• I Morecroft, A Murray, M Nilsen, A M Gurney, and M R MacLean.
• Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK. i.morecroft@bio.gla.ac.uk
• Br. J. Pharmacol. 2009 Aug 1; 157 (7): 1241-9.

Background And PurposeVoltage-gated potassium (K(v)) channels contribute to resting membrane potential in pulmonary artery smooth muscle cells and are down regulated in patients with pulmonary arterial hypertension (PAH) and a contribution from K(v)7 channels has been recently proposed. We investigated the effect of the K(v)7 channel activator, flupirtine, on PAH in two independent mouse models: PAH induced by hypoxia and spontaneous PAH in mice over-expressing the 5-HT transporter (SERT(+) mice).Experimental ApproachRight ventricular pressure was assessed in vivo in mice chronically treated with flupirtine (30 mg.kg(-1).day(-1)). In separate in vitro experiments, pulmonary arteries from untreated mice were mounted in a wire myograph. Relaxations to acute administration of flupirtine and contractions to K(v) channel blocking drugs, including the K(v)7 channel blocker linopirdine, were measured.Key ResultsIn wild-type (WT) mice, hypoxia increased right ventricular pressure, pulmonary vascular remodelling and right ventricular hypertrophy. These effects were attenuated by flupirtine, which also attenuated these indices of PAH in SERT(+) mice. In the in vitro experiments, flupirtine induced a potent relaxant response in arteries from untreated WT and SERT(+) mice. The relaxation was fully reversed by linopirdine, which potently contracted mouse pulmonary arteries while other K(v) channel blockers did not.Conclusions And ImplicationsFlupirtine significantly attenuated development of chronic hypoxia-induced PAH in mice and reversed established PAH in SERT(+) mice, apparently via K(v)7 channel activation. These results provide the first direct evidence that drugs activating K(v)7 channels may be of benefit in the treatment of PAH with different aetiologies.

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