Activation of renin synthesis is dependent on intact nitric oxide production

Abstract

The present study investigated whether or not nitric oxide (NO) synthesis mediates mechanisms regulating activation of renin formation. Studies were performed on afferent arterioles freshly isolated from the rat kidney. We have shown previously that this preparation is a useful model to study regulation of renin synthesis and secretion. The expression of renin mRNA was assessed by ribonuclease protection assay, and total renin content and renin secretion by radioimmunoassay. In afferent arterioles isolated from rats treated with the angiotensin-converting enzyme inhibitor ramipril, renin mRNA levels, total renin content and renin secretion were increased threefold compared to untreated controls. Inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-NAME) in the ramipril-treated rats, abolished the increase in renin mRNA levels, total renin content and renin secretion. In other animals furosemide, a diuretic acting on macula densa cells, activated renin synthesis to a level similar to that found in the ramipril-treated group. Addition of L-NAME to the furosemide-treated rats suppressed the increases in renin mRNA levels, total renin content and renin secretion, suggesting that NO acts on renin activation by a mechanism independent of angiotensin II. In separate experiments, the inhibitory effect of L-NAME on the activation of renin secretion was abolished when afferent arterioles were treated with nicardipine, an L-type Ca2+ channel blocker, suggesting that the suppression of renin activation during NO inhibition is due to increased Ca2+ entry. Since endothelin is a potent mediator of Ca2+ influx and an inhibitor of renin release, we tested whether or not endothelin could be involved in the inhibitory effect of L-NAME on renin secretion. Application of the endothelin receptor antagonist, bosentan, in vitro mimicked the effect of nicardipine. In addition, bosentan coadministered with L-NAME in vivo blunted the inhibitory effect of L-NAME and restored the increases in renin mRNA level, synthesis and secretion. These data indicate that the physiological mechanism(s) regulating activation of renin synthesis and secretion are impaired during NO inhibition, probably because of increased Ca2+ influx. This increase in calcium flux is mediated at least partially by the action of endothelin.

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

“…These data indicate that the adenylyl cyclase-mediated mechanism regulating renin release is impaired when NO synthesis is inhibited. Tharaux et al (1997) reported that in afferent arterioles isolated from rats treated with ramipril, renin mRNA levels, total renin content, and renin secretion were increased compared with untreated controls, with the effect of ACE inhibition being abolished by L-NAME; similar data were found in the arterioles from furosemide-treated rats, suggesting that NO acts on renin activation by a mechanism independent of ANG II. The inhibitory effect of L-NAME on the activation of renin secretion was abolished when afferent arterioles were 80 treated with nicardipine, an L-type Ca 2ϩ channel blocker.…”

Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats

“…Tuning of NO/ ET-1 balance also regulates the VSMC phenotype in vivo. 11 In contrast, other investigators did not observe increased levels of ET-1 mRNA 26,27 or peptide 28 in aortas of rats chronically treated with L-NAME. However, as pointed out in these previous reports, aortic ET-1 synthesis may not reflect alterations of ET-1 levels in renal resistance vessels.…”

“…11 Vascular preparations containing Ͼ90% of preglomerular vessels were retained for subsequent experiments. The protein vascular content was measured according to Bradford's method.…”

Chronic Nitric Oxide Inhibition Model Six Years On

“…Several in vitro studies provided evidence that NO might act as an inhibitor of renin release. 58,59 However, other in vitro observations 60 and experiments in isolated perfused kidneys 61 suggested that NO stimulates the synthesis and/or secretion of renin. In addition, several investigators reported decreased circulating renin in the chronic NOS inhibition model, 28,29,51,62,63 even in animals in which PRA was initially elevated by restricted dietary sodium intake 62 or reduction of renal perfusion pressure.…”