptors, the second messenger systems, mechanisms of stimulating ET-1 production and how the ET system is involved in the development of hypertension.     

THE EFFECT OF RENAL DENERVATION ON ACTH-INDUCED HYPERTENSION IN SHEEP

1. The effect of renal denervation on ACTH-induced hypertension in sheep has been examined. 2. Both intact and renally denervated sheep showed similar rises in blood pressure following ACTH treatment. 3. Following renal denervation, the initial urinary sodium retention and ACTH-withdrawal natriuresis typical of ACTH administration in intact sheep were absent, and the fall in blood pressure was delayed.     

DIFFERENTIAL BLOCKADE OF THE RENAL VASOCONSTRICTOR AND DIURETIC RESPONSES TO ENDOTHELIN-1 BY ENDOTHELIN ANTAGONIST

1. The effect of cyclo(d-Trp-d-Asp—Pro-d-Val—Leu) (or BQ123), a selective ETa receptor antagonist, on the vasoconstrictor and diuretic responses elicited by endothelin-1 (ET-1) was examined in conscious sheep with chronic indwelling renal arterial cannulae. 2. Using low dose close renal arterial infusion, ET-1 has potent effects on the kidney causing a marked decrease in effective renal plasma flow and an increase in urine output and free water clearance in the normally hydrated animal. 3. The vasoconstrictor response to renal arterial infusion of ET-1 at 5 μg/h was blunted by renal arterial infusion of the ET_A receptor selective antagonist, BQ123 (400 μg/h). 4. In contrast, the effect of ET-1 on urine production and free water clearance was not affected by this dose of BQ123. 5. The differential effect of BQ123 on renal blood flow and urine production suggests that these effects of endothelin on the kidney are mediated through different receptor mechanisms.     

EFFECTS OF SARAFOTOXIN S6c ON RENAL HAEMODYNAMICS AND URINE FORMATION IN ANAESTHETIZED DOGS

1. The effects of sarafotoxin S6c (S6c), a selective endothelin ETB receptor agonist, on renal haemodynamics and urine formation were examined in anaesthetized dogs. 2. Intrarenal arterial infusion of S6c at a rate of 1 or 5 ng/kg per min produced a transient increase in renal blood flow (RBF), with no change in systemic blood pressure and heart rate; RBF then decreased gradually to below the basal value. There were significant and dose-dependent increases in urine flow and free water clearance and decreases in urine osmolality during S6c infusion, whereas urinary excretion of sodium and glomerular filtration rate (GFR) remained unchanged. Simultaneously, S6c administration elicited a marked increase in urinary excretion of nitric oxide (NO) metabolites, N0₂^? and N0₃^? (UNO*V). 3. In dogs simultaneously administered S6c (5 ng/kg per min) and iV^G-nitro-L-arginine (NOARG; 40 (jig/kg per min), a NO synthase inhibitor, the renal vasodilator effect of S6c was abolished and marked reductions in RBF and GFR were observed. The S6c-induced diuretic action was not affected by NOARG. In the presence of NOARG, there was a small amount of UNO_xV at the basal level and the administration of S6c did not increase UNOxV. 4. These results suggest that an intrarenal arterial infusion of S6c enhances the production of NO in the kidney and that this enhancement contributes to the peptide-induced renal vasodilation. In contrast, it is unlikely that S6c-induced water diuresis is related to NO production stimulated by this peptide.