An endothelium-derived 21-residue peptide, endothelin, has been shown to be a constrictor of arteriolar smooth muscle. This study investigated the effect of endothelin on isolated pulmonary veins and arteries using tissue bath techniques. Endothelin elicited concentration-dependent contractions and maximal responses were equal in magnitude to those of phenylephrine (PE) or norepinephrine (NE). Responses to endothelin were long lasting and persisted despite repeated washing. The following agents had no significant effect on endothelin-induced contractions: FPL 55712 (1 microM), indomethacin (10 microM), methysergide (3 microM), phentolamine (3 microM), pyrilamine (3 microM) and the putative thromboxane A2 receptor antagonist SQ 29,548 (3 microM). Moreover, removal of the endothelium did not alter responses to endothelin. Isoproterenol, forskolin, and 8-bromo-cAMP had a differential inhibitory effect on matched contractions induced by endothelin and the putative thromboxane A2 receptor agonist U-46619. Isoproterenol (0.1 microM) relaxed endothelin and U-46619 contractions by 2 +/- 1% and 74 +/- 5%, respectively; forskolin (3 microM) by 12 +/- 3% and 84 +/- 9%, respectively and 8-bromo-cAMP (10 mM) by 23 +/- 8% and 82 +/- 9%, respectively. Likewise, 10 microM sodium nitroprusside relaxed endothelin contractions by 32 +/- 4% and PE contractions by 80 +/- 9%. Endothelin is a very potent pulmonary vasoconstrictor that appears to have a direct effect on vascular smooth muscle. Compared to U-46619 or PE, endothelin-induced contractions are highly resistant to relaxing agents that increase either cAMP or cGMP. Moreover, resistance to cAMP does not appear to involve inhibition of adenylate cyclase.