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


METHODS
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.


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
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.
Morecroft
I
I
Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK. i.morecroft@bio.gla.ac.uk
Murray
A
A
Nilsen
M
M
Gurney
A M
AM
MacLean
M R
MR
D000631:Aminopyridines / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D066298:In Vitro Techniques; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D024642:Potassium Channels, Voltage-Gated / Q000819:agonists* / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics
D000631:Aminopyridines; D024642:Potassium Channels, Voltage-Gated; D050486:Serotonin Plasma Membrane Transport Proteins; C034161:flupirtine