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

Vojtech Sedivy,Alison M Gurney,Jana Novotna,Jan Herget,Sean Brennan,Shreena Joshi,Marie Zaloudikova,Roman Mizera,Youssef Ghaly

doi:10.1152/ajplung.00362.2013

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.

Highlights

HYPOXIC PULMONARY VASOCONSTRICTION (HPV) is an important physiological mechanism that helps to match ventilation with perfusion in the lungs
Kv7 channels are new potential candidates, because several genes encoding Kv7 channel ␣-subunits (KCNQ1, KCNQ4, and KCNQ5) are expressed in pulmonary artery smooth muscle cells (PASMC) and the channels appear to be active at the resting membrane potential [24, 25]
In the absence of priming, pulmonary perfusion pressure was unaffected by linopirdine

Summary

Introduction

HYPOXIC PULMONARY VASOCONSTRICTION (HPV) is an important physiological mechanism that helps to match ventilation with perfusion in the lungs. Kv7 channels are new potential candidates, because several genes encoding Kv7 channel ␣-subunits (KCNQ1, KCNQ4, and KCNQ5) are expressed in PASMC and the channels appear to be active at the resting membrane potential [24, 25] This was demonstrated by the selective Kv7 channel inhibitors, linopirdine and XE991, causing pulmonary selective, endothelium-independent, but Ca2ϩinflux dependent vasoconstriction [24]. Following prolonged exposure to a hypoxic environment, for example in obstructive lung disease patients or at high altitude, the pulmonary circulation becomes hypertensive This disease state is associated with sustained depolarization of the PASMC, along with loss of Kϩ channel activity [39, 47, 49, 55]. Despite the reduced sensitivity of pulmonary arteries to Kv7 modulators in mice with PH, the Kv7 activator, flupirtine, was able to return pulmonary artery pressure to normal, and it was able to prevent

Methods

Results

Conclusion