Protection of IB-MECA against myocardial stunning in conscious rabbits is not mediated by the A1 adenosine receptor

Abstract

The goal of this study was to determine whether the protective effects of the A₃AR agonist N ⁶-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) against myocardial stunning are mediated by the A₁AR. Six groups of conscious rabbits underwent a sequence of six 4-minute coronary occlusion (O)/4-minute reperfusion (R) cycles for three consecutive days (days 1, 2, and 3). In vehicle-treated rabbits (group I), the recovery of systolic wall thickening (WTh) in the ischemic/reperfused region was markedly depressed on day 1, indicating the presence of severe myocardial stunning. On days 2 and 3, however, the recovery of systolic WTh was markedly accelerated, indicating the presence of late ischemic preconditioning (PC). When rabbits were pretreated with the A₁AR agonist 2-chloro-N ⁶-cyclopentyladenosine (CCPA, 100 μg/kg i.v.) or with IB-MECA (100 μg/kg i.v.) 10 min prior to the first sequence of O/R cycles on day 1 (group III and V, respectively), the recovery of systolic WTh was markedly accelerated compared to vehicle-treated animals (reflected as an ∼48 % decrease in the total deficit of systolic WTh). The magnitude of the protection afforded by adenosine receptor agonists was equivalent to that provided by late ischemic PC. Pre-treating rabbits with the A₁AR antagonist N-0861 completely blocked both the hemodynamic and the cardioprotective effects of CCPA (group IV). However, the same dose of N-0861 did not block the cardioprotective actions of IB-MECA (group VI). Importantly, N-0861 did not influence the degree of myocardial stunning in the absence of PC (group II) and it did not block the development of late ischemic PC. Taken together, these results provide conclusive evidence that the cardioprotective effects of IB-MECA are not mediated via the A₁AR, supporting the concept that activation of A₃ARs prior to an ischemic challenge provides protection against ischemia/reperfusion injury.