Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition.

Abstract

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

Pressure Natriuresis in AT2 Receptor–Deficient Mice with L-NAME Hypertension

“…However, there is evidence that the renin-angiotensin system is largely responsible for renal and systemic alterations when NO synthesis is reduced. Chronic AT 1 receptor blockade or converting enzyme inhibition prevents the development of hypertension after L-NAME (6). Furthermore, the L-NAME-induced BP increase was completely reversed by AT 1 receptor blockade in both AT 2 Ϫ/Ϫ and AT 2 ϩ/ϩ mice, underscoring the importance of the AT 1 receptor for BP changes after L-NAME.…”

“…Furthermore, L-NAME treatment reduced in AT 2 ϩ/ϩ mice renal AT 1 receptor expression, whereas the AT 1 receptor expression in AT 2 Ϫ/Ϫ mice was not significantly changed. L-NAME application produces an AngII-dependent form of hypertension (6). The physiologic results on sodium and water reabsorption and renal hemodynamic may have been aggravated in AT 2 Ϫ/Ϫ mice by the deletion of the AT 2 receptor and the upregulation of the AT 1 receptor.…”

“…The renin-angiotensin system participates in the renal and systemic alterations induced by NO synthesis blockade (9). Chronic AT 1 receptor or converting enzyme blockade prevents the development of L-NAME hypertension (6,10). However, pretreatment with losartan had no effect on the impaired pressure natriuresis produced by NO-synthesis blockade in another study (11), suggesting that the AT 1 receptor may not or only partially be involved in L-NAME-induced changes.…”

Effect of angiotensin II on corpus cavernosum smooth muscle in relation to nitric oxide environment: in vitro studies in canines

“…10,12 It has recently been shown that the modulation of regional blood¯ow in vascular tissues depends in part on a balance between NO and Ang II, and that an imbalance between these substances can result in hypertension. 18,19 Administration of Ang II receptor antagonists has been shown to restore normal blood pressure and normal renal hemodynamics in humans with essential hypertension, as well as in experimental rats with spontaneous hypertension, 20 with hypertension induced by chronic NOS inhibition, 16 and with renovascular hypertensive disease. 21 Our results suggests that, as in conventional vascular tissue, a relative increase in Ang II in the modi®ed vascular tissue of the corpus cavernosum may contribute to erectile dysfunction.…”

Involvement of nitric oxide, but not prostaglandins, in the vascular sympathoinhibitory effects of losartan in the pithed spontaneously hypertensive rat

“…Recently, nitric oxide (NO) has been reported to be involved in the vasodilator and antihypertensive effects of losartan in different experimental models (Cachofeiro et al, 1992; Kumagai et al, 1993;Pollock et al, 1993;Sudhir et al, 1993) and to modulate sympathetic neurotransmission (Zanzinger et al, 1994). Moreover, in porcine cultured endothelial vascular smooth muscle cells (Jaiswal et al, 1991) and in rabbit vas deferens tissue (Catalioto et al, 1994), losartan has been reported to increase vasodilator prostaglandin (PGs) synthesis and/or release.…”