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Treatment with the K v 7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension
Author(s) -
Morecroft I,
Murray A,
Nilsen M,
Gurney AM,
MacLean MR
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00283.x
Subject(s) - myograph , pulmonary artery , potassium channel , chemistry , pulmonary hypertension , pharmacology , activator (genetics) , hypoxia (environmental) , potassium channel blocker , in vivo , right ventricular hypertrophy , channel blocker , medicine , endocrinology , artery , receptor , biology , oxygen , microbiology and biotechnology , organic chemistry , calcium
Background and purpose: Voltage‐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 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 K v channel blocking drugs, including the K v 7 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 K v 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 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.