POTENTIATION BY ENALAPRILAT OF FENOLDOPAM EVOKED NATRIURESIS IS DUE TO BLOCKADE OF INTRARENAL PRODUCTION OF ANGIOTENSIN-II IN RATS

We have previously shown that the natriuretic response to DA-1 recepto r agonist fenoldopam is markedly potentiated by angiotensin converting enzyme inhibitor captopril. Since inhibition of angiotensin convertin g enzyme can lead to decreased production of angiotensin-II and increa sed levels of kinins (e.g., bradykinin), it is Likely that both of the se mechanisms might be involved in this phenomenon. However, it is not known whether and to what degree the accumulation of kinins contribut es to the overall potentiation of natriuretic response to fenoldopam s een during angiotensin converting enzyme inhibition. In the present st udy, we have examined the effect of angiotensin converting enzyme inhi bitor enalaprilat and angiotensin-II receptor antagonist losartan as w ell as bradykinin-2 receptor antagonist HOE 140 on fenoldopam-induced natriuresis. Intravenous infusion of fenoldopam (1 mu g/kg/min) for 30 min produced significant increases in urine output and urinary sodium excretion without causing any changes in glomerular filtration rate, renal blood how and mean arterial blood pressure, a phenomenon suggest ive of a direct tubular site of action. In animals treated with either the angiotensin converting enzyme inhibitor enalaprilat or angiotensi n-II receptor antagonist losartan, the diuretic and natriuretic effect s of fenoldopam were potentiated to a similar degree. Whereas no signi ficant changes in glomerular filtration rate occurred when fenoldopam alone was given to control rats, in animals treated with either enalap rilat or losartan, fenoldopam produced a modest but significant increa se in glomerular filtration rate. In a separate group of animals, the effects of bradykinin-2 receptor antagonist HOE 140 on potentiation of fenoldopam-induced natriuresis by enalaprilat was examined. It was fo und that the magnitude of changes in urine output, sodium excretion an d glomerular filtration rate in animals receiving pretreatment with bo th enalaprilat and HOE 140 were similar to those with enalaprilat pret reatment alone. These findings suggest that the potentiation of natriu retic response to fenoldopam by enalaprilat is solely due to blockade of angiotensin-II production and kinins do not appear to contribute to this phenomenon.