Role of endothelin-1 in hypertension induced by long-term inhibition of nitric oxide synthase.

We examined the effect of long-term nitric oxide (NO) synthase inhibition on vascular and renal endothelin-1 levels and evaluated the antihypertensive effect of endothelin ETA receptor antagonist FR139317 ((R)2(-)[(R)-2(-)[(S)-2(-)[[1-(hexahydro-1H-azepinyl)]- carbonyl]amino-4-methyl-pentanoyl]amino-3(-)[3-(1-methyl-1H- indolyl)]propionyl]amino-3-(2-pyridyl) proprionic acid] on rats in which NO synthase was blocked. Chronic NO blockade was produced by oral administration of the NO synthase inhibitor NG-nitro-L-arginine for 4 weeks, which produced sustained hypertension. At the end of this time, there were no significant changes in aortic and renal immunoreactive-endothelin levels between NG-nitro-L-arginine-treated hypertensive rats and normotensive control rats. Intravenous injection of FR139317 (10 mg/kg), which had a sufficient hypotensive effect on deoxycorticosterone acetate-salt hypertensive rats, to NG-nitro-L-arginine-treated hypertensive rats produced only a moderate hypotensive effect, to the same degree as seen in normotensive rats. The results indicate that long-term NO synthase inhibition did not affect vascular and renal endothelin-1 levels in these rats. It seems likely that endothelin-1 and ETA receptors do not contribute to the sustained hypertension induced by NO synthesis blockade.