The KCNQ channel blockers, linopirdine and XE991, were recently shown to produce pulmonary vasoconstriction.¹ Retigabine and flupirtine are KCNQ channel openers that have been shown to activate recombinant and native neuronal KCNQ currents and are being developed as treatment for epilepsy. We have now investigated the actions of KCNQ channel modulators on a range of arteries and the resting K⁺ conductance of rat pulmonary artery smooth muscle cells (PASMCs), as well as the expression of KCNQ channel subunits in pulmonary artery. Male Sprague-Dawley rats (250-300g) were sacrificed in accordance with Schedule 1 of the Animal (Scientific Procedure) Act 1986. Intrapulmonary arteries (IPA 300-400μm) were dissected and mounted on a wire myograph for isometric tension studies. mRNA was isolated, reverse transcribed to cDNA and amplified using gene-specific primers for KCNQ1-5, following established protocols. Whole-cell, patch-clamp recording was used to record current under voltage clamp and membrane potential under current clamp conditions, from PASMCs.² KCNQ subunit protein expression was analysed by immunostaining and western blot. Data are expressed as mean ± s.e.m. of n animals/cells and compared using Student’s t-test. While the KCNQ blockers constricted IPA, they did not affect other systemic vessels, including cerebral, carotid, coronary, mesenteric, renal, femoral and tail arteries. In isolated PASMCs, linopirdine (10μM) and XE991 (5μM) inhibited a background K⁺ current by 38±4% (n=11) and 36±5% (n=15) at 0mV and depolarized the membrane by 14±2 mV (n=5) and 15±6 mV (n=6), respectively. The KCNQ channel opener flupirtine relaxed IPA pre-constricted with 10μM phenylephrine with IC₅₀ = 14±1μM (n=5). Retigabine was significantly more potent than flupirtine, often producing relaxation below 100nM (p〈0.05). The IC₅₀ was 2.5±0.2 μM (n=5) and 3.1±1 μM (n=3) against phenylephrine and PGF2α-induced constriction, respectively. Retigabine was less effective at relaxing vessels constricted with 50mM K⁺, where 6±1% (n=6) relaxation was seen at 10μM and 40±5% (n=6) at 100μM, and was ineffective on vessels constricted with 130mM K⁺, suggesting its action via K⁺ channel opening. Furthermore, relaxation was preserved in the presence of glibenclamide, implying no involvement of K_ATP channels. KCNQ openers shifted the concentration-response curves for the blockers to the right, suggesting an action on the same channels. Expression studies indicated that mRNA and protein for KCNQ1, 4 and 5 subunits are expressed in IPA. Taken together these results suggest that KCNQ channels are functionally expressed in PASMCs. Inhibition by KCNQ blockers promotes depolarisation and contraction, while KCNQ openers promote relaxation. Therefore KCNQ openers might have potential as therapeutic pulmonary vasodilators.