The role of phospholipase A2 in calcium-induced damage in cardiac and skeletal muscle.
This study compares the action of inhibitors of the eicosanoid cascade on calcium-induced myofilament damage in cardiac muscle of the perfused frog heart and incubated frog ventricle slices, and in skeletal muscle of incubated mammalian diaphragm and isolated and saponin-skinned amphibian pectoris cutaneous muscle. Mepacrine (10(-5) M) and indomethacin (3 x 10(-6) M) protected completely against myofilament damage induced by entry of calcium in the 'calcium-paradox' in frog heart. However, inhibition of phospholipase A2 (PLA2) (with chlorpromazine, 2 x 10(-4) M, or mepacrine, 10(-5) M, 5 x 10(-5) M), of cyclo-oxygenase enzymes (with indomethacin, 3 x 10(-6) M to 10(-5) M or BW755C, 3.8 x 10(-4) M), or of lipoxygenase enzymes (with BW755C, 3.8 x 10(-4) M or nordihydroguaiaretic acid, 2 x 10(-6) M or 5 x 10(-6) M) all failed in intact cardiac or skeletal muscle cells to prevent the myofilament damage that is rapidly triggered by 10(-2) M caffeine, 6 x 10(-6) M ruthenium red, 10(-4) M DNP or 5 micrograms ml-1 A23187. These agents also failed completely to protect against myofilament damage in saponin-skinned amphibian skeletal muscle when [Ca]i was raised to 8 x 10(-6) M. Thus, inhibition of PLA2 does not protect the myofilament apparatus against calcium released intracellularly, and it is suggested that mepacrine and indomethacin can block entry of calcium in the calcium-paradox in the amphibian heart. Chlorpromazine (2 x 10(-4) M) and mepacrine (10(-3) M) at zero [Ca] caused severe myofilament damage in skinned muscle, possibly due to an effect on membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002746:Chlorpromazine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009132:Muscles / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D010740:Phospholipases / Q000502:physiology*; D010741:Phospholipases A / Q000378:metabolism / Q000502:physiology*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology; D011896:Rana temporaria; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure
D004791:Enzyme Inhibitors; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D002118:Calcium; D002746:Chlorpromazine; D007213:Indomethacin