The purpose of this study was to examine the role of endothelium-derived nitric oxide in modulating the effect of renal perfusion pressure (RPP) on renal interstitial hydrostatic pressure (RIHP) and urinary Na⁺ excretion (UNaV). The effects of RPP on renal hemodynamics, RIHP, and Na⁺ and Li⁺ excretions were determined in control Sprague-Dawley rats, in Sprague-Dawley rats pretreated with intravenous infusion of N^G-nitro-L-arginine methyl ester (L-NAME) at doses of 1, 5, and 50 µg/kg/min, and in rats pretreated with L-NAME (5 µg/kg/min) plus L-arginine (10 mg/kg/min). The RPP was changed from 95 to 135 mm Hg by an electronically servo-controlled aortic occluder above the renal arteries in all groups. Increasing RPP in control rats from 95 to 135 mm Hg increased RIHP (from 4.4 ± 0.5 to 8.7 ± 1.2 mm Hg), UNaV (from 2.37 ± 0.61 to 8.29 ± 1.59 µEq/min), and fractional excretion of Li⁺ (from 38.0 ± 2.5 to 51.4 ± 6.0%). In rats pretreated with L-NAME (5 µg/kg/min), increases in RPP from 95 to 135 mm Hg had no effect on RIHP (from 1.6 ± 0.4 to 2.2 ± 0.6 mm Hg) or fractional excretion of Li⁺ and markedly attenuated pressure-natriuresis relationship (from 1.84 ± 0.50 to 2.88 ± 0.65 µEq/min). Although L-NAME did reduce renal plasma flow and glomerular filtration rate, the autoregulatory responses to RPP were maintained. In rats pretreated with L-NAME plus L-arginine, RIHP, UNaV, and fractional excretion of Li⁺ responses to RPP were similar to the control rats. The results of this study indicate that endothelium-derived nitric oxide plays an important role in modulating the effect of RPP on Na⁺ excretion by enhancing the transmission of RPP into the renal interstitium.

We have shown that NO production, assessed by measuring changes in plasma nitrate concentration, is down-regulated when blood pressure falls. This study intended to determine first, whether NO-derived plasma nitrate varies in response to increases in blood pressure induced by different mechanical and pharmacologic stimuli, including angiotensin II and catecholamines; and second, specifically to study the interaction between angiotensin II and NO production. An intravenous infusion (4-10 min) of norepinephrine (7.5 microg/kg/min), phenylephrine (30 microg/kg/min), or angiotensin II (0.3 and 3 microg/kg/min) caused hypertension accompanied by an increase in plasma nitrate, as assessed by high-performance capillary electrophoresis. Mechanical hypertension elicited by aortic occlusion also was accompanied by an increase in plasma nitrate. Angiotensin II (0.03, 0.3, and 3 microg/kg/min, 10 min) dose-dependently increased blood pressure. The intermediate and high dose, but not the low dose, of angiotensin II increased plasma nitrate concentration. N(G)-nitro-L-arginine methyl ester (L-NAME) lowered the basal concentration of plasma nitrate, abolished the increase in plasma nitrate elicited by angiotensin II and norepinephrine, and potentiated the pressor effect of the low dose of angiotensin II, although this dose did not increase NO production. L-NAME also potentiated the pressor effects of the intermediate dose of angiotensin II. This study demonstrates that an augmented systemic production of NO, measured as an increase in plasma nitrate, takes place after acute hypertension. The results of this study suggest that an increase in NO generation occurs when angiotensin II hypertension exceeds a certain limit, below which the basal production of NO is sufficient to compensate the vasoconstriction.

Recent findings suggest that nitric oxide plays a pivotal role in maintaining homeostasis of the extracellular volume. This short review provides evidence supporting the important role of nitric oxide in the regulation of sodium excretion during increments of arterial pressure and in response to acute and prolonged increments of extracellular volume.

