Reduction of infarct size and preservation of endothelial function by multidose intravenous adenosine during extended reperfusion

Abstract

It has been proposed that infarct extension is developed from the early to the late phase of reperfusion (R). This study compares the protective effect of single or multidose administration of adenosine (Ado) on infarct size during early and late phases of R by attenuating neutrophil (PMN) recruitment. Forty-one dogs underwent 60-min left anterior descending artery (LAD) ischemia followed by 6, 24, and 48 h of R, respectively. Infarct size (%) increased over 6 to 24 h (27 ± 2 to 38 ± 4; P < 0.05 24 h versus 6 h group), with a corresponding increase in creatine kinase activity. Transmural myocardial blood flow (mL/min/g) decreased from 6 to 24 h (0.47 ± 0.02 to 0.29 ± 0.02; P < 0.05 24 h versus 6 h group). PMN localization (mm 2 myocardium) in the perinecrotic tissue detected by immunohistochemistry with anti-CD18 antibody, and accumulation detected by myeloperoxidase (MPO, ΔAbs/min/g) increased from 6 to 24 h (292 ± 25 to 605 ± 44; P < 0.05 24 h versus 6 h group; and 55 ± 7 to 96 ± 5; P < 0.05 24 h versus 6 h group), respectively. In in vitro analysis, PMN adherence (mm 2 endothelium) to postischemic LAD increased from 98 ± 2 to 125 ± 3 ( P < 0.05 24 h versus 6 h group) and maximal LAD endothelium-dependent relaxation (%) impaired from 6 to 24 h (74 ± 7 to 42 ± 10; P < 0.05 24 h versus 6 h group). Intravenous Ado (140 μg/kg/min) for 2 h at R reduced infarct size (17 ± 2; P < 0.05 Ado versus 6 h group), CD18 positive cells (130 ± 10; P < 0.05 Ado versus 6 h group), MPO (14 ± 3; P < 0.05 Ado versus 6 h group), PMN adherence (57 ± 2; P < 0.05 Ado versus 6 h group), and augmented LAD vascular relaxation (102 ± 5 versus 74 ± 7; P < 0.05 Ado versus 6 h group). However, this protection by Ado was lost when R was extended to 24 h. Treatment with multiple infusion of Ado at 2, 6, 12, and 18 h R significantly preserved protective effects seen at 6 h R in the Ado group. Protection by multidose Ado was still preserved when R was extended to an additional 24 h. These data suggest that interventions aiming at permanently reducing R injury may thus need to be administered not only at early R, but also during late phase. A slow wave of PMN accumulation at late R may be involved in the extension of infarction and endothelial dysfunction.