Effect of adenosine on atrioventricular conduction. I: Site and characterization of adenosine action in the guinea pig atrioventricular node.

Abstract

Adenosine has a negative dromotropic effect and modulates hypoxia-induced atrioventricular (AV) conduction delay. To further characterize the negative dromotropic effect of adenosine in the guinea pig heart, we determined the site of adenosine-induced AV conduction block; the effect of uptake and deamination of adenosine on its concentration-negative dromotropic effect, and the adenosine receptor that mediates this action. In isolated AV node preparations (n = 16), adenosine in a dose-dependent manner decreased significantly the duration and amplitude of the action potential of atrionodal and nodal cells and, in addition, markedly depressed the maximum rate of rise of the action potential of nodal cells. At high concentrations (greater than 20 microM), adenosine rendered nodal cells inexcitable. In isolated perfused hearts (n = 7), adenosine (5.7 microM) prolonged total AV conduction time by 21 +/- 2 msec. Of this prolongation, 83% was due to an increase in the nodal-to-His-bundle interval and the remaining 17% to an increase in the atrionodal to nodal interval. Infusion of adenosine to cause a 50% increase (EC50) in atria-to-His bundle (AH) interval prolongation resulted in a perfusate (arterial) adenosine concentration of 5.0 +/- 0.6 microM and effluent (venous) adenosine concentrations of 2.8 +/- 0.4 microM, i.e., an arteriovenous difference of 44% (n = 4). When adenosine uptake and deamination were inhibited with dipyridamole (0.5 microM) plus erythro-9-(2-hydroxy-3-nonyl)adenine (5 microM), respectively, the EC50s were 0.28 +/- 0.02 (perfusate) and 0.32 +/- 0.03 microM (effluent). These data indicate that when nucleoside metabolism is inhibited, arterial and venous concentrations of adenosine reach equilibrium. In an additional 10 hearts, the following rank order of potency of adenosine agonists in causing AH interval prolongation was found: N6-cyclopentyladenosine greater than N6-(L-2-phenyl-isopropyl)adenosine greater than 5'-N-ethylcarboxyamidoadenosine greater than or equal to 2-chloroadenosine greater than adenosine, which is compatible with activation of an A1-type receptor. In summary: the site of adenosine-induced AV conduction block is the nodal zone of the AV node, when adenosine uptake and deamination are inhibited, adenosine in concentrations similar to that released by hypoxia causes significant AH interval prolongation, and the adenosine receptor mediating the negative dromotropic effect of adenosine is of the A1-type.