CONTRIBUTION BY BRADYKININ TO THE NATRIURETIC RESPONSE TO THE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR RAMIPRILAT IN SPONTANEOUSLY HYPERTENSIVE RATS

It is well documented that angiotensin converting enzyme inhibitors decrease blood pressure, which is associated with natriuresis in humans and certain animal models of hypertension. However, it is not clear whether these beneficial effects are due solely to blockade of angiotensin-II production and/or also involves any contribution by kinins. The present study was performed in Inactin (R) (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium)-anesthetized spontaneously hypertensive rats aged 10-13 wks to examine the relative influence of the angiotensin receptor antagonist losartan (2-n-butyl-4chloro-5-hydroxymethyl- 1-[(2 '-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole potassium salt) and the bradykinin receptor 2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) on renal and hemodynamic responses to the angiotensin converting enzyme inhibitor ramiprilat. We found that ramiprilat (1 mg/kg, i.v.) caused sustained reduction in mean blood pressure, marked increases in urine output and urinary sodium excretion without alteration in glomerular filtration rate. In a separate group of animals, it was found that losartan (1mg/kg, i.v.) decreased blood pressure to a similar degree as ramiprilat and the magnitude of blood pressure fall seen following the combined administration of ramiprilat and losartan was similar to that caused by either compound alone. However, the increase in urinary sodium excretion seen following losartan administration was significantly smaller than that following ramiprilat or ramiprilat plus losartan. It was also found that HOE 140 (50 mu/kg, i.v.), which did not significantly affect both hemodynamic and renal parameters when administered alone, significantly attenuated the natriuretic and diuretic, but not the antihypertensive effect of ramiprilat. These results indicate that inhibition of angiotensin II formation accounts for the major portion of antihypertensive, diuretic and natriuretic effects of ramiprilat and that the accumulation of kinins contributes significantly to renal but not the acute antihypertensive effects of ramiprilat.