Arachidonic acid and lipoxygenase metabolites uncouple neonatal rat cardiac myocyte pairs

The effects of arachidonic acid (AA) and its metabolites on the conductance (g(j)) of the gap junctions between neonatal rat myocardial cells was investigated. AA reduced g(j) in a dose- (2, 5, and 20 μM) and time- dependent fashion. Pretreatment of the cells with an inhibitor of the 5- lipoxygenase pathway, U-70344A, shifted the dose-response curve to the right; pretreatment with indomethacin, an inhibitor of the cyclooxygenase pathway, had no effect. The mean time to uncoupling was 3.7 ± 0.3, 3.8 ± 0.9, and 4.6 ± 0.6 min (means ± SE, P < 0.05) for 5 μM AA, 5 μM AA + indomethacin, and 5 μM AA + U-70344A, respectively. Incorporation of AA into membrane phospholipids was not affected by the inhibitor. These studies suggest that complete uncoupling of the cells occurred at membrane concentrations of 3-4 mol%. The data indicate that AA and a 5-lipoxygenase metabolite uncouple neonatal rat heart cells. The data are discussed with respect to the possible underlying mechanism of uncoupling and the potential role of gap junctions in arrhythmia formation in ischemic heart disease.