Systemic intermedin (IMD)1-47 administration has been reported to result in vasodilation and marked hypotension through calcitonin-related receptor complexes. However, its effects on the coronary circulation and the heart have not been examined in vivo. The present study was therefore planned to determine the primary in vivo effect of IMD1-47 on coronary blood flow and cardiac function and the involvement of the autonomic nervous system and nitric oxide (NO). In 35 anesthetized pigs, IMD1-47, infused into the left anterior descending coronary artery at doses of 87.2 pmol/min, at constant heart rate and arterial blood pressure, augmented coronary blood flow and cardiac function. These responses were graded in a further five pigs by increasing the infused dose of IMD1-47 between 0.81 and 204.1 pmol/min. In the 35 pigs, the blockade of cholinergic receptors (intravenous atropine, 5 pigs), alpha-adrenoceptors (intravenous phentolamine, 5 pigs), and beta1-adrenoceptors (intravenous atenolol, 5 pigs) did not abolish the cardiac response to IMD1-47, the effects of which were prevented by blockade of beta2-adrenoceptors (intravenous butoxamine, 5 pigs), NO synthase (intracoronary N(omega)-nitro-l-arginine methyl ester, 5 pigs), and calcitonin-related receptors (intracoronary CGRP8-37/AM22-52, 10 pigs). In porcine coronary endothelial cells, IMD1-47 induced the phosphorylation of endothelial NO synthase and NO production through cAMP signaling leading to ERK, Akt, and p38 activation, which was prevented by the inhibition of beta2-adrenoceptors, calcitonin-related receptor complexes, and K+ channels. In conclusion, IMD1-47 primarily augmented coronary blood flow and cardiac function through the involvement of calcitonin-related receptor complexes and beta2-adrenoreceptor-mediated NO release. The intracellular signaling involved cAMP-dependent activation of kinases and the opening of K+ channels.