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)
Full text not currently available from Enlighten.
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 > School of Cardiovascular & Metabolic Health |
Journal Name: | British Journal of Pharmacology |
Journal Abbr.: | Brit J Pharmacol |
ISSN: | 0007-1188 |
Published Online: | 05 June 2009 |
University Staff: Request a correction | Enlighten Editors: Update this record