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

Morecroft, I., Murray, A., Nilsen, M., Gurney, A.M. and MacLean, M.R. (2009) Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension. British Journal of Pharmacology, 157(7), pp. 1241-1249. (doi: 10.1111/j.1476-5381.2009.00283.x) (PMID:19508393) (PMCID:PMC2743843)

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Publisher's URL: http://dx.doi.org/10.1111/j.1476-5381.2009.00283.x

Abstract

<b>Background and purpose</b>: Voltage-gated potassium (K<sub>v</sub>) 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<sub>v</sub>7 channels has been recently proposed. We investigated the effect of the K<sub>v</sub>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<sup>+</sup> mice). <b>Experimental approach</b>: Right ventricular pressure was assessed <i>in vivo</i> in mice chronically treated with flupirtine (30 mg·kg<sup>-1</sup>·day<sup>-1</sup>). In separate <i>in vitro</i> experiments, pulmonary arteries from untreated mice were mounted in a wire myograph. Relaxations to acute administration of flupirtine and contractions to K<sub>v</sub> channel blocking drugs, including the K<sub>v</sub>7 channel blocker linopirdine, were measured. <b>Key results</b>: 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 SERTSERT<sup>+</sup> mice. In the <i>in vitro</i> experiments, flupirtine induced a potent relaxant response in arteries from untreated WT and SERTSERT<sup>+</sup> mice. The relaxation was fully reversed by linopirdine, which potently contracted mouse pulmonary arteries while other K<sub>v</sub> channel blockers did not. <b>Conclusions and implications</b>: Flupirtine significantly attenuated development of chronic hypoxia-induced PAH in mice and reversed established PAH in SERTSERT<sup>+</sup> mice, apparently via K<sub>v</sub>7 channel activation. These results provide the first direct evidence that drugs activating K<sub>v</sub>7 channels may be of benefit in the treatment of PAH with different aetiologies

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Nilsen, Mrs Margaret and Morecroft, Dr Ian
Authors: Morecroft, I., Murray, A., Nilsen, M., Gurney, A.M., and MacLean, M.R.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:British Journal of Pharmacology
Journal Abbr.:Brit J Pharmacol
ISSN:0007-1188
Published Online:05 June 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
460941The role of endothelial tryptophan hydroxylase in pulmonary vascular remodelling: an integrated approachMargaret MacLeanBiotechnology and Biological Sciences Research Council (BBSRC)BB/F005423/1Institute of Cardiovascular and Medical Sciences