Influence of ATP-sensitive K+ channel modulation on the mechanical properties of diabetic myocardium

ATP-sensitive K+ (KATP) channels are therapeutic targets for hypertension and diabetes. KATP channel opening elicits vasorelaxation and myocardial protection, whereas its closing stimulates insulin secretion. The cardiac KATP conductance is believed altered under diabetes. This study was to evaluate the influence of KATP channel openers and blocker on myocardial contractile dysfunction in diabetes. Adult rats were made diabetic with streptozotocin (55 mg/kg) and maintained for eight weeks. Contractile properties were studied using isolated papillary muscles in the absence or presence of KATP channel openers (BRL 38227 and pinacidil) and KATP blocker (glyburide). Experimental diabetes led to hyperglycemia, reduced growth, cardiac hypertrophy and hepatomegaly. Mechanical properties exhibited prolonged duration and reduced velocity of both contraction and relaxation in diabetic myocardium, characteristic of diabetic cardiomyopathy. Acute exposure to both KATP channel openers induced concentration-dependent negative inotropic effects (NIE) on myocardial contraction. The magnitude of the NIE was similar between the normal and diabetic groups and was fully reversible upon washout for BRL 38227 although not for pinacidil. Both KATP channel openers depressed the velocity of contraction and relaxation, whereas exerted no effect on the duration of contraction and relaxation, in myocardium from both groups. Acute exposure to glyburide, a KATP channel blocker, failed to alter any of the mechanical parameters measured. These data suggest that acute modulation of KATP channel with channel opener or blocker had little influence on diabetic cardiomyopathy, at least in the setting of multicellular preparations.