title: Role of Kv7 channels in responses of the pulmonary circulation to hypoxia.
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.
authors.affiliation: 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.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Sedivy
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Shreena
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Physiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic;
authors.forename: Youssef
authors.initials: Y
authors.lastname: Ghaly
authors.affiliation: Department of Physiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic;
authors.forename: Roman
authors.initials: R
authors.lastname: Mizera
authors.affiliation: Department of Pathophysiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic;
authors.forename: Marie
authors.initials: M
authors.lastname: Zaloudikova
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Sean
authors.initials: S
authors.lastname: Brennan
authors.affiliation: Department of Biochemistry, Charles University - Second Faculty of Medicine, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Novotna
authors.affiliation: Department of Physiology, Charles University - Second Faculty of Medicine, Prague, Czech Republic;
authors.forename: Jan
authors.initials: J
authors.lastname: Herget
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Alison M
authors.initials: AM
authors.lastname: Gurney
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000700:Analgesics; D007211:Indoles; D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D011725:Pyridines; C061017:linopirdine; C034161:flupirtine
keywords: KCNQ; Kv7 channels; P/Q relationship; flupirtine; hypoxic pulmonary vasoconstriction; isolated lungs