CARDIAC FUNCTIONAL-RESPONSES TO ADENOSINE BY PD-81723, AN ALLOSTERIC ENHANCER OF THE ADENOSINE-A1-RECEPTOR

Adenosine, a locally released and rapidly metabolized nucleoside, protects the heart from damage during ischemia by reducing oxygen demand and increasing oxygen supply. The aminothiophene derivative (2-amino-4,5-dimethylthien-3-yl)[3-(trifluoromethyl)phenyl]-methanone (PD 81,723) has been shown to act as an allosteric enhancer of the adenosine A1 receptor in brain membranes and thyroid cells. The present study investigates the effects of PD 81,723 in spontaneously contracting right atria and electrically stimulated left atria isolated from Sprague-Dawley rats. N6-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, produced concentration-dependent inhibition of heart rate in right atria and contractile parameters in left atria. In the right atrium, 5 muM of PD 81,723 significantly shifted the concentration-response curves for CPA to the left, both in the absence and presence of a nonselective adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT, 10 muM). In the left atrium, PD 81,723 also shifted the concentration-response curves for CPA to the left, but only in the presence of 8-SPT. Potentiation of CPA-induced negative chronotropic and inotropic responses with PD 81,723, although not significant, was also observed in the presence of a selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 1 nM). These results demonstrate that PD 81,723 enhances the direct negative chronotropic and inotropic effects of adenosine A1 receptor activation in rat atria.