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.
Fujita
K
K
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.
Matsumura
Y
Y
Miyazaki
Y
Y
Takaoka
M
M
Morimoto
S
S
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004791:Enzyme Inhibitors; D007211:Indoles; D044022:Receptor, Endothelin A; C079574:FR 139317; D019335:Nitroarginine; D003900:Desoxycorticosterone; D001120:Arginine; D019001:Nitric Oxide Synthase