Cardioprotection with pre‐ and postischemic adenosine and A3 receptor activation: Differing mechanisms and effects on necrosis versus stunning

Abstract

AbstractThe importance of pre‐ versus postischemic treatment in adenosine‐mediated cardioprotection is unclear. We characterized effects of pre‐ and postischemic adenosine or A3 adenosine receptor (A3AR) agonism in Langendorff perfused mouse hearts subjected to 20 min global ischemia and 45 min reperfusion. In untreated hearts, diastolic pressure remained elevated at 21±2 mmHg, ventricular pressure development recovered to 75±3 mmHg (50% of pre‐ischemia), and 24±3 IU/ lactate dehydrogenase (LDH) was lost. Adenosine (50 µM) treatment prior to ischemia reduced LDH efflux by 40% (15±2 IU/g) yet exerted only modest effects on recovery of force (83±2 mmHg). Additional treatment during the first 15 min reperfusion was no more effective in reducing LDH efflux (14±2 IU/g) but further limited contractile dysfunction (93±2 mmHg). Continued treatment throughout 45 min reperfusion most effectively limited LDH efflux (10±1 IU/g) and contractile dysfunction (124±6 mmHg). Some protection was also observed with treatment during reperfusion only (16±1 IU/g and 106±3 mmHg). Effects of pre‐ and postischemic adenosine on necrosis and contractile dysfunction were not mimicked by pre‐ and postischemic A3AR agonism with 100 nM 2‐chloro‐N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methyluronamide (Cl‐IB‐MECA), or mitochondrial KATP channel activation with 50 µM diazoxide. Protection with Cl‐IB‐MECA and diazoxide was less than with adenosine, maximal with treatment during ischemia alone, and absent with treatment during reperfusion alone. Data indicate antinecrotic effects of adenosine are primarily mediated prior to and during ischemia and are consistent with A3AR and mitochondrial KATP channel activation. In contrast, protection against contractile dysfunction involves other mechanisms and is enhanced with prolonged postischemic treatment. Drug Dev. Res. 58:447–453, 2003. © 2003 Wiley‐Liss, Inc.