A partial agonist of the A1-adenosine receptor selectively slows AV conduction in guinea pig hearts

Abstract

The use of full agonists of the A1-adenosine receptor (A1-ADOR) as antiarrhythmic agents is limited by their actions to cause high-grade atrioventricular (AV) block, profound bradycardia, atrial fibrillation, and vasodilation. It may be possible to avoid these undesired actions by use of partial agonists. We determined the effects of CVT-2759, a potential partial agonist of A1-ADORs, on guinea pig hearts. CVT-2759 (0.1–100 μM) increased the 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 μM. CVT-2759 did not cause second-degree AV block. CVT-2759 significantly attenuated the actions of the full agonists N 6-cyclopentyladenosine and adenosine. CVT-2759 caused a moderate slowing of atrial rate by ≤13% and did not shorten the durations of either the atrial or the ventricular monophasic action potential. Coronary conductance was increased by CVT-2759 only at concentrations >10 μM. In contrast, CVT-2759 was a full agonist to decrease cAMP content of rat adipocytes and Fischer rat thyroid line 5 cells. Results of radioligand binding assays indicated that CVT-2759 stabilized a high-affinity, G protein-coupled state of the A1-ADOR in membranes prepared from rat adipocytes but not in membranes prepared from the guinea pig brain. The results suggest that a weak A1-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.