In epicardial conduit coronary artery strips obtained during autopsy within 2.5 h after death, relaxations induced by low concentrations of histamine were reversed to contractions by removal of endothelium, whereas those caused by bradykinin, substance P, and Ca2+ ionophore A23187 were almost abolished. In the artery strips with intact endothelium, which responded to histamine, bradykinin, and substance P with moderate or marked relaxations, acetylcholine elicited contractions. Endothelium denudation failed to potentiate the contractile response to acetylcholine and serotonin. Relaxant responses to histamine, bradykinin, and substance P did not significantly differ in coronary arteries from adults (35-48 yr old) and seniors (63-82 yr old). Two strips from a 2-mo-old male responded to acetylcholine only with contractions, and their responses to the vasodilators were not greater than those seen in the adult and senior arteries. Histamine increased guanosine 3',5'-cyclic monophosphate (cGMP); the increments did not differ in the arteries from adults and seniors. It may be concluded that endothelium is a major site for relaxant actions of histamine, bradykinin, and substance P, whereas muscarinic receptors, if any, in endothelium do not play an important role in the generation of relaxing factor from human coronary arteries. The endothelium-dependent relaxations do not appear to be altered with increasing age or in the arteries with slight atherosclerotic changes.