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.

• MeSH
• aminopyridiny farmakologie   MeSH
• analgetika farmakologie   MeSH
• arteria pulmonalis metabolismus   patologie   patofyziologie   MeSH
• blokátory draslíkových kanálů farmakologie   MeSH
• cévní rezistence účinky léků   MeSH
• draslíkové kanály KCNQ antagonisté a inhibitory   metabolismus   MeSH
• hladké svalstvo metabolismus   patologie   patofyziologie   MeSH
• hypoxie * metabolismus   patologie   patofyziologie   MeSH
• indoly farmakologie   MeSH
• krysa rodu rattus MeSH
• membránové potenciály účinky léků   MeSH
• plíce * krevní zásobení   metabolismus   patologie   patofyziologie   MeSH
• plicní hypertenze metabolismus   patologie   patofyziologie   MeSH
• plicní oběh * MeSH
• potkani Wistar MeSH
• pyridiny farmakologie   MeSH
• regulace genové exprese účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH