Blockade of the renin-angiotensin system was studied in male Sprague-Dawley rats during long-term inhibition of nitric oxide synthase. Nitro-L-arginine-methyl ester (L-NAME) was placed in the drinking water for 4 weeks (-100 nig/kg per day). Separate groups of rats were coadministered the angiotensin II antagonist A-81988 in the drinking water ranging from approximately 0.001 to 1 ing/kg per day. Control groups received only tap water or A-81988 alone. Each week, rats were placed in metabolic cages, and tail-cuff blood pressures and blood samples were taken. L-NAME produced a sustained elevation in tail-cuff pressure that was completely prevented by A-81988. No changes in creatinine clearance, sodium excretion, plasma creatinine concentration, or blood urea nitrogen were observed. Food and water intakes were identical in all groups. Water excretion was significantly increased in L-NAME-treated animals regardless of additional inhibitor treatment, suggesting a possible role for nitric oxide synthase in the control of water excretion; this effect was independent of blood pressure. Although less potent than A-81988, the angiotensin II antagonist losartan and the angiotensin converting enzyme inhibitor enalapril also blocked L-NAME-induced hypertension. In a separate series of experiments, rats were not given A-81988 until 2 weeks after hypertension had fully developed in L-NAME-treated rats. Within 1 week of treatment with the angiotensin II antagonist, tail-cuff pressure returned to normal. We conclude from these studies that long-term inhibition of endogenous nitric oxide production produces an angiotensin II-dependent form of hypertension. {Hypertension 1993;21:660-666) KEY WORDS • endothelium-derived relaxing factor • nitro-L-arginine-methyl ester • hypertension, essential • angiotensin converting enzyme inhibitors • renin-angiotensin system • kidney • rat studies • renal function T he endothelium-derived relaxing factor nitric oxide (NO) appears to play a significant role in the regulation of renal and systemic hemodynamics. One line of evidence that supports such a role is the observation of increased vascular resistance and blood pressure after acute inhibition of NO synthase, the enzyme responsible for production of NO and L-citrulline from L-arginine and oxygen.1 Recently, it has been reported that long-term inhibition of NO synthase will produce a sustained hypertension in otherwise normotensive rats or dogs.2 -4 This prolonged hypertension was associated with a mild degree of renal failure, as evidenced by decreases in glomerular filtration rate (GFR), proteinuria, and glomerular sclerotic injury. -4In addition to the enzyme present in vascular endothelium (type III), several isoforms of NO synthase have been identified in a variety of tissues, including the brain (type I).5 " 8 Interestingly, type I NO synthase is present in regions of the hypothalamus thought to be important in fluid-volume regulation, which suggests a role for this isoform in the central nervous

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Endothelins are ubiquitous in the canine lower GU tract with predominant localization to the epithelial elements. Endothelins are also functionally active in canine GU tissues, but the specific role of endothelins in the physiology and pathophysiology of GU tissues requires further investigation.