This laboratory and others have shown that methylprednisolone sodium succinate and betahistine hydrochloride can each reduce the size of experimental myocardial infarct in dogs at six hours. In light of the fact that these two agents probably act via different mechanisms, a study was carried out to determine if there would be cumulative effects of using these two agents together. Using a left anterior descending coronary artery ligation model to create an experimental myocardial infarction and an intracellular lactic dehydrogenase (LDH) stain to measure the infarct size, 66 dogs were studied. Nineteen dogs served as controls with no therapy; 20 received a continuous intravenous infusion of betahistine hydrochloride (0.24 mg/kg/min) for six hours following ligation; 10 dogs received methylprednisolone sodium succinate intravenously 30 mg/kg at one hour postligation; and 17 other dogs received betahistine hydrochloride intravenously (0.24 mg/kg/min) over six hours following ligation, plus methylprednisolone sodium succinate intravenously (30 mg/kg) at one hour postligation. At six hours, the combined treatment demonstrated no significant improvement over betahistine HCl alone (control, 16.0%; betahistine HCl, 11.4%; combined, 11.2% P less than 0.05). At 24 hours, only the combined treatment group demonstrated a significant infarct size reduction (control, 15.5%; methylprednisolone, 13.1%; betahistine--HCl, 14.2%; combined, 9.7%; P less than 0.0025). Other parameters that were evaluated and analyzed include mean aortic pressure, left atrial pressure, cardiac index, total peripheral resistance, arterial and coronary sinus pH, pCO2, pO2, hematocrit, O2 consumption, O2 content difference, and coronary sinus lactate and creatine phosphokinase (CPK). These results suggest a significant cumulative effect in reducing infarct size over that achieved with one agent alone; however, further studies are needed to determine the appropriate dosage and temporal factors.