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

被引:34
|
作者
Sedivy, Vojtech [1 ,4 ,5 ]
Joshi, Shreena [2 ]
Ghaly, Youssef [1 ]
Mizera, Roman [1 ]
Zaloudikova, Marie [3 ]
Brennan, Sean [2 ]
Novotna, Jana [6 ]
Herget, Jan [1 ]
Gurney, Alison M. [2 ]
机构
[1] Charles Univ Prague, Fac Med 2, Dept Physiol, Prague 15000, Czech Republic
[2] Univ Manchester, Fac Life Sci, Manchester, Lancs, England
[3] Charles Univ Prague, Fac Med 2, Dept Pathophysiol, Prague 15000, Czech Republic
[4] Charles Univ Prague, Fac Med 2, Dept Pediat, Prague 15000, Czech Republic
[5] Univ Hosp Motol, Prague, Czech Republic
[6] Charles Univ Prague, Fac Med 2, Dept Biochem, Prague 15000, Czech Republic
关键词
KCNQ; Kv7; channels; flupirtine; isolated lungs; hypoxic pulmonary vasoconstriction; P/Q relationship; KCNQ POTASSIUM CHANNELS; SMOOTH-MUSCLE-CELLS; GATED K+ CHANNELS; RAT PULMONARY; MOLECULAR-IDENTIFICATION; VASOCONSTRICTION; CURRENTS; ARTERIES; TONE; LINOPIRDINE;
D O I
10.1152/ajplung.00362.2013
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 alpha-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.
引用
收藏
页码:L48 / L57
页数:10
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