REDUCTION OF CANINE MYOCARDIAL INFARCT SIZE BY A DIFFUSIBLE REACTIVE OXYGEN METABOLITE SCAVENGER - EFFICACY OF DIMETHYLTHIOUREA GIVEN AT THE ONSET OF REPERFUSION

A number of scavengers of reactive oxygen metabolites reduce myocardial injury when given before ischemia and reperfusion, but few, if any, have proven to be effective when given near the onset of reperfusion. This is particularly true when infarct size is measured after at least 48 hours of reperfusion, when the full extent of myocardial damage has become apparent. Dimethylthiourea (DMTU) is an extremely diffusible, potent scavenger of hydroxyl radical, hydrogen peroxide, and hypochlorous acid, with a long half-life of 43 hours. Sixteen chloralose-anesthetized dogs underwent 90 minutes of left anterior descending coronary artery (LAD) occlusion followed by 48 hours of reperfusion. Collateral flow was measured by radioactive microspheres. Infarct size and risk area were measured by a postmortem dual-perfusion technique using triphenyl tetrazolium chloride and Evan's blue dye. In eight dogs, therapy with DMTU (500 mg/kg i.v.) was given during the last 15 minutes of ischemia and the first 15 minutes of reperfusion. In eight control dogs, the same volume of 0.9% saline was given during the last 15 minutes of ischemia through the first 15 minutes of reperfusion. Infarct size as a percent of risk area was reduced in the DMTU-treated group compared with the saline-treated controls (DMTU = 42 +/- 4% versus saline = 59 +/- 4%, p < 0.01). There were no differences between the groups in risk area as a percent of the left ventricle (DMTU = 25 +/- 2% versus saline = 21 +/- 2%, p = NS), in LAD endocardial flow during ischemia (DMTU = 3.5 +/- 0.4 versus saline = 4.0 +/- 0.5 ml/100 g/min, p = NS), in LAD transmural flow during ischemia (DMTU = 13.3 +/- 1.3 versus saline = 12.0 +/- 1.5 ml/100 g/min, p = NS), or in the heart rate-blood pressure product. Histological and in vitro biochemical analyses confirmed that the tetrazolium method accurately delineated infarct size in saline- and DMTU-treated dogs. Thus, DMTU given near the onset of reperfusion dramatically reduced infarct size measured after an interval sufficient for irreversibly damaged cells to become necrotic. The efficacy of DMTU in reducing infarct size may reflect its rapid entry into myocardial cells as well as continued protection for a prolonged period during reperfusion.