Hamsters fed a Mg-deficient diet (MD) develop a cardiomyopathy (CM) with foci of myocardial necrosis, calcification, and modest mononuclear and giant cell infiltration. We hypothesize that the lesions are secondary to Ca overload following an increase in myocardial Na due to inhibition of (Na.K)-ATPase and secondary Na-Ca exchange. Nifedipine and digoxin were selected as agents to test this hypothesis. Hamsters were given nifedipine, digoxin, or placebo as sustained release subcutaneous pellets the same day they were started on the MD diet. Animals were killed after 14 days, and MD lesions were quantified in H&E stained slides. Regression analysis showed that nifedipine produced a dose-dependent reduction in lesion abundance (p less than .005) and diameter (p less than .05), while digoxin produced a dose-dependent increase in lesion abundance (p less than .005) and diameter (p less than .005). These results support the hypothesis that MDCM is secondary to Ca overload coupled to inhibition of (Na.K)-ATPase of cardiac myocytes.