Novel approach for enhancing atrioventricular nodal conduction delay mediated by endogenous adenosine

Abstract

The 2-amino-3-benzoylthiophene derivative PD 81,723 potentiates the A1 receptor-mediated negative dromotropic effect of exogenous adenosine and adenosine receptor agonists in guinea pig isolated perfused and in situ hearts. The objective of this study was to determine whether PD 81,723 could amplify the cardiac actions of endogenous adenosine. Two approaches known to increase the myocardial interstitial concentration of adenosine-hypoxia, which increases the production of adenosine and the inhibition of adenosine kinase, which decreases its metabolism - were used to test this hypothesis. In guinea pig hearts in situ, PD 81,723 (2 mg/kg IV) potentiated the atrioventricular (AV) nodal conduction delay caused by hypoxemia (PaO2 14 to 19 mm Hg). In guinea pig isolated hearts, PD 81,723 (5 μmol/L) increased by twofold the stimulus-to-His bundle (S-H) interval prolongations induced by both a 5-minute period of hypoxia (25% O2/70% N2/5% CO2) and the administration of the adenosine kinase inhibitor iodotubercidin (40 to 70 nmol/L) but had no effect on coronary conductance. Hypoxia and hypoxia plus PD 81,723 (5 μmol/L) caused equivalent increases in the concentration of adenosine in epicardial transudate, from 0.13±0.15 to 0.48±0.1 and 0.45±0.4 μmol/L, respectively. Similar to the allosteric enhancer, the nucleoside uptake blocker draflazine (0.1 μmol/L) also increased by twofold the S-H interval prolongation caused by hypoxia. In contrast to the allosteric enhancer, draflazine increased the concentration of adenosine in epicardial transudate during hypoxia from 0.48±0.15 to 1.5 ±0.4 μmol/L. Draflazine also increased coronary conductance by approximately twofold in guinea pig normoxic constant-flow perfused hearts. In conclusion, PD 81,723 enhances the AV nodal conduction delay, but not the coronary vasodilation, caused by interventions known to increase the concentration of adenosine in myocardial interstitial fluid. Thus, allosteric potentiation of the cardiac actions of adenosine by PD 81,723 is receptor subtype selective and event specific.