Inhibition of myocardial rotenone-insensitive NADH cytochrome c reductase by amphiphilic compounds.
Because myocardial ischemia is correlated with both an elevation of intracellular levels of amphiphilic lipid metabolites and a decrease in the rotenone-insensitive NADH cytochrome c reductase (RINCR), we investigated the effects in vitro of some amphiphilic lipid metabolites and synthetic detergents on the activity of RINCR-enriched subfractions of microsomes from isolated cardiac myocytes. RINCR activity was unaffected in vitro by the addition of lysophosphatidylethanolamine (up to 0.5 mM) but was inhibited (maximum 63%) by lysophosphatidylcholine (8 microM). Palmitoyl carnitine (up to 2 mM) was ineffective, but the coenzyme A thioesters of palmitate, stearate, oleate, and arachidonate were inhibitory at concentrations (less than 3 microM) below their critical micellar concentrations. Arachidonyl CoA was approximately one order of magnitude more inhibitory than the other long-chain acyl CoA thioesters. Kinetic analyses revealed the effect of arachidonyl CoA on RINCR activity to be exclusively an alteration of the Vmax with no change in the Km for cytochrome c. The inhibition of myocytic RINCR activity by long-chain acyl CoA may be unrelated to the bulk-phase detergency of this lipid amphiphile since the effects were observed at concentrations below the critical micellar concentration, and other lipid amphiphiles had no effect on RINCR activity. Inhibition of microsomal RINCR activity may result from localized disruption of the membrane microenvironment of the enzyme complex by penetration or dissolution of long-chain acyl CoA into the membrane. The pronounced sensitivity of myocytic RINCR activity to long-chain acyl CoA suggests a relationship between the decreased RINCR activity and the increased levels of this class of lipid metabolites observed in the ischemic myocardium.
D000214:Acyl Coenzyme A / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003579:Cytochrome Reductases / Q000037:antagonists & inhibitors*; D003902:Detergents / Q000494:pharmacology*; D004285:Dogs; D004351:Drug Resistance; D050356:Lipid Metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D012402:Rotenone / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*
D000214:Acyl Coenzyme A; D003902:Detergents; D013501:Surface-Active Agents; D012402:Rotenone; D009247:NADH, NADPH Oxidoreductases; D003579:Cytochrome Reductases; C014227:ferricyanide reductase; D009245:NADH Dehydrogenase