Role of adenosine as mediator of bradyarrhythmias during hypoxia in isolated guinea pig hearts

Tissue concentrations of adenosine, an endogenous metabolite with negative chronotropic and dromotropic actions, are known to increase when myocardial oxygen supply is reduced. In this study the concentrations of endogenous adenosine released during a period of hypoxic perfusion were measured to determine whether they are sufficient to account for the effect of hypoxia on atrioventricular conduction in isolated perfused guinea pig hearts. In addition, the efficacy of competitive adenosine antagonism in reversing the effect of hypoxia on atrioventricular conduction and atrial automaticity were compared. Effluent samples for adenosine were collected at the onset of spontaneous and atrial pacing induced second degree atrioventricular block during hypoxic perfusion (Po2 3.07 kPa) and during the combined infusion of adenosine plus the nucleoside transport blocker, dipyridamole (Po2 71.1 kPa). The mean (SEM) atrial cycle lengths associated with the onset of atrioventricular block were 333(10) and 297(2) ms respectively. Effluent concentrations of adenosine associated with atrioventricular block during hypoxia (2342(160) pmol·min−1·g−1 heart weight) were approximately equal to those obtained during the infusion of adenosine plus dipyridamole (2538(256) pmol·min−1·g−1 heart weight) (no statistically significant difference). During hypoxic perfusion, among hearts showing spontaneous atrioventricular block and those in which atrial slowing prevented the onset of spontaneous block, the competitive adenosine antagonist aminophylline (60 μmol·litre−1) reversed either spontaneous or atrial pacing induced block without any effect on spontaneous atrial cycle length. In conclusion, the production and release of endogenous adenosine are sufficient to account for the effects (negative chronotropic and dromotropic) of hypoxia. Moreover, the effect of endogenously released adenosine during hypoxia is greater on atrioventricular conduction than on atrial automaticity. There may be an important role for adenosine antagonists in the treatment of atrioventricular block.