The KCNQ (Kv7) potassium channel activator flupirtine attenuates elevated right ventricular pressure in 2 models of pulmonary hypertension

Ian Morecroft1, Alicia McGuckin1, Margaret Nilsen1, Lynn Loughlin1, Alison Gurney2, Margaret MacLean1
1University of Glasgow, Glasgow, United Kingdom, 2University of Manchester, Manchester, United Kingdom

Pulmonary arterial hypertension (PAH) is characterised by elevated PA pressure, pulmonary vascular remodelling and right heart failure and is associated with an extremely poor prognosis. Mice over expressing the 5-hydroxytrypamine transporter (5-HTT) (5-HTT+ mice) develop spontaneous PAH and are more susceptible to hypoxia-induced PAH (MacLean et al., 2004). Down regulation of voltage gated potassium channels (Kv) occurs in chronic hypoxia-induced PAH (Osipenko et al., 1998). Recent evidence suggests that KCNQ potassium (Kv7) channels play a functional role in pulmonary artery smooth muscle and KCNQ channel blockers are potent pulmonary arterial vasoconstrictors (Joshi et al., 2006).

Here we investigate the effects of the KCNQ K+ channel activator, flupirtine, in chronic hypoxia induced PAH in wild-type (WT) mice and in mice that over-express the 5-HTT (5-HTT+). Female mice (C57BL/6 x CBA, WT and 5-HTT+, 5-6 months) were dosed daily for 16 days with vehicle (1% carboxymethylcellulose) or flupirtine at 30mg/kg by oral gavage. On day 3 of the dosing regimen, some of the WT mice were subjected to 14 days of hypobaric hypoxia (10% O2). Under isoflurane anaesthesia, right ventricular pressure (RVP) was obtained by transdiaphragmatic right ventricular cannulation. Right ventricular (RV) / left ventricle+septum (LV+S) ratio was determined as described previously (MacLean et al., 2004). Statistical comparisons were made by one-way ANOVA with a Neuman-Keuls multiple comparison test. Data are expressed as mean ± s.e.mean.

Hypoxia induced an increase in mean RVP (mRVP) (21.6 ± 2.0 mmHg vs normoxic: 13.4 ± 0.9mmHg, n=8, P<0.01) and right ventricular hypertrophy (RV/LV+S ratio = 0.293 ± 0.010 vs normoxia: 0.216 ± 0.005, n=-6-7; P<0.001) in WT mice. Treatment with flupirtine attenuated the elevation in both mRVP (14.7 ± 0.7mmHg; n=9;P<0.01versus hypoxia) and right ventricular hypertrophy (RV/LV+S ratio = 0.241 ± 0.02, n=8; P<0.05 vs hypoxia). mRVP was markedly elevated in normoxic 5-HTT+ mice (29.9 ± 2.7, n=6; P<0.001 versus WT) and treatment with flupirtine attenuated this response (mRVP = 17.1 ± 1.9, n=6; P<0.001). Right ventricular hypertrophy was observed in the 5-HTT+ mice (RV/LV+S ratio = 0.251 ± 0.007, n=6; P<0.01 versus WT) and this was slightly attenuated by flupirtine treatment (RV/LV+S ratio =0.226 ± 0.004, n=6; P<0.05 versus 5-HTT+).

The Kv7 activator flupirtine markedly attenuates the elevated right ventricular pressure observed in chronic hypoxic mice and in mice over expressing the 5-HTT. This, and other drugs that activate Kv7 channels may be of benefit in the treatment of PAH.

Joshi et al., (2006). Respir Res, 7: 31
MacLean et al., (2004). Circulation, 109: 2150-2155.
Osipenko et al., (1998). Brit. J. Pharmac. 124:1335-1337.