The aim of the present study was to investigate the endothelial influence on renin secretion of isolated juxtaglomerular cells. Specifically the role of nitric oxide (NO) and of endothelin was studied. Coculture of primary cultures of juxtaglomerular cells with aortic and microvascular endothelial cells decreased renin secretion. Inhibition of NO formation by absence of l-arginine or presence of N omega-nitro-l-arginine caused a marked decrease in cGMP accumulation and a reduction in renin secretion in cocultures. Exogenous NO (NO liberators sodium nitroprusside/SIN 1) stimulated the 20-hour renin secretion from juxtaglomerular cells markedly, too. The effect of NO on renin secretion was biphasic: short-time inhibition and long-time stimulation of renin release. NO's stimulatory effect on renin secretion is dependent on extracellular calcium, but independent on cAMP or cGMP accumulation. Endothelin 1, 2, and 3 did not affect basal renin secretion, but inhibited cAMP stimulated renin release to a similar extent. Endothelin's action is not mediated via the subtype A endothelin receptor, but seems to involve calcium mobilization in juxtaglomerular cells that is dependent on extracellular calcium and associated with prominent calcium activated chloride channels. Taken together, coculture of juxtaglomerular cells with endothelial cells inhibits renin secretion despite the stimulatory effect of native NO released from endothelial cells. cAMP stimulated renin secretion is inhibited by all three endothelin isoforms thus contributing to the inhibition of renin secretion in coculture.