Carperitide is effective for heart failure (HF) owing to its diuretic and vasodilatory effects. This recombinant peptide may also have direct cardioprotective effects because carperitide reduces the severity of heart failure and limits infarct size. Because coronary vasodilation is an important cardioprotective treatment modality, we investigated whether carperitide increased coronary blood flow (CBF) and improved myocardial metabolic and contractile dysfunction during ischemia in canine hearts. We also tested whether carperitide is directly responsible for limiting the infarct size. We infused carperitide at 0.025-0.2 μg kg(-1) min(-1) into the canine coronary artery. A minimum dose of 0.1 μg kg(-1) min(-1) was required to obtain maximal vasodilation. To test the effects of carperitide on ischemic hearts, we reduced perfusion pressure in the left anterior descending coronary artery such that CBF decreased to one-third of the baseline value. At 10 min after carperitide was infused at a dose of 0.1 μg kg(-1) min(-1), we observed increases in CBF, fractional shortening (FS) and pH levels in coronary venous blood without concomitant increases in cardiac nitric oxide (NO) levels; these changes were attenuated using either the atrial natriuretic peptide receptor antagonist HS-142-1 or the NO synthase inhibitor L(ω)-nitroarginine methyl ester (L-NAME). Cyclic guanosine monophosphate (GMP) levels in the coronary artery were elevated in response to carperitide that also limited the infarct size after 90 min of ischemia and subsequent reperfusion. Again, these effects were blunted by L-NAME. Carperitide increases CBF, reduces myocardial contractile and metabolic dysfunction and limits infarct size. In addition, NO is necessary for carperitide-induced vasodilation and cardioprotection in ischemic hearts.