Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension

Ian Morecroft, A. Murray, M. Nilsen, A. M. Gurney, M. R. MacLean

    Research output: Contribution to journalArticlepeer-review


    Background and purpose: Voltage-gated potassium (Kv) 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 Kv7 channels has been recently proposed. We investigated the effect of the Kv7 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 approach: Right 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 Kv channel blocking drugs, including the Kv7 channel blocker linopirdine, were measured. Key results: In 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 Kv channel blockers did not. Conclusions and implications: Flupirtine significantly attenuated development of chronic hypoxia-induced PAH in mice and reversed established PAH in SERT+ mice, apparently via Kv7 channel activation. These results provide the first direct evidence that drugs activating Kv7 channels may be of benefit in the treatment of PAH with different aetiologies. © 2009 The British Pharmacological Society All rights reserved.
    Original languageEnglish
    Pages (from-to)1241-1249
    Number of pages8
    JournalBritish Journal of Pharmacology
    Issue number7
    Publication statusPublished - 2009


    • 5-HT
    • Kv7 channels
    • Pulmonary hypertension


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