Studies on the mechanism underlying the antifibrillatory effect of the A1-adenosine agonist, R-PIA, in rat isolated hearts.

Previous studies in pigs have shown that the A1-adenosine receptor agonist, R-PIA, is a potent antifibrillatory agent during myocardial ischaemia and that this effect can be overriden by atrial pacing. However, reports of A1-adenosine receptor down-regulation following chronic exposure to A1-receptor agonists suggest that this may limit their use as potential antiarrhythmic therapy. The acute and chronic effects of R-PIA were examined on ventricular arrhythmias and hemodynamics in Langendorff-perfused rat isolated hearts subjected to acute regional myocardial ischemia in an attempt to confirm the heart rate dependency of the antifibrillatory mechanism of R-PIA and to assess the effects of chronic treatment on this protection. Acute challenge with R-PIA (10(-10) to 5 x 10(-8) M; n = 10 for all groups) produced a concentration-dependent bradycardia prior to coronary occlusion. Coronary artery occlusion in control hearts (n = 20) resulted in an immediate increase in perfusion pressure, from 61 +/- 6 to 87 +/- 7 mmHg within 5 minutes, followed by a gradual continued rise reaching a maximum of 123 +/- 9 mmHg by the end of the 30-minute experimental period. R-PIA significantly attenuated the sustained increase in perfusion pressure in a non-concentration-dependent manner. A concentration of 10(-10) M R-PIA had no effect on the incidence of ventricular fibrillation (VF), while all higher concentrations reduced the incidence of VF to a similar degree (from 60% in controls to 10%, 20%, 10%, and 0% with 10(-9), 5 x 10(-9), 10(-8), and 5 x 10(-8) M R-PIA, respectively). R-PIA also reduced the total ventricular premature beat (VPB) count, but in a concentration-dependent manner. Chronic treatment of the rats with R-PIA (50 microg/kg i.p., bd; n = 10) for 7 days caused a significant attenuation of the bradycardic response to acute perfusion in vitro with R-PIA (10(-8) M) and abolished the attenuation of the sustained rise in perfusion pressure during myocardial ischemia. The antifibrillatory effect of R-PIA, however, was unaffected by chronic pretreatment (VF incidence 0% vs. 70% in control hearts from rats that had been given chronic saline ip injections n = 10; P < 0.01). These results suggest that the bradycardia induced by acute R-PIA may not be the mechanism underlying the antifibrillatory effect of R-PIA, while the reduction in the less severe arrhythmias is heart rate dependent. Furthermore, while chronic treatment with R-PIA significantly attenuates the heart rate response to acute R-PIA challenge, the antifibrillatory properties remain intact.