The antiadrenergic effect of cyclopentyladenosine on myocardial contractility is reduced in vivo in diabetic rats

Abstract

The aim of this study was to test the hypothesis that the antiadrenergic action of adenosine is reduced in diabetes. This was determined by evaluating the effect of experimental diabetes mellitus on the in vivo myocardial antiadrenergic action of cyclopentyladenosine, an adenosine A1- receptor agonist. Changes in heart rate and ventricular performance in response to infusion of dobutamine, a β1-adrenergic agonist, were determined in the absence and presence of cyclopentyladenosine, in anesthetized, 10- to 12-week male diabetic (60 mg/kg streptozotocin), insulin-treated diabetic and control rats. Intravenous dobutamine (16 μg/kg) increased +dP/dtmax and −dP/dtmax in control rats from 7 706 ± 553 and 5 449 ± 403 mmHg/s (1 mmHg = 133.3 Pa) to 19 170 ± 465 and 8 855 ± 317 mmHg/s, respectively. In diabetic rats dobutamine increased +dP/dtmax and −dP/dtmax from 5 733 ± 541 and 4 016 ± 426 to 15 015 ± 1 521 and 7 039 ± 809 mmHg/s, respectively. Cyclopentyladenosine significantly attenuated dobutamine-stimulated increases in +dP/dtmax and −dP/dtmax in both control and diabetic rats in a dose-dependent (0.1–3.0 μg/kg) manner. Cyclopentyladenosine potency to attenuate dobutamine-enhanced +dP/dtmax was reduced significantly (p < 0.05) in diabetic rats compared with controls (ID50, 1.07 vs. 0.59 μg/kg, respectively) with no change in efficacy. The magnitude of cyclopentyladenosine inhibition of dobutamine-enhanced −dP/dtmax was greater in control than diabetic rats (81 vs. 54%, respectively), but ID50 values were not different. Insulin treatment of diabetic rats prevented the observed changes. These data suggest that the antiadrenergic action of adenosine is compromised in diabetes and that this may contribute to the development of diabetic cardiomyopathy.Key words: adenosine, dobutamine, ventricle, left ventricular pressure, streptozotocin.