CALCIUM OVERLOAD AND CARDIAC MYOCYTE CELL-DAMAGE INDUCED BY ARACHIDONATE LIPOXYGENATION

The accumulation of arachidonic acid and lipoxygenase metabolites of a rachidonate occurs in ischemic-reperfused myocar dium. Although lipoxy genase inhibitors have been shown to attenuate myocardial infarct size after ischemia-reperfusion, the relationship between arachidonate lip oxygenation and myocardial injury remains unclear. To investigate the direct effect of arachidonate lipoxygenation on cardiac myocytes, isol ated rat cardiac myocytes loaded with indo 1 were superfused with Tyro de solution containing arachidonic acid mixed with soybean lipoxygenas e. Although neither arachidonic acid nor lipoxygenase alone had any ef fects, arachidonic acid plus lipoxygenase induced an increase in the t witch amplitude associated with an increased intracellular Ca2+ concen tration ([Ca2+](i)) and irreversible hypercontracture. Nordihydroguaia retic acid, a lipoxygenase inhibitor, blocked these effects. Linolenic acid, which is also a lipoxygenase substrate, caused the same effects as arachidonic acid in the presence of lipoxygenase, whereas oleic an d stearic acid, which do not function as lipoxygenase substrates, did not. Both ascorbic acid and cr-tocopherol attenuated an increase in [C a2+](i) and the cellular damage, whereas nicardipine and superoxide di smutase had no effects. These results suggest that lipoxygenase metabo lites of arachidonic acid cause intracellular Ca2+ overload and cellul ar damage to cardiomyocytes, probably through augmentation of lipid pe roxidation of the cell membranes by free radicals.