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(Hypertension. 2003;42:802.)
© 2003 American Heart Association, Inc.

Scientific Contributions

SR141716A-Sensitive Enhancement of ET-1 Hypotensive Effect by Chronic NOS Inhibition

Hugo C.D. Souza; Helio C. Salgado; Gustavo Ballejo; Maria Cristina O. Salgado

From the Departments of Pharmacology and Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.

Correspondence to Dr Maria Cristina O. Salgado, Department of Pharmacology, School of Medicine-USP, 14049-900 Ribeirão Preto, SP, Brazil. E-mail mcdosalg{at}fmrp.usp.br

The present study evaluated the potential mechanism involved in the hypotensive effect induced by ET-1 in rats treated with the NO synthase inhibitor N^G-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 ET_B 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 ET_B receptor activation.

Key Words: endothelin • L-NAME • nitric oxide • prostaglandins • potassium channels