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

Research output: Contribution to journalArticle

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

Original languageEnglish
Pages (from-to)404-411
Number of pages7
JournalCardiovascular Research
Issue number3
Early online date25 May 2013
E-pub ahead of print25 May 2013

Bibliographical note

An important paper that shows an entirely novel, unsuspected but critical role for gap junctions in sustained hypoxic pulmonary vasoconstriction and Rho kinase mediated calcium sensitisation. Our results explain the long known but not previously understood requirement for an intact endothelium, and may have relevance for the pathophysiology of pulmonary hypertension. Kizub and Stielkov were visiting research fellows at King's.


King's Authors


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.

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