Prolonging the delayed phase of myocardial protection:: Repetitive adenosine A1 receptor activation maintains rabbit myocardium in a preconditioned state

Objectives. This study was designed to examine whether the myocardium can be maintained in a protected state by extending the delayed phase of cardioprotection with chronic, intermittent adenosine A(1) receptor activation. Background. Several recent studies hare explored the temporal characteristics of the protective effects of ischemic preconditioning. Two distinct phases of myocardial protection have been described: the short-lived immediate phase, or "classic" preconditioning, and the delayed phase, or "second window of protection" (SWOP). Previous studies have examined the potential for extending the duration of classic preconditioning by repeated application of the preconditioning stimulus. Pretreatment with either multiple episodes of ischemia or continuous infusion of a selective adenosine A(1) receptor agonist, 2-chloro-N-6-cyclopentyladenosine (CCPA), resulted in attenuation of the protective effects of preconditioning, implying downregulation of the receptors involved in triggering classic preconditioning. Methods. Male New Zealand White rabbits were treated with repeated intravenous boluses of CCPA, 100 mu g/kg body weight, or 0.9% saline at 18-h intervals. Forty-eight hours after the fifth dose (day 10), the animals were anesthetized and subjected to 30 min of coronary occlusion, followed by 120 min of reperfusion, Infarct size was determined as a percentage of myocardial risk volume using tetrazolium staining. To further explore whether the rabbits had developed tolerance to the effects of adenosine Al receptor activation, a subgroup of animals were treated with a further bolus of CCPA 100 mu g/kg, at the end of the reperfusion period, and the hemodynamic response was monitored for 10 min before excision of the heart. Results. Pretreatment with intermittent doses of CCPA resulted in a 42% reduction in the infarct to risk ratio compared with vehicle pretreatment (26.6 +/- 3.7% vs. 45.9 +/- 5.5%, p < 0.01) Furthermore, CCPA treatment at the end of reperfusion resulted in identical hypotension and bradycardia in both groups. a Conclusions. We conclude that rabbits can be maintained in a protected state against myocardial infarction by repeated activation of adenosine A(1) receptors, with no evidence of tachyphylaxis to the infarct-limiting or hemodynamic effects of CCPA, This finding suggests that adenosine A(1) receptor activation may hold promise as a new approach to long-term cardioprotection. (C)1998 by the American College of Cardiology.