The effects of afterload reduction with and without calcium blockade on reperfusion injury were studied in the pig. Reversible occlusion of the left anterior descending coronary artery was performed for 60 minutes followed by 120 minutes of reperfusion. For 15 minutes prior to and throughout reperfusion, treatment was administered with a calcium blocker (nifedipine or verapamil), a metallic organic dye and Ca2+ antagonist (ruthenium red), a vasodilator (nitroprusside), or saline. Biochemical functions, i.e., mitochondrial oxidative phosphorylation, myocardial ATP and Ca2+ content, and sarcoplasmic reticulum Ca2+ uptake were determined. Regional left ventricular wall motion was measured echocardiographically. Nifedipine and ruthenium red improved biochemical indices of ischemic myocardium in part by reducing afterload and thereby reducing oxygen demand and in part by reducing calcium entry into cells and mitochondria. Verapamil in the doses used failed to reduce afterload and demonstrated no salutary effect on biochemical parameters in ischemic myocardium. Nitroprusside reduced afterload, improved mitochondrial ATP production and increased percent wall thickening. Our findings suggest that afterload reduction with and without calcium blockade during the early reperfusion phase improves ischemic myocardium. These changes are predominantly biochemical in nature.