Potassium channels play an important role in pulmonary artery smooth muscle cells (PASMCs), maintaining a negative resting potential and preventing the cells from firing spontaneous action potentials. Consequently, PASMCs are electrically silent and this contributes to low intrinsic tone, which is important for maintaining the low arterial pressure that is characteristic of the healthy pulmonary circulation. The molecular correlates of the K⁺ channels that determine the resting potential are unclear. There is strong evidence that voltage-independent TASK-like channels are important (Gurney et al. 2003). A substantial body of evidence also implicates Kv channels, especially Kv1.5 and Kv2.1, although conflicting evidence argues against a major role for this class of channel in maintaining the resting potential (Gurney, 2003). Although it is widely agreed that the background K⁺ conductance giving rise to the resting potential contains a voltage-dependent component, its biophysical and pharmacological properties are inconsistent with the involvement of Kv channels