THE ANTIADRENERGIC EFFECT OF CYCLOPENTYLADENOSINE ON MYOCARDIAL-CONTRACTILITY IS REDUCED IN-VIVO IN DIABETIC RATS

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 A(1)-receptor agonist. Changes in heart rate and ventricular performance in response to infusion of dobutamine, a beta(1)-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 mu g/kg) increased +dP/dt(max) and -dP/dt(max) in control rats from 7706 +/- 553 and 5449 +/- 403 mmHg/s (1 mmHg = 133.3 Pa) to 19170 +/- 465 and 8855 +/- 317 mmHg/s, respectively. In diabetic rats dobutamine increased +dP/dt(max) and -dP/dt(max) from 5733 +/- 541 and 4016 +/- 426 to 15015 +/- 1521 and 7039 + 809 mmHg/s, respectively. Cyclopentyladenosine significantly attenuated dobutamine-stimulated increases in +dP/dt(max) and -dP/dt(max) in both control and diabetic rats in a dose-dependent (0.1-3.0 mu g/kg) manner. Cyclopentyladenosine potency to attenuate dobutamine-enhanced +dP/dt(max) was reduced significantly (p < 0.05) in diabetic rats compared with controls (ID50 1.07 vs. 0.59 mu g/kg, respectively) with no change in efficacy. The magnitude of cyclopentyladenosine inhibition of dobutamine-enhanced -dP/dt(max) 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.