Low doses (< or = 100 pmol/kg) of endothelin-1 (ET-1) and endothelin-3 (ET-3) elicited a fall in mean arterial pressure (MAP) and a dose-related reduction in hindquarter vascular resistance in anesthetized rats. The depressor response to low doses of ET-1 or ET-3 was short-lived (about 10 sec) and reversible. High doses (> or = 200 pmol/kg) of ET-1 and ET-3 elicited a biphasic response; an initial fall in MAP followed by a gradual increase in MAP. The pressor response to large doses of ET-3 was less than that to large doses of ET-1. On the other hand, the depressor response to low doses of ET-3 was similar to that to low doses of ET-1. Both ET-1 and ET-3 at low doses exhibited primarily a vasodilatory activity. Pretreatment with NG-monomethyl-L-arginine (L-NMMA), a compound that inhibits nitric oxide (NO) production by endothelial cells, attenuated the hypotensive and hindquarter vasodilating effects of low doses of these isopeptides, indicating that the hindquarter vasodilating responses to these peptides depend upon the release of NO from endothelial cells. On the other hand, pretreatment with either aspirin or indomethacin did not alter the hypotensive or the hindquarter vasodilating effects of either ET-1 or ET-3, indicating that cyclooxygenase products may not be involved in the vasodepressive mechanisms of these peptides. L-NMMA attenuated the vasodilating effects of these peptides, but did not completely inhibit the response, suggesting that NO production by endothelial cells plays only a partial role in the vasodilation of ET in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)