A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts

The use of full agonists of the A(1)-adenosine receptor (A(1)-ADOR) as anti arrhythmic agents is limited by their actions to cause high-grade atriovent ricular (AV) block, profound bradycardia, atrial fibrillation, and vasodila tion. It may be possible to avoid these undesired actions by use of partial agonists. We determined the effects of CVT-2759, a potential partial agoni st of A(1)-ADORs, on guinea pig hearts. CVT-2759 (0.1-100 muM) increased th e S-H interval of the isolated heart from 45 +/- 1 to 60 +/- 3 ms (P< 0.01) with a half-maximal effect at 3.1 <mu>M. CVT-2759 did not cause second-deg ree AV block. CVT-2759 significantly attenuated the actions of the full ago nists N-6-cyclopentyladenosine and adenosine. CVT-2759 caused a moderate sl owing of atrial rate by less than or equal to 13% and did not shorten the d urations of either the atrial or the ventricular monophasic action potentia l. Coronary conductance was increased by CVT-2759 only at concentrations >1 0 muM. In contrast, CVT-2759 was a full agonist to decrease cAMP content of rat adipocytes and Fischer rat thyroid line 5 cells. Results of radioligan d binding assays indicated that CVT-2759 stabilized a high-affinity, G prot ein-coupled state of the A(1)-ADOR in membranes prepared from rat adipocyte s but not in membranes prepared from the guinea pig brain. The results sugg est that a weak A(1)-ADOR agonist, such as CVT-2759, may be useful to slow AV nodal conduction and thereby ventricular rate without causing AV block, bradycardia, atrial arrhythmias, or vasodilation.