Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction.

Abstract

BACKGROUND: Recent data from this laboratory indicate that pretreatment with adenosine can protect the heart against infarction via A1-receptors, but because of systemic hypotension, adenosine had to be given into the coronary circulation. METHODS AND RESULTS: In this study, we tested whether the protection could be achieved by intravenous administration of the A1-selective adenosine agonists N6-(phenyl-2R-isopropyl)-adenosine (PIA) and 2-chloro-N6-cyclopentyladenosine (CCPA). Nine groups of open-chest anesthetized rabbits were subjected to 30 minutes of regional coronary ischemia and 3 hours of reperfusion. Infarct size was determined by tetrazolium staining. Control hearts receiving no treatment had 38 +/- 4% of the risk zone infarcted. Preconditioning with 5 minutes of ischemia and 10 minutes of reperfusion before ischemia limited the infarct to 8 +/- 4%. Intravenous PIA 15 minutes before 30-minute ischemia also limited infarct size to 6 +/- 2% at the highest dose. CCPA offered similar protection. When the PIA was given at reperfusion, infarct size was 46 +/- 6%, indicating that receptor activation must precede ischemia to protect. Pretreatment with CGS 21680, a selective A2-receptor agonist, caused identical hypotension but failed to limit infarct size (43 +/- 3%), indicating again that the A1-receptor is involved. When rabbits pretreated with PIA were paced at 220 beats per minutes, PIA still limited infarct size (16 +/- 4%), indicating that protection was not the result of bradycardia. CONCLUSIONS: These results indicate that stimulation of adenosine A1-receptors causes the heart to become resistant to ischemia and that this protection can be achieved with intravenous administration of A1-selective agents.