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

Abstract

The importance of pre-versus postischemic treatment in adenosine-mediated cardioprotection is unclear. We characterized effects of pre-and postischemic adenosine or A 3 adenosine receptor (A 3 AR) agonism in Langendorff perfused mouse hearts subjected to 20 min global ischemia and 45 min reperfusion. In untreated hearts, diastolic pressure remained elevated at 2172 mmHg, ventricular pressure development recovered to 7573 mmHg (50% of pre-ischemia), and 2473 IU/ lactate dehydrogenase (LDH) was lost. Adenosine (50 mM) treatment prior to ischemia reduced LDH efflux by 40% (1572 IU/g) yet exerted only modest effects on recovery of force (8372 mmHg). Additional treatment during the first 15 min reperfusion was no more effective in reducing LDH efflux (1472 IU/g) but further limited contractile dysfunction (9372 mmHg). Continued treatment throughout 45 min reperfusion most effectively limited LDH efflux (1071 IU/g) and contractile dysfunction (12476 mmHg). Some protection was also observed with treatment during reperfusion only (1671 IU/g and 10673 mmHg). Effects of preand postischemic adenosine on necrosis and contractile dysfunction were not mimicked by pre-and postischemic A 3 AR agonism with 100 nM 2-chloro-N 6 -(3-iodobenzyl)-adenosine-5 0 -N-methyluronamide (Cl-IB-MECA), or mitochondrial K ATP channel activation with 50 mM 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 A 3 AR and mitochondrial K ATP channel activation. In contrast, protection against contractile dysfunction involves other mechanisms and is enhanced with prolonged postischemic treatment. Drug Dev.

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…Inhibitory effects of 5-HD may reflect antagonism of these actions and/or activation to 5-HD-CoA with modulation of fatty acid oxidation and mitochondrial metabolism (97). Given the common effects of adenosine and diazoxide (77,207,210,228) and inhibition of adenosinergic protection by 5-HD (113,118,207,210,228), it is possible acute adenosinergic protection involves the above-mentioned inhibitory actions on ROS generation, mitochondrial metabolism, and nucleotide-dependent enzymatic activity as opposed to mitoK ATP activation. In this respect, a number of investigations verify that adenosine receptor activation modifies mitochondrial energy metabolism (2, 43, 79, 112) and inhibits ROS generation (210) in ischemic-reperfused myocardium.…”

“…Nonetheless, postischemic contractility is enhanced by exogenous and endogenous adenosinergic stimuli under conditions of limited or no detectable cell death (149,161,165,200,201,210,215,234,235,246,258,318). In addition, recent work has identified differential effects of adenosine (77,228) and adenosinergic preconditioning (226) on oncosis versus contractile function, supporting amelioration of both injuries via different pathways.…”

“…However, again there is also evidence that postischemic adenosine protects in blood-free models (75,86,225,317). Additionally, whereas recent studies indicate A 3 AR activation on reperfusion limits neutrophil-mediated reperfusion injury in vivo (133) and apoptotic death and injury in isolated hearts and cardiomyocytes (188), there is also evidence for minimal postischemic protection in isolated hearts (77).…”

Protective Mechanism of Adenosine to the Rat Arterial Endothelial Dysfunction Induced by Hydrogen Peroxide

“…12) However, there was no detectable protective effects of A 2B adenosine receptor on coronary dysfunction. 34) Flood et al 32) found substantial protection against coronary dysfunction via A 1 adenosine receptor activation by endogenous adenosine. Exogenous A 3 adenosine receptor activation further limits dysfunction and improves post-ischemic vasoregulation.…”

“…30,31) A 2 adenosine receptor activation was found to protect against postischemic vascular endothelial injury. 10,32,33) Protection via A 2A adenosine receptor sub-type likely involved modulation of blood-cell dependent processes. 12) However, there was no detectable protective effects of A 2B adenosine receptor on coronary dysfunction.…”