Endogenous Vasoactive Systems and the Pressor Effect of Acute N ω-Nitro-L-Arginine Methyl Ester Administration

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Abstract
Summary: The contribution of the renin-angiotensin system (RAS) and various endogenous vasoconstrictors on the pressor response to acute N ω-nitro-L-arginine methyl ester (L-NAME) administration (200 μg/kg/min) was assessed in anesthetized Wistar rats. Activity of the endogenous RAS was suppressed either by chronic treatment by a nonpeptide angiotensin II (AII) receptor antagonist (losartan) or an angiotensin-converting enzyme inhibitor (ACEI: enalapril), DOCA-salt pretreatment (without previous uninephrectomy), and binephrectomy (36–40 hours before experiments). We also studied the influence of chronic dietary sodium restriction. The role of α1-adrenoceptor activity, endothelin (ET), and eicosanoids was evaluated in rats pretreated by prazosin, phosphoramidon (a nonspecific blocker of the conversion of big ET to ET), indomethacin, and the tromboxane A2 (TXA2) prostaglandin H2 (PGH2)-receptor antagonist SQ 29548, respectively. Finally, we tested the influence of the calcium channel blocker nicardipine on the vasopressor effect of L-NAME. In nonpretreated animals, L-NAME in fusion induced an increase in mean arterial pressure (MAP) of 38 ± 4 mm Hg. Chronic suppression of the RAS by losartan, enalapril, or DOCA did not alter the response to L-NAME, but the effect of L-NAME was moderately blunted in binephrectomized rats. Moderate attenuation (∼25%) and to a similar extent of the pressor effect of L-NAME was afforded by the low-sodium diet, phosphoramidon, SQ 29548, and indomethacin, whereas nicardipine markedly blunted by 74% the effect of L-NAME. We conclude that the acute pressor effect of L-NAME is mediated (at least in part) by cyclooxyenase-dependent products (mainly TXA2) and ET, but not by the RAS. Unmasking by L-NAME of the vasoconstrictor effect of endogenous vasoconstrictors of endothelial origin (TXA2, ET) may be an important contributor to the acute pressor effect of nitric oxide (NO) synthesis inhibition.

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