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Am J Physiol Heart Circ Physiol 280: H334-H343, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 1, H334-H343, January 2001

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

Lin Wu1, Luiz Belardinelli2, Jeffrey A. Zablocki2, Venkata Palle2, and John C. Shryock1

1 Department of Medicine, University of Florida, Gainesville, Florida 32610; and 2 CV Therapeutics, Palo Alto, California 94304

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 N6-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.

CVT-2759; FRTL-5; adipocyte; cyclopentyladenosine; iodotubercidin; atrioventricular


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