Abstract

There is now good evidence that inhibitors of PARP activity reduce the tissue injury caused by regional myocardial ischemia and reperfusion. For instance, various, chemically distinct inhibitors of PARP activity [including 3-aminobenzamide (3-AB) and 1, 5-dihydroxyisoquinoline (ISO)] reduce the infarct size caused by ischaemia-reperfusion injury of the rabbit heart in vivo. In addition, 3-AB and ISO also reduce the infarct size caused by regional myocardial ischaemia and reperfusion in the heart of the rat in vivo and in vitro. Moreover, ISO reduces the contractile dysfunction, the fall in high-energy phosphates caused by global myocardial ischemia and reperfusion in the rat heart. Exposure of human cardiac myoblasts in vitro results in an increase in PARP activity, and secondary cell death. Inhibition of this increase in PARP activity reduces the impairment in mitochondrial respiration as well as the associated cell death caused by these reactive oxygen species. The tissue injury caused by coronary artery occlusion and reperfusion in PARP-1 knock out mice is substantially reduced (when compared to their wild-type litter mates). Potent, water-soluble inhibitors of PARP activity (including 5-aminoisoquinolinone, PJ-34 and others) cause a substantial reduction in myocardial infarct size in the rat in vivo. Taken together, these findings support the view that (1) the excessive activation of PARP contributes to myocardial reperfusion injury, and (2) potent, water-soluble inhibitors of PARP activity may be useful in conditions associated with acute myocardial ischemia and reperfusion. These conditions may include acute myocardial infarction, coronary angioplasty, cardiac transplantation and bypass heart surgery. References: 1.Thiemermann C et al: Proc Natl Acad Sci USA, 1997; 94: 679-683

Keywords: Heart, Infarction, 5-AIQ, Reperfusion Injury, cardiac ischemia, ischaemia