SR141716A-sensitive enhancement of ET-1 hypotensive effect by chronic NOS inhibition.
The present study evaluated the potential mechanism involved in the hypotensive effect induced by ET-1 in rats treated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the drinking water during 7 days. Hypertension developed in the L-NAME-treated rats (164+/-3 versus 112+/-1 mm Hg in untreated control rats), and the hypotensive effect of ET-1 (100 pmol/kg IV) was significantly enhanced compared with control rats (32+/-2% versus 20+/-1% fall in mean arterial pressure). The enhanced ET-1 hypotensive effect in L-NAME-treated rats was abolished by the ETB receptor antagonist BQ-788 but was unaltered by the cyclooxygenase inhibitor diclofenac, the cytochrome P450 inhibitor fluconazole, or the potassium channel blockers apamin, glibenclamide, tetraethylammonium, and 4-aminopyridine. Pretreatment with the cannabinoid CB1 receptor antagonist SR141716A significantly reduced the hypotensive response to ET-1 in L-NAME-treated rats (20+/-1%), although it did not modify the response in untreated control rats (17+/-1%). These findings indicate that in rats under chronic NOS inhibition, the hypotensive effect of ET-1 is unexpectedly enhanced and appears to be mediated by a non-NO/non-prostanoid mechanism and involves an SR141716A-sensitive mechanism triggered by ETB receptor activation.
Souza
Hugo C D
HC
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Salgado
Helio C
HC
Ballejo
Gustavo
G
Salgado
Maria Cristina O
MC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D014665:Vasodilator Agents / Q000494:pharmacology*
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014665:Vasodilator Agents; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester