Mechanisms of increased digitalis tolerance in streptozotocin-induced diabetic rat myocardium

Abstract

Our earlier studies revealed that the inotropic and cardiotoxic responses to ouabain are depressed significantly in chronically-induced diabetic rats (Navaratnam S and Khatter JC, Arch Int Pharmacodyn 301: 151–164, 1989). In the present study, we examined the Na +-Ca 2+ exchange mechanism in sarcolemmal membrane vesicles (right-side out orientation) isolated from chronically-induced diabetic rat hearts. The apparent initial rates of Na +-dependent 45Ca 2+ uptake were substantially lower in vesicles from 6- and 12-week diabetic rat hearts when compared to non-diabetic controls. These rates were reduced further in vesicles of 24-week diabetic rat hearts. Associated with the progressive reduction in initial rates was also a progressive reduction in the maximum amount of 45Ca 2+ accumulated by the vesicles. A kinetic analysis revealed a significant reduction in the maximum initial rate of 45Ca 2+ uptake ( V max) in vesicles of 24-week diabetic rat hearts. Affinity for 45Ca 2+, however, was the same for both diabetic and control groups. The efflux rate of 45Ca 2+ was also depressed in these vesicles, and they retained significantly more 45Ca 2+ than controls after 2–4 min of initiation of Na +-dependent 45Ca 2+ efflux. These data demonstrate that the trans-sarcolemmal Ca 2+ flux through Na +-Ca 2+ exchange is depressed and may explain the observed increase in digitalis tolerance of the myocardium in diabetic rats.