SELECTIVE POTENTIATION BY AN A(1) ADENOSINE RECEPTOR ENHANCER OF THE NEGATIVE DROMOTROPIC ACTION OF ADENOSINE IN THE GUINEA-PIG HEART

The drug yl-3-thienyl)-[3(trifluoromethyl)-phenyl]methanone (PD 81,723 ) has been shown to enhance allosterically Al adenosine receptor bindi ng in brain membranes. The objective of this study was to determine th e specificity and selectivity (Al versus A2) of PD 81,723 as an enhanc er of the negative dromotropic effect of exogenous adenosine in guinea pig isolated and in situ hearts. In isolated hearts, PD 81,723 alone produced only a small stimulus to His bundle (S-H) interval prolongati on of 1.5 to 4 msec, which was completely reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase . PD 81,723 (5 muM) significantly decreased the EC50 value of adenosin e for prolongation of the S-H interval from 6.7 +/- 0.6 to 4.4 +/- 0.5 muM. The potentiation of the negative dromotropic effect of adenosine by PD 81,723 was dose dependent, i.e., 5 and 10 muM PD 81,723 enhance d the maximal S-H interval prolongation caused by 3 muM adenosine by 2 07% and 609%, respectively. In contrast, the same concentration of PD 81,723 had no effect on either the S-H interval prolongation caused by carbachol or MgCl2 or the coronary vasodilatory effect of adenosine. In in situ hearts, PD (2 mumol/kg i.v.) alone caused only a small but not significant negative dromotropic effect, increasing the atrium to His interval from 58 +/- 2 to 61 +/- 1 msec. However, the same dose of PD 81,723 caused a significant leftward and upward shift of the adeno sine dose-response curve for inducing atrium to His bundle interval pr olongation and increased the degree of atrioventricular block caused b y adenosine. Thus, PD 81,723 enhanced the A1 adenosine receptor-mediat ed negative dromotropic effect both in vitro and in vivo but had no si gnificant effect on A2 adenosine receptor-mediated coronary vasodilati on in vitro. In conclusion, PD 81,723 is a specific and selective enha ncer of the A1 receptor, with the potential to act as a site- and even t-specific modulator of the cardiac actions of endogenous adenosine.