To investigate the effect of endothelin on renin release, experiments were performed in barbiturate-anaesthetized dogs with denervated kidneys. Intrarenal infusion of endothelin (1 ng min-1kg-1body wt) reduced renal blood flow (RBF) from 145 ± 10 ml min-1to 98 ± 9 ml min-1without altering renin release (1 ± 1 μg angiotensin I (AI) min-1). Renin release was then increased either by renal arterial constriction or ureteral occlusion. When renal arterial pressure was reduced to 50 mmHg, renin release averaged 79 ± 20 μg AI min-1in six dogs and fell significantly to 24 ± 6 μg AI min-1during endothelin infusion. During ureteral occlusion the inhibitory effect of endothelin on renin release either during inhibition of β-adrenergic activity with propranolol or after inhibiting prostaglandin synthesis by indomethacin during intrarenal infusion of isoproterenol was examined. After propranolol administration ureteral occlusion increased renin release from 5 ± 2 μg AI min-1to 38 ± 12 μg AI min-1in six dogs. Subsequent intrarenal endothelin infusion (1 ng min-1kg-1body wt) during maintained ureteral occlusion reduced renin release to 10 ± 3 μg AI min-1. In six other dogs prostaglandin synthesis was inhibited by indomethacin. Subsequent infusion of isoproterenol (0.2 μg min-1kg-1body wt) to stimulate β-adrenoceptor activity increased renin release from 13 ± 4 μg AI min-1to 68 ± 8 μg AI min-1during ureteral occlusion. Intrarenal endothelin infusion (1 ng min-1kg-1body wt) reduced renin release to 22 ± 3 μg AI min-1during continuous isoproterenol infusion and ureteral occlusion. Hence endothelin inhibits renin release induced by renal arterial constriction or ureteral occlusion. Similar inhibitory effects whether renin release was raised by increasing prostaglandin synthesis or by stimulating β-adrenergic activity suggest a direct effect of endothelin on the juxtaglomerular cells.