The potential role of nitric oxide in angiotensin II-receptor blockade

Angiotensin II (A II), the active component of the renin-angiotensin system, plays a major role in the regulation of blood pressure and renal function. A II actions are mediated by the interaction of this peptide with specific receptors that have been classified into two major types. AT1 and AT2. AT1 receptors have been associated with all of the known cardiovascular and renal effects of A II. Losartan, the first nonpeptide A II-receptor antagonist, exerts its antihypertensive action through the inhibition of A II binding to AT1 receptors. However, additional mechanisms seem to be involved in the actions of losartan in the rat. Administration of the nitric oxide (NO)-synthase inhibitor, NG-nitro-L-arginine methyl ester (LNAME), prevented the hypotensive effect induced by losartan in spontaneously hypertensive rats (SHR). Similarly, pretreatment with LNAME reduced the increases in renal plasma flow and glomerular filtration rate produced by this AT1-receptor antagonist in SHR. Furthermore, concurrent administration of the prostaglandin (PG)-synthesis inhibitor indomethacin attenuated vasodepressor, diuretic, and natriuretic effects of losartan in SHR. Finally, it should be mentioned that losartan was able to reduce the "ex vivo" vasoconstriction induced by phenylephrine in aortic rings from SHR. This effect was not observed in endothelium-denuded rings, suggesting a mediatory role of an endothelium-derived factor in this effect of losartan. Consequently, these data suggest a contributory role of NO and PGs in the vasodepressor and renal actions of AT1-receptor antagonists in SHR.