Ohya et al. (2003) showed the expression of KCNQ transcripts in murine portal vein (mPV) myocytes. These channels are implicated in long QT syndrome, however little work on KCNQ channels in vascular smooth muscle has been documented. Here we show the effects of the KCNQ blocker XE991 on ion currents from mPV myocytes and highlight a physiological role for these channels.

Female BALB/c mice aged 6 to 8 weeks were sacrificed by cervical dislocation and single mPV cells were obtained by enzymatic dispersion. Recordings were made using the whole cell voltage-clamp techniques with an external solution of (mM): NaCl 126, KCl 5, MgCl ₂ 1, CaCl₂ 0.1, glucose 11, HEPES 10, adjusted to pH 7.2 with NaOH. The internal solution contained (mM): KCl 130, MgCl₂ 1, ATP 2, HEPES 10, EGTA 5, adjusted to pH 7.2 with KOH. Currents were evoked from a holding potential
(V_H) of –60 mV to various test potentials (V_T).

XE991 reduced the total outward delayed rectifier-like K⁺ current in a concentration-dependent manner. The IC₅₀ was calculated to be 5.9 µM (n=3-6, V_T = +20mV); compared to linopirdine (Costa & Brown, 1997; Wang et al., 1998), this reflects an 8-fold increase in sensitivity (48 µM, Ohya et al., 2003). Inhibition was reversible at concentrations of 30 µM. Block was not voltage-dependent and did not significantly change the rate of current activation.

Application of 30 µM XE991 in current clamp mode (100 pA injection, 20 ms duration, RMP (resting membrane potential) = -60 mV) evoked a significant membrane depolarization (15 ± 3 mV, n=5), increased the action potential amplitude and broadened the duration. These effects were fully reversible on washout of the drug.

Isometric tension recordings of whole PV tissue showed rhythmic contractions under control conditions, which increased in frequency in the presence of 10 µM XE991. Moreover, basal tone increased and the maximal force of contraction decreased.

These data show XE991 to be a more potent inhibitor than linopirdine; and this agent revealed a significant functional role for KCNQ channels in the mPV.

Costa, A.M.N. & Brown, B.S. (1997) Neuropharmacol.36, 1747-1753
Ohya, S., Sergeant, G.P., Greenwood, I.A. & Horowitz, B. (2003) Circ Res.92, 1016-1023
Wang, H.-S., Pan, Z., Shi,W., Brown,B.S., Wymore, R.S., Cohen, I.S., Dixon, J.E. & McKinnon, D. (1998) Science 282, 1890 -1893

This work was supported by the British Heart Foundation