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Am J Physiol Lung Cell Mol Physiol. 2015 Jan 1;308(1):L48-57. doi: 10.1152/ajplung.00362.2013. Epub 2014 Oct 31.

Role of Kv7 channels in responses of the pulmonary circulation to hypoxia.

Author information

1
Department of Physiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic; Department of Paediatrics, Charles University - Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic; and vojtech.sedivy@seznam.cz.
2
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
3
Department of Physiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic;
4
Department of Pathophysiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic;
5
Department of Biochemistry, Charles University - Second Faculty of Medicine, Prague, Czech Republic.

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K(+) channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3-5 days in an isobaric hypoxic chamber (FiO2 = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease.

KEYWORDS:

KCNQ; Kv7 channels; P/Q relationship; flupirtine; hypoxic pulmonary vasoconstriction; isolated lungs

PMID:
25361569
PMCID:
PMC4281702
DOI:
10.1152/ajplung.00362.2013
[Indexed for MEDLINE]
Free PMC Article

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