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

Hatter Institute for Cardiovascular Studies, Department of Academic and Clinical Cardiology, University of College Hospital and Medical School, London, England, United Kingdom.

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 A1 receptor activation. BACKGROUND: Several recent studies have 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 A1 receptor agonist, 2-chloro-N6-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 microg/kg body weight, or 0.9% saline at 48-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 A1 receptor activation, a subgroup of animals were treated with a further bolus of CCPA, 100 microg/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. CONCLUSIONS: We conclude that rabbits can be maintained in a protected state against myocardial infarction by repeated activation of adenosine A1 receptors, with no evidence of tachyphylaxis to the infarct-limiting or hemodynamic effects of CCPA. This finding suggests that adenosine A1 receptor activation may hold promise as a new approach to long-term cardioprotection.

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