Effect of adenosine on atrioventricular conduction. II: Modulation of atrioventricular node transmission by adenosine in hypoxic isolated guinea pig hearts.

Abstract

Adenosine as well as hypoxia and ischemia are known to cause atrioventricular conduction block. To test the hypothesis that adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay in isolated perfused guinea pig hearts, we characterized a) the time courses of hypoxia-induced adenosine release and delay in atrioventricular conduction, b) the relationships between oxygen tension, adenosine concentration in the effluent, and atria-to-His-bundle interval, and c) the adenosine receptor mediating the negative dromotropic effect of hypoxia. Oxygen tension and effluent adenosine levels were linearly related with a correlation coefficient (r) of -0.85 and a slope of -6.3 +/- 0.37 pmol/min/g/torr. Likewise, oxygen tension and atria-to-His-bundle interval prolongation were linearly related with r = -0.85 and a slope of -0.180 +/- 0.013 msec/torr. The EC50 of effluent adenosine in causing atria-to-His-bundle prolongation was 0.26 +/- 0.02 microM. Adenosine deaminase, an enzyme that deaminates adenosine to inosine and is limited to the extracellular space, significantly attenuated (61%) the atria-to-His-bundle interval prolongation caused by hypoxia. This prolongation was further reduced (81%) by a combination of adenosine deaminase and theophylline, an adenosine receptor blocker. Adenosine deaminase also reduced (by 95%) the atria-to-His-bundle interval prolongation in normoxic recipient hearts caused by the effluent of hypoxic donor hearts. Several adenosine antagonists, i.e., theophylline, 8-phenyltheophylline, and 8-(p-sulfophenyl)theophylline antagonized in a dose-dependent manner the negative dromotropic effect of exogenous adenosine and hypoxia. Schild analysis of the antagonism of hypoxia-induced atria-to-His-bundle interval prolongation by 8-(p-sulfophenyl)theophylline yielded the following pA2 values: 5.30 +/- 0.25 and 5.28 +/- 0.31 using oxygen tension and effluent adenosine vs. AH interval prolongation, respectively. 8-(p-Sulfophenyl)theophylline also antagonized to an equal extent atria-to-His-bundle interval prolongations of similar magnitude caused either by adenosine or hypoxia. We conclude that 1) adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay, and 2) the adenosine receptor that mediates the negative dromotropic effect of hypoxia is similar to that of exogenous adenosine.