Gap junctions support the sustained phase of hypoxic pulmonary vasoconstriction by facilitating calcium sensitization

Igor V. Kizub, Ievgen V. Strielkov, Yasin Shaifta, Silke Becker, Jesus Prieto-Lloret, Vladimir A. Snetkov, Anatoly I. Soloviev, Philip I. Aaronson, Jeremy P.T. Ward

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    Abstract

    Aims: To determine the role of gap junctions (GJ) in hypoxic pulmonary vasoconstriction (HPV).

    Methods and results: Studies were performed in rat isolated intrapulmonary arteries (IPA) mounted on a myograph, and in anesthetized rats. Hypoxia induced a biphasic HPV response in IPA preconstricted with prostaglandin F2α (PGF2α, 3 µM) or 20 mM K+. The GJ inhibitors 18β-glycyrrhetinic acid (18β-GA, 30 µM), heptanol (3.5 mM) or 2-aminoethoxydiphenyl borate (2-APB) (75 µM) had little effect on the transient phase 1 of HPV, but abolished the sustained phase 2 which is associated with Ca2+ sensitisation. The voltage-dependent Ca2+ channel blocker diltiazem (10 µM) had no effect on HPV, and did not alter the inhibitory action of 18β-GA. Sustained HPV is enhanced by high glucose (15 mM) via potentiation of Ca2+ sensitization; in the presence of high glucose 18β-GA still abolished sustained HPV. Simultaneous measurement of tension and intracellular Ca2+ using Fura PE-3 demonstrated that whilst 18β-GA abolished tension development during sustained HPV, it did not affect the elevation of intracellular Ca2+. Consistent with this, 18β-GA abolished hypoxia-induced phosphorylation of the Rho kinase target MYPT-1. In anaesthetized rats hypoxia caused a biphasic increase in systolic right ventricular pressure. Treatment with oral 18β-GA (25 mg/kg) abolished the sustained component of the hypoxic pressor response.

    Conclusion: These results imply that GJs are critically involved in the signalling pathways leading to Rho kinase-dependent Ca2+ sensitization during sustained HPV, but not elevation of intracellular Ca2+, and may explain the dependence of the former on an intact endothelium.
    Original languageEnglish
    Pages (from-to)404-411
    Number of pages7
    JournalCardiovascular Research
    Volume99
    Issue number3
    Early online date25 May 2013
    DOIs
    Publication statusPublished - 2013

    Keywords

    • hypoxic pulmonary vasoconstriction
    • Gap junctions
    • Rho kinase

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