Using the isolated and blood-perfused dog atrial preparation, chronotropic and inotropic responses to 3 kinds of alpha-adrenergic blockers, phentolamine, phenoxybenzamine, and E-643, were compared. When phenoxybenzamine was administered into the cannulated sinus node artery, positive chronotropic and inotropic responses were induced in doses of 10-300 microgram. Phentolamine also produced positive responses, but at larger doses such as 100 and 300 microgram, accompanying initial negative responses. E-643 usually produced only negative chronotropic and inotropic effects. Positive responses to phenoxybenzamine and phentolamine were significantly suppressed by propranolol, and negative responses to E-643 and phentolamine were not modified by atropine treatment. From these results and previous reports, it is assumed that sinus tachycardia induced by alpha-blockers in situ may be due to 3 different mechanisms, i.e., 1) reflex tachycardia induced by the hypotension, 2) augmented catecholamine release mediated by the block of the presynaptic alpha-adrenoceptors, and 3) direct catecholamine release from locally innervated sympathetic nerve terminals.