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

Abstract：

AIMS:To determine the role of gap junctions (GJs) in hypoxic pulmonary vasoconstriction (HPV). METHODS AND RESULTS:Studies were performed in rat isolated intrapulmonary arteries (IPAs) mounted on a myograph and in anaesthetized rats. Hypoxia induced a biphasic HPV response in IPAs 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⁺ sensitization. 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Kizub IV,Strielkov IV,Shaifta Y,Becker S,Prieto-Lloret J,Snetkov VA,Soloviev AI,Aaronson PI,Ward JP

doi

10.1093/cvr/cvt129

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

404-11

issue

3

eissn

0008-6363

issn

1755-3245

pii

cvt129

journal_volume

99

pub_type

杂志文章

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