3-HYDROXY-3-METHYL GLUTARYL COENZYME-A REDUCTASE INHIBITION MODULATESVASOPRESSIN-STIMULATED CA2-MUSCLE CELLS( RESPONSES IN RAT A10 VASCULAR SMOOTH)

Previous evidence has indicated a role for changes in cell membrane ch olesterol in the modulation of [Ca2+](i) responses and smooth muscle c ontraction to vascular agonists. However, the actions of plasma choles terol-lowering agents such as 3-hydroxy-3-methyl glutaryl coenzyme A r eductase inhibitors leg, simvastatin) have not been defined. Such agen ts may in addition affect isoprenoid intermediates that may pray a rol e in signal transduction pathways involving G proteins. Arginine vasop ressin-induced [Ca2+](i) responses in A10 rat vascular myocytes were t herefore studied in vitro. Vasopressin stimulated an initial peak [Ca2 +](i) that was independent of extracellular Ca2+ entry and a subsequen t plateau that was dependent on Ca2+ influx, mainly through receptor-o perated dihydropyridine-insensitive divalent cation channels. Simvasta tin-treated A10 cells (5 mg/L for 24 hours) showed a normal initial pe ak response to vasopressin, but the plateau phase of Ca2+ entry was si gnificantly impaired. By use of Mn2+ quenching of intracellular fura 2 to measure divalent cation entry, the maximal rate of vasopressin-sti mulated Mn2+ entry was impaired in simvastatin-treated cells by 52%. M evalonate (I mmol/L for 4 hours at 37 degrees C) reversed all the chan ges in simvastatin-treated cells. There were no associated changes in total cellular cholesterol or fluorescence anisotropy measurements wit h simvastatin treatment. Measurements of inositol-1,4,5-trisphosphate mass showed that simvastatin did not impair the initial peak response to vasopressin but significantly reduced the subsequent plateau phase. These changes were also reversed with mevalonate incubation. These fi ndings suggest that simvastatin has additional effects on [Ca2+](i) ho meostasis that are independent of changes in total cell cholesterol.