There are reports of an increase in renin release after the administration of fenoldopam which probably results from the activation of dopamine (DA)-1 receptors located on juxtaglomerular cells in the kidney. However, the functional significance of this finding in terms of modulating the tubular response to DA-1 receptor stimulation remains to be determined. In this study we have examined the effect of an increase in renin-angiotensin system activity during the administration of fenoldopam on the natriuretic and diuretic action of this compound. Intravenous infusion of fenoldopam (0.5 microgram/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 flow and mean arterial blood pressure, a phenomenon suggestive of a direct tubular site of action. In animals treated with the angiotensin converting enzyme inhibitor captopril, both the diuretic and natriuretic effects of fenoldopam were potentiated markedly. In comparison with fenoldopam infusion in control animals, urine output, urinary sodium excretion and potassium excretion increased by approximately 4-fold (375 +/- 24 vs. 97 +/- 3 microliters/30 min, P less than .01), 9-fold (50 +/- 5 vs. 6 +/- 1 microEq/30 min, P less than .001) and 2-fold (46 +/- 8 vs. 24 +/- 2 microEq/30 min, P less than .05), respectively, in animals receiving a bolus injection of captopril (1 mg/kg i.v.) 30 min before onset of fenoldopam infusion. Whereas no significant changes in renal blood flow occurred when fenoldopam was given to control rats, in animals treated with captopril, fenoldopam produced a modest but significant increase in renal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)