title: Propofol regulation of calcium entry pathways in cultured A10 and rat aortic smooth muscle cells.
abstract: 1. We have investigated the effect of propofol, an intravenous anaesthetic, on the intracellular calcium concentration ([Ca2+]i), Ca2+ entry pathways and on inositol phosphate formation in vascular smooth muscle cells. [Ca2+]i and Ca2+ flux were monitored with the Ca(2+)-sensitive fluorescent dye, fura-2, and by 45Ca2+ uptake. Production of labelled inositol phosphates was analysed by anion-exchange chromatography. 2. Treatment of the cells with endothelin-1 (ET-1) increased formation of inositol phosphates and elevated [Ca2+]i due to both release of Ca2+ from intracellular pools and prolonged entry of Ca2+ from outside the cell. Propofol reduced production of inositol phosphates mediated by ET-1 and arginine vasopressin which activate phospholipase C. 3. The sustained Ca2+ entry stimulated by ET-1 was found to occur through the activation of L-type Ca channels. This was inhibited by propofol in a dose-dependent manner. 4. Activation of protein kinase C (PKC) by phorbol esters activated a pharmacologically-similar channel and produced a similar change in [Ca2+]i due to Ca2+ entry. The entry was blocked by an L-type channel antagonist, nicardipine and by the anaesthetic drug, propofol. 5. Treatment of the cells with thapsigargin, a selective inhibitor of the sarcoplasmic reticulum Ca(2+)-ATPase, also elevated [Ca2+]i by inducing the release of intracellular Ca2+ and the continued entry of extracellular Ca2+ through a nicardipine-insensitive Ca channel. Neither release nor entry induced by thapsigargin was affected by propofol. 6. These findings suggest that propofol selectively inhibits Ca2+ entry through the L-type channel induced by ET-1 and phorbol esters but has no effects on Ca2+ entry via the nicardipine-insensitive channel and on Ca2+ release from intracellular pools initiated by thapsigargin. This may represent one of the mechanisms responsible for propofol-induced vasodilatation.
authors.affiliation: Department of Anaesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Y T
authors.initials: YT
authors.lastname: Xuan
authors.forename: P S
authors.initials: PS
authors.lastname: Glass
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D015220:Calcium Channels; D019332:Endothelin-1; D007295:Inositol Phosphates; D019284:Thapsigargin; D009529:Nicardipine; D000252:Calcium-Transporting ATPases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D015742:Propofol