Mechanisms of increased digitalis tolerance in streptozotocin-induced diabetic rat myocardium.
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(-)-Ca2+ exchange mechanism in sarcolemmal membrane vesicles (right-side out orientation) isolated from chronically-induced diabetic rat hearts. The apparent initial rates of Na(+)-dependent 45Ca2+ 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 45Ca2+ accumulated by the vesicles. A kinetic analysis revealed a significant reduction in the maximum initial rate of 45Ca2+ uptake (Vmax) in vesicles of 24-week diabetic rat hearts. Affinity for 45Ca2+, however, was the same for both diabetic and control groups. The efflux rate of 45Ca2+ was also depressed in these vesicles, and they retained significantly more 45Ca2+ than controls after 2-4 min of initiation of Na(+)-dependent 45Ca2+ efflux. These data demonstrate that the trans-sarcolemmal Ca2+ flux through Na(+)-Ca2+ exchange is depressed and may explain the observed increase in digitalis tolerance of the myocardium in diabetic rats.
Khatter
J C
JC
Department of Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Agbanyo
M
M
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004071:Digitalis Glycosides / Q000008:administration & dosage*; D004361:Drug Tolerance; D066298:In Vitro Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D012508:Sarcolemma / Q000201:enzymology; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger; D013311:Streptozocin
D002352:Carrier Proteins; D004071:Digitalis Glycosides; D019831:Sodium-Calcium Exchanger; D013311:Streptozocin; D012964:Sodium; D002118:Calcium