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Abstract

We have previously reported that N-ω-nitro-L-arginine-methyl ester (L-NAME)-induced hypertensive rats exhibited an enhanced expression of Gi proteins. In addition, losartan, AT1 receptor antagonist, has been shown to decrease L-NAME-induced increase in the blood pressure. The present study was designed to evaluate the involvement of AT1 receptor in L-NAME-induced alterations in blood pressure and G-protein adenylyl cyclase signaling pathway. L-NAME (70 mg/kg body weight), Losartan (10 mg/kg b.wt) alone or in combination were given orally for 4 weeks. Control group received only plain tap water. The expression of Giα-2 and Giα-3 proteins and mRNA was enhanced in L-NAME-treated rats which was reversed by losartan treatment. However, losartan alone did not alter the levels of Gi-α proteins or mRNA. On the other hand, the expression of Gsα was not altered by these treatments. Guanosine 5'-o-(3-thiophosphate) (GTPγS)- stimulated adenylyl cyclase activity in both control and L-NAME-treated groups, but the extent of stimulation was significantly attenuated in L-NAME-treated rats, which was reversed by losartan. Similarly, stimulation of adenylyl cyclase exerted by isoproterenol, 5'-N-ethylcarboxamideadenosine (NECA) glucagon, forskolin and sodium fluoride were diminished in L-NAME-treated rats and were reversed by losartan treatment. On the other hand, inhibition of forskolin-stimulated enzyme activity by low concentrations of GTPγS that was significantly enhanced in L-NAME- treated rats, was attenuated by losartan. In addition, oxotremorine- and angiotensin II-mediated inhibiton of adenylyl cyclase activity was completely attenuated in L-NAME-treated rats which was reversed by losartan. These results suggest the implication of AT1 receptor in L-NAME-induced enhanced expression of Giα proteins and hypertension.

(Supported by grant from Medical Research Council of Canada)

Losartan, L-NAME-induced hypertension, G-protein-adenylyl cyclase signaling
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© American Journal of Hypertension, Ltd. 2001
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