Experiments were conducted in anesthetized dogs to determine the mechanism primarily responsible for the increase in myocardial contractile function during intravenous infusion of nicotine. Myocardial function was assessed regionally by measuring segment shortening using ultrasonic dimension gauges. The role of cardiac neural stimulation in the absence of direct effects of nicotine and other circulating factors was evaluated by perfusing a region of left ventricular myocardium with blood from a reservoir during systemic nicotine infusion. Segment shortening increased from 11 to 19% in normally perfused myocardium but deteriorated to nearly 0% in reservoir-perfused myocardium. To evaluate direct effects of nicotine on cardiac function, nicotine was infused directly into a perfused coronary artery. An intracoronary concentration of nicotine equivalent to that caused by intravenous administration (0.69 +/- 0.08 micrograms/ml plasma) had no effect on myocardial contractile function. An intracoronary nicotine concentration of 5 micrograms/ml was required to directly increase contractile function to approximately the same extent observed during intravenous nicotine. To evaluate the role of circulating catecholamines in the myocardial response to intravenous nicotine, observations were made before and after bilateral adrenalectomy. Adrenalectomy markedly attenuated the pressor response to intravenous nicotine and abolished the positive cardiac inotropic response. We conclude that the adrenal release of catecholamines is primarily responsible for increased myocardial contractile function during intravenous nicotine.