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A Ca 2+ ‐dependent chloride current and Ca 2+ influx via Ca v 1.2 ion channels play major roles in P2Y receptor‐mediated pulmonary vasoconstriction
Author(s) -
Mitchell Callum,
Syed NawazishiHusain,
Gurney Alison M,
Kennedy Charles
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01892.x
Subject(s) - niflumic acid , p2y receptor , myograph , dids , chloride channel , chemistry , channel blocker , biophysics , extracellular , receptor , vascular smooth muscle , vasoconstriction , medicine , nifedipine , endocrinology , calcium , vasodilation , biochemistry , agonist , biology , organic chemistry , membrane , smooth muscle
BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH Isometric tension was recorded from endothelium‐denuded rat intrapulmonary artery rings (i.d. 200–500 µm) mounted on a wire myograph. KEY RESULTS 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. CONCLUSIONS AND IMPLICATIONS ICl,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.