Linopirdine is a putative cognition-enhancing agent. It acts by blocking M-current (I_KM), which is carried by heteromeric KCNQ2/3 channels (Wang et al. 1998). A non-inactivating potassium current identified in pulmonary artery smooth muscle cells has kinetic properties similar to I_KM (Evans et al. 1996). Moreover, KCNQ channel expression in murine portal vein (Ohya et al. 2003) raises the possibility of a role in the vasculature. Therefore, we investigated the expression of KCNQ subunits and the effects of the KCNQ channel blockers, linopirdine and XE991, in rat isolated intra-pulmonary artery. Male Sprague-Dawley rats (250-300g) were humanely killed. Arteries (300-400 μm) were dissected and mounted on a wire myograph for isometric tension studies. An RNeasy Midi Kit was used to isolate mRNA from tissue preserved with RNAlater. It was reverse transcribed to cDNA, which was amplified using gene-specific primers for mouse KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5, following an established protocol (Osipenko et al. 2000). Data are expressed as mean±S.E.M. of n animals and compared using Student′s t test with significance indicated by p≤0.05. RT-PCR showed the presence of mRNA for KCNQ1, KCNQ4 and KCNQ5 subunits. Both linopirdine and XE991 produced pronounced constriction of pulmonary, but not mesenteric, arteries. The maximum response to linopirdine, seen at 10 μM, was 85 ± 12% (n=20) of the response to 50mM KCl in pulmonary arteries compared with 5 ±2% in mesenteric arteries. XE991 produced a maximum response at 1μM of 79 ± 8% (n=21) in pulmonary and 4±1% (n=6) in mesenteric arteries. The concentration producing 50% maximum response was 1.3 ± 0.5 μM for linopirdine (n=5) and 0.4 ± 0.3 μM (n=6) for XE991, close to the 50% blocking concentrations at recombinant KCNQ channels. Neither removal of the endothelium nor applying 10 μM phentolamine (to block effects of nerve released noradrenaline) significantly affected the contractile response to either drug. Constrictor responses were abolished in calcium-free medium. Nifedipine (1 μM, n=5) blocked contractions produced by linopirdine (10 μM) and XE991 (1 μM) by 99 ±0.01% and 98 ±1% , respectively, while levocromakalim (10 μM) reduced the responses to both drugs by 98 ± 1% (n=4). The results indicate a functional role for KCNQ channels in pulmonary artery smooth muscle, to regulate Ca²⁺ influx through voltage-dependent Ca²⁺ channels, and suggest that pulmonary vasoconstriction is a potential side-effect of cognition enhancers that block KCNQ channels.