Abstract-The benefits of the simultaneous administration of low doses of a calcium antagonist and a converting enzyme inhibitor in the treatment of hypertension and renal vasoconstriction are well established. The objective of this study was to evaluate whether the administration of low doses of a calcium antagonist and a converting-enzyme inhibitor have beneficial effects in treating the renal alterations induced by the acute administration of a cyclooxygenase inhibitor when nitric oxide synthesis is reduced. These effects were examined in anesthetized dogs before and during an acute sodium load. It was found that the intrarenal infusion of meclofenamate (5 g ⅐ kg, produced a 40% decrease of renal blood flow and glomerular filtration rate and a reduction in the renal excretory response to the sodium load. In a second group of dogs, intrarenal verapamil (0.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was effective in blocking the effects of nitric oxide and prostaglandin synthesis inhibition on sodium excretion and glomerular filtration rate but did not modify the effects on renal blood flow. An intrarenal infusion of trandolapril (0.3 g ⅐ kg Ϫ1 ⅐ min Ϫ1) was effective in a third group of dogs in reducing the renal hemodynamic effects but not in preventing the antinatriuretic effect observed in the first group. Finally, in a fourth group, the simultaneous administration of verapamil and trandolapril was effective in treating all the renal changes induced by the cyclooxygenase inhibitor when nitric oxide synthesis was reduced. These results suggest that the combination of low doses of trandolapril and verapamil has additive effects in treating the renal vasoconstriction and antinatriuresis induced by the acute administration of a cyclooxygenase inhibitor, when nitric oxide synthesis is reduced. (Hypertension. 1998;31:657-664.) Key Words: vasoconstriction Ⅲ nitric oxide Ⅲ prostaglandin Ⅲ sodium sensitivity Ⅲ calcium antagonists converting enzyme inhibitors T he role of NO in mediating the renal response to short-and long-term increments in sodium intake is supported by studies showing that a decrease in NO synthesis reduces the renal ability to eliminate a sodium load and induces the development of sodium-sensitive hypertension.1-5 On the other hand, it has been suggested that there is an important interaction between NO and PG in the regulation of the renal hemodynamic and excretory function.2,3 The existence of this interaction is supported by the results obtained in acute studies showing that meclofenamate administration produces renal vasoconstriction and reduces the excretory response to an acute sodium load when NO synthesis is reduced.2,3 These results support the hypothesis that the intake of cyclooxygenase inhibitors can induce the development of hypertension and important changes in renal function in situations where NO synthesis is partially decreased. In support of this hypothesis, it has been reported that NO synthesis seems to be reduced in salt-sensitive hypertension 6 and that the administration of a cyclooxygenase inhi...

We examined the renal functional and hemodynamic changes induced by prolonged cyclooxygenase (COX) inhibition when angiotensin II levels are elevated during several consecutive days. The effects induced by the infusion of either initially subpressor or pressor angiotensin II doses (1 and 5 ng/kg/min) were examined in dogs with or without the simultaneous infusion of meclofenamate (5 microg/kg/min). Experiments were performed in conscious permanently instrumented dogs. Infusion of the lower angiotensin II dose alone (n = 6) caused a late 12+/-2% increase in arterial pressure, a 25+/-6% decrease in renal blood flow (RBF), and a transitory decrease in urinary sodium excretion. COX inhibition reduced the hypertension and renal vasoconstriction, but enhanced the sodium retention, induced by the lower dose angiotensin II infusion (n = 6). The higher angiotensin II dose (n = 6) caused a 25+/-4% increase in arterial pressure, a 24+/-5% decrease in RBF, and a transitory decrease in urinary sodium excretion. Finally, COX inhibition did not modify the renal effects elicited by the higher angiotensin II dose (n = 6). The results of this study suggest that endogenous prostaglandins play an important role in the regulation of the renal and systemic changes induced by prolonged administration of initially subpressor angiotensin II doses. It has also been demonstrated that prolonged COX inhibition does not modify the renal functional and hemodynamic changes elicited by the long-term infusion of a pressor angiotensin II dose.

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