NITRIC-OXIDE AND PROSTAGLANDINS IN THE PROLONGED EFFECTS OF LOSARTAN AND RAMIPRIL IN HYPERTENSION

We investigated the role of endogenous nitric oxide, kinins, and prost aglandins in the vasodepressor and renal excretory effects of the angi otensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor ramipril administered for 1 week to spontaneously hy pertensive rats. To this end, either losartan (10 mg/kg per day) or ra mipril (2.5 mg/kg per day) was administered in drinking water with or without simultaneous administration of (1) the nitric oxide synthesis inhibitor N-G-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg per day), (2) the cyclooxygenase inhibitor indomethacin (5 mg/kg per day), (3) the bradykinin B-2 receptor antagonist Hoe 140 (0.5 mg/kg per day SC), or (4) L-NAME plus indomethacin. Both losartan and ramipril significa ntly reduced blood pressure as measured by the tail-cuff method. L-NAM E increased brood pressure when administered solely or in combination with losartan. However, L-NAME attenuated the hypotensive effect of ra mipril. Indomethacin did not affect blood pressure but it reduced the antihypertensive action of losartan and ramipril. Indomethacin adminis tration did not potentiate the increase in blood pressure induced by L -NAME. However, the concurrent administration of both inhibitors almos t totally blunted the vasodepressor action of ramipril. By contrast, l osartan administration in the presence of L-NAME and indomethacin incr eased blood pressure to a level similar to that after losartan plus L- NAME. Hoe 140 did not modify either blood pressure or the hypotensive effects of losartan or ramipril. Increases in diuresis and water intak e were observed during ramipril administration. Both effects were blun ted only with the concurrent administration of L-NAME and indomethacin . None of the cotreatments were able to modify renal excretory functio n by themselves. These data suggest a contribution of endogenous nitri c oxide and prostaglandins but not of kinins in the prolonged antihype rtensive effect of both losartan and ramipril in the spontaneously hyp ertensive rat.