Conflicting data have been reported for the role of endothelium-derived relaxing factor (EDRF) in the control of renin release from juxtaglomerular (JG) cells of the kidney. We have examined, in the isolated perfused rat kidney, how renin secretion is influenced by inhibitors or stimulators of EDRF, as well as by nitric oxide-generating drugs. Acetylcholine (15 nM) or carbachol (5μM) stimulated renin release. These effects could be attenuated by N-nitro-L-arginine (L-NNA, 20μM) or N-monomethyl-L-arginine (L-NMMA, 50μM).When given alone, these inhibitors of NO-synthase reduced basal renin release by 30-60%. Infusion of L-arginine (2 mM), the precursor of EDRF, stimulated renin release, restored L-NNA-inhibited renin release and prevented inhibition by L-NMMA. The NO-generating sydnonimine SIN-1 (2μM), induced an increase in renin release, which was not altered by L-NNA. In hydronephrotic rat kidneys lacking tubular structures, N-nitro-arginine methylester (L-NAME, 20μM) inhibited, while carbachol (1μM), SIN-1 (10μM) and sodium nitroprusside (5μM) stimulated renin release, indicating that the effects of these agents on renin release do not depend on tubular mechanisms. It is concluded that EDRF is a stimulator of renin release with a direct action on JG-cells.