Secretin has been implicated in the regulation of the cardiovascular system through specific receptors and the involvement of b-adrenoreceptors and nitric oxide (NO). However, information regarding its direct actions on coronary blood flow and cardiac function is scarce. Therefore, the present study was planned to determine the primary in vivo effect of secretin on cardiac function and perfusion and the involvement of the autonomic nervous system, secretin receptors and NO. In 30 pigs, infusion of secretin into the coronary artery at 2.97 pg for each ml/min of coronary blood flow, at heart rate and aortic blood pressure constant, increased coronary blood flow, dP/dt_max, segmental shortening and cardiac output, respectively, by about 14.4%, 13.8%, 9.6% and 19.2% of control values (P<0.05). These effects were accompanied by an increase of coronary NO release of about 50% (P<0.05) of control values. The above responses were graded in a further 5 pigs. Moreover, while the blockade of muscarinic cholinoreceptors and of a-adrenoreceptors failed to affect the responses to secretin, blocking of b1 and b2 adrenoreceptors and NO-synthase prevented the effects of secretin on cardiac function, on cardiac perfusion and NO release. Finally, all effects were abolished by secretin receptors inhibitor. In conclusion, in anesthetized pigs secretin primarily increased coronary blood flow and cardiac function through the involvement of specific receptors, b-adrenoreceptors and NO release.