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A Ca2+-dependent chloride current and Ca2+ influx via Cav1.2 ion channels play major roles in P2Y receptor-mediated pulmonary vasoconstriction

Mitchell, Callum and Syed, Nawazish-I-Husain and Gurney, Alison and Kennedy, Charles (2012) A Ca2+-dependent chloride current and Ca2+ influx via Cav1.2 ion channels play major roles in P2Y receptor-mediated pulmonary vasoconstriction. British Journal of Pharmacology, 166 (4). pp. 1503-1512.

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ATP, UTP and UDP act at smooth muscle P2X and P2Y receptors to constrict rat intrapulmonary arteries, but the underlying signalling pathways are poorly understood. Here, we determined the roles of the Ca(2+) -dependent chloride ion current (I(Cl,Ca) ), Ca(v) 1.2 ion channels and Ca(2+) influx. Isometric tension was recorded from endothelium-denuded rat intrapulmonary artery rings (i.d. 200-500 µm) mounted on a wire myograph. The I(Cl,Ca) blockers, niflumic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and the Ca(v) 1.2 channel blocker, nifedipine, reduced peak amplitude of contractions evoked by UTP and UDP by ∼45-50% and in a non-additive manner. Ca(2+) -free buffer inhibited responses by ∼70%. Niflumic acid and nifedipine similarly depressed contractions to ATP, but Ca(2+) -free buffer almost abolished the response. After peaking, contractions to UTP and UDP decayed slowly by 50-70% to a sustained plateau, which was rapidly inhibited by niflumic acid and nifedipine. Contractions to ATP, however, reversed rapidly and fully. Tannic acid contracted tissues per se and potentiated nucleotide-evoked contractions. I (Cl,Ca) and Ca(2+) influx via Ca(v) 1.2 ion channels contribute substantially and equally to contractions of rat intrapulmonary arteries evoked by UTP and UDP, via P2Y receptors. ATP also activates these mechanisms via P2Y receptors, but the greater dependence on extracellular Ca(2+) most likely reflects additional influx through the P2X1 receptor pore. The lack of a sustained response to ATP is probably due to it acting at P2 receptor subtypes that desensitize rapidly. Thus multiple signalling mechanisms contribute to pulmonary artery vasoconstriction mediated by P2 receptors.

Item type: Article
ID code: 40677
Notes: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Keywords: pulmonary artery, P2Y receptor, P2X receptor, Ca2+-dependent chloride channels, Cav1.2 ion channels, Therapeutics. Pharmacology, Pharmacology
Subjects: Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Depositing user: Pure Administrator
Date Deposited: 02 Aug 2012 13:08
Last modified: 05 Jan 2016 13:10

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