@article {Sill1006, author = {J C Sill and C Uhl and S Eskuri and R Van Dyke and J Tarara}, title = {Halothane inhibits agonist-induced inositol phosphate and Ca2+ signaling in A7r5 cultured vascular smooth muscle cells.}, volume = {40}, number = {6}, pages = {1006--1013}, year = {1991}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Halothane, an anesthetic with marked depressant effects on the circulation, was studied for its ability to inhibit inositol phosphate and Ca2+ signaling evoked by the vasoactive hormone arginine vasopressin (AVP) and Ca2+ responses elicited by platelet-derived growth factor and by thapsigargin in cultured A7r5 vascular smooth muscle cells. Changes in apparent [Ca2+]i were measured using the indicator indo-1 and flow cytometry, whereas inositol phosphate levels were determined using myo-[3H]inositol and column chromatography. Preincubation with clinically relevant concentrations of halothane resulted in dose-dependent depression of [Ca2+]i responses evoked on stimulation with AVP. Halothane (2.0\%) inhibited the increases in [Ca2+]i by 34-45\%. In cells incubated in Ca(2+)-free medium plus 0.5 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N{\textquoteright},N{\textquoteright}-tetraacetic acid, the halothane effect was more marked, with 1.5\% halothane inhibiting the responses by approximately 53-61\%. However, when Ca2+ influx was stimulated by addition of 5 mM Ca2+ in the continued presence of the agonist, the [Ca2+]i response was inhibited by only 15\%, suggesting that release of Ca2+ rather than Ca2+ influx is more sensitive to inhibition by the anesthetic. The effects of halothane on Ca2+ homeostasis are not explained solely by anesthetic-induced depletion of Ca2+ from intracellular stores, because the anesthetic inhibited increases in [Ca2+]i elicited by thapsigargin in cells suspended in Ca(2+)-free medium by only 31\%. Halothane inhibited inositol phosphate formation elicited by AVP, suggesting an additional means by which the anesthetic may alter agonist-induced Ca2+ responses. The current results also demonstrate that halothane actions are not specific solely to responses evoked by AVP, which acts via a guanine nucleotide-binding protein-linked signaling pathway, but include responses stimulated by platelet-derived growth factor, an agonist that elevates [Ca2+]i via receptor-latent tyrosine kinase activity. The current results demonstrate that, in vascular smooth muscle cells, halothane alters Ca2+ homeostasis, an action that may underlie the in vivo vasodilator effects of the anesthetic.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/40/6/1006}, eprint = {https://molpharm.aspetjournals.org/content/40/6/1006.full.pdf}, journal = {Molecular Pharmacology} }