Effects of AQ-AH 208, a New Specific Bradycardic Agent, on Myocardial Ischemia–Reperfusion Injury in Anesthetized Dogs

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Abstract
Summary: The effects of a new specific bradycardic agent, AQ-AH 208—3,4-dihydro-6,7-dimethoxy-2-[3-([2-(3,4-dimethoxyphenyl) - ethyl] - aminoethyl) - propyl]-1(2H)isochinolinon—on ischemia–reperfusion-induced myocardial infarct size following a 2-h occlusion and 30-min reperfusion period of the left anterior descending coronary artery (LAD) were determined in anesthetized dogs. Regional myocardial blood flow was measured by use of radioactive microspheres (15 μm), and tissue injury was determined by use of the triphenyltetrazolium chloride histochemical stain. In two groups of dogs, vehicle (saline) or AQ-AH 208 (500-μg/kg bolus followed by 25 μg/kg/min) was administered intravenously 10 min prior to LAD occlusion and infused throughout the occlusion and reperfusion periods. In a third group, AQ-AH 208 was given 10 min after LAD occlusion and infused throughout the remainder of the experiment. AQ-AH 208 treatment resulted in a significant reduction in heart rate and heart rate–systolic pressure product during occlusion and reperfusion. AQ-AH 208 produced variable increases in collateral blood flow as compared with the saline-treated group 20 min and 2 h following LAD occlusion. These increases in collateral perfusion were primarily to the midmyocardium and subendocardium, as reflected by increases in the endocardial/epicardial blood flow ratio (endo/epi). During reperfusion, subendocardial flow was significantly elevated and subepicardial flow reduced in both AQ-AH 208–treated groups, as compared with control, and the endo/epi was markedly increased. In all three groups, left ventricular weight, area at risk, percent of the left ventricle at risk, and retrograde flow and pressure prior to drug treatment were similar. Compared with the saline-treated dogs, AQ-AH 208 pre- or posttreatment produced nearly identical decreases (66%) in the three indices of tissue injury: absolute infarct weight (g) and percent of the left ventricle and area at risk infarcted. The beneficial effect of AQ-AH 208 has a multifactorial basis, including a decrease in myocardial oxygen requirements and/or an increase in collateral perfusion.