3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibition modulates vasopressin-stimulated Ca2+ responses in rat A10 vascular smooth muscle cells.
Previous evidence has indicated a role for changes in cell membrane cholesterol in the modulation of [Ca2+]i responses and smooth muscle contraction to vascular agonists. However, the actions of plasma cholesterol-lowering agents such as 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (eg, simvastatin) have not been defined. Such agents may in addition affect isoprenoid intermediates that may play a role in signal transduction pathways involving G proteins. Arginine vasopressin-induced [Ca2+]i responses in A10 rat vascular myocytes were therefore studied in vitro. Vasopressin stimulated an initial peak [Ca2+]i that was independent of extracellular Ca2+ entry and a subsequent plateau that was dependent on Ca2+ influx, mainly through receptor-operated dihydropyridine-insensitive divalent cation channels. Simvastatin-treated A10 cells (5 mg/L for 24 hours) showed a normal initial peak response to vasopressin, but the plateau phase of Ca2+ entry was significantly impaired. By use of Mn2+ quenching of intracellular fura 2 to measure divalent cation entry, the maximal rate of vasopressin-stimulated Mn2+ entry was impaired in simvastatin-treated cells by 52%. Mevalonate (1 mmol/L for 4 hours at 37 degrees C) reversed all the changes in simvastatin-treated cells. There were no associated changes in total cellular cholesterol or fluorescence anisotropy measurements with 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 findings suggest that simvastatin has additional effects on [Ca2+]i homeostasis that are independent of changes in total cell cholesterol.
Ng
L L
LL
Department of Pharmacology, Leicester Royal Infirmary, UK.
Davies
J E
JE
Wojcikiewicz
R J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007295:Inositol Phosphates / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D019821:Simvastatin; D014667:Vasopressins / Q000494:pharmacology*
D015220:Calcium Channels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007295:Inositol Phosphates; D014667:Vasopressins; D008345:Manganese; D008148:Lovastatin; D019821:Simvastatin; D008798:Mevalonic Acid; D002118:Calcium