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Br J Pharmacol. 2009 Aug;157(7):1241-9. doi: 10.1111/j.1476-5381.2009.00283.x. Epub 2009 Jun 5.

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

Author information

1
Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK. i.morecroft@bio.gla.ac.uk

Abstract

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.

PMID:
19508393
PMCID:
PMC2743843
DOI:
10.1111/j.1476-5381.2009.00283.x
[Indexed for MEDLINE]
Free PMC Article

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