Streptozotocin-induced diabetes has previously been shown to alter the sensitivity and responsiveness of rat myocardial tissues to cardiotonic agonists. The objective of the present study was to determine if these alterations were due to the diabetogenic or possible direct cardiotoxic effects of streptozotocin. One month after streptozotocin treatment the following changes were observed in the rat: decrease in body weight; elevation of blood glucose and glycosylated hemoglobin levels; decrease in spontaneously beating atrial rate; elevation in basal developed force of electrically driven right ventricle; and inotropic subsensitivity of right ventricle to isoproterenol, which was associated with decreased beta-adrenoceptor density and supersensitivity to calcium. Pretreatment with the nonmetabolizable glucose analog 3-O-methyl glucose prevented these alterations. Chronic insulin replenishment also reversed the effects of streptozotocin, with the exception of complete normalization of elevations in blood glucose and basal developed force. Acute exposure to high glucose in the medium preserved the subsensitivity to isoproterenol but resulted in an elevated basal developed force in both control and streptozotocin groups. These observations indicate that myocardial alterations after streptozotocin treatment are not the result of direct cardiotoxic effects but rather a consequence of the drug-induced diabetic state. They also suggest that the increase in basal developed force might be related to elevated glucose concentrations.