ANTAGONISM OF THE EFFECTS OF ADENOSINE AND HYPOXIA ON ATRIOVENTRICULAR-CONDUCTION TIME BY 2 NOVEL ALKYLXANTHINES - CORRELATION WITH BINDING TO ADENOSINE-A1-RECEPTORS

  • 1 August 1987
    • journal article
    • research article
    • Vol. 242  (2) , 478-484
Abstract
Adenosine has been shown to have a negative dromotropic effect and has been implicated in mediating atrioventricular conduction disturbances induced by hypoxia. This study was designed to determine the ability of various alkylxanthines including two novel derivatives, i.e., BW A533U and BW A1433U, to 1) attenuate adenosine- and hypoxia-induced atrial to His bundle (AH) interval prolongation, 2) compete for binding of 125I-aminobenzyladenosine to ventricular membranes and 3) inhibit myocardial phosphodiesterase. In normoxic isolated perfused hearts (n = 20) instrumented for measurement of atrioventricular conduction time and left ventricular pressure, BW A1433U (0.1 .mu.M) or BW A533U (5 .mu.M) attenuated AH interval prolongation induced by adenosine (5 .mu.M) by 90%, but neither xanthine derivative attenuated the AH interval prolongation induced by acetylcholine (0.11 .mu.M), digoxin (0.91 .mu.M) or D600 (1.3 .mu.M). In four additional hearts, BW A1433U at concentrations of up to 10 .mu.M had no effect on left ventricular pressure or AH interval. BW A1433 or BW A533U (50 .mu.M) inhibited myocardial cyclic AMP phosphodiesterase by only 11.5 .+-. 1.6 and 26.6 .+-. 2.6%, respectively. Schild analysis of adenosine concentration-response curves obtained in the absence and presence of BW A533U and BW A1433U (n = 14) yielded pA2 values of (mean .+-. S.E.M.) 6.32 .+-. 0.10 and 7.70 .+-. 0.08, respectively. pKd values for BW A533U and BW A1433U binding to adenosine receptors on ventricular membranes were 6.36 and 6.94, respectively. In a separate series of 19 hearts, BW A533U and BW A1433U were shown to attenuate hypoxia-induced AH interval prolongation. BW A533U (5 .mu.M) reduced hypoxia-induced AH interval prolongation by 78 .+-. 7%, and 0.2, 2 and 20 .mu.M BW A1433U attenuated hypoxia-induced AH interval prolongation by 66 .+-. 5%, 81 .+-. 4 and 91 .+-. 1%, respectively. In summary, BW A1433U and BW A533U antagonize the adenosine- and hypoxia-induced AH interval prolongation by selective blockade of adenosine receptors. These findings suggest that AH interval prolongation during acute hypoxia in isolated perfused guinea pig hearts is mediated almost entirely by endogenously released adenosine.