The inotropic effect of endothelin-2 was investigated on isolated preparations of human atrium taken from patients undergoing cardiac surgery. Pectinate muscle fragments were set up in isolated organ chambers under isometric conditions and electrically stimulated through two ring platinum electrodes. Endothelin-2 (10(-11)-10(-8) M) increased both the force and velocity of contraction in a concentration-dependent manner, giving a maximum response of about 70% of that attainable with histamine or epinephrine. The putative endothelin B receptor agonist, the C-terminal hexapeptide endothelin-(16-21), did not affect inotropic activity. The action of endothelin-2 was not modified by indomethacin and propranolol, thus excluding an involvement of endogenous prostaglandins or catecholamines. The adenylate-cyclase activator, forskolin, and the calcium agonist, Bay K 8644, at concentrations able to enhance the inotropic effect induced by histamine and epinephrine, did not modify the action of endothelin-2. The data show that endothelin-2 has a strong positive inotropic effect on the isolated human myocardium. The effect seems to be independent of the sympathetic system and is unlikely to involve slow channel conductance or cyclic AMP. The lack of activity of endothelin fragment suggests that an endothelin receptor subtype, similar to that found in rat aorta, is present on human atrium.