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

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.