To determine whether digoxin protects the myocardium during the initial phases of hypertension and diabetes combined, adult male Wistar rats with two-kidney, one-clip renal hypertension and streptozotocin-induced diabetes mellitus were treated with digoxin (500 micrograms.kg-1.day-1) by gavage for 10 wk immediately after the onset of hypertension and diabetes. Systemic arterial blood pressures, ventricular pressures, the first time derivative of left ventricular pressure, diastolic wall stress, and the quantitative analysis of the number and distribution of myocardial lesions and capillary density of the myocardium were measured. In comparison to untreated hypertensive-diabetic animals, digoxin-treated rats showed a lesser elevation in left ventricular end-diastolic pressure and diastolic and systolic wall stress despite comparable degrees of hypertension and blood glucose levels. In addition, chamber diameter was smaller and the diffusion distance for oxygen was within normal values in animals treated with this glycoside. However, the numerical density of the foci of replacement fibrosis was similar to that found in untreated hypertensive-diabetic animals. In conclusion, digoxin reduces the magnitude of ventricular remodeling and diastolic wall stress in this model of hypertension and diabetes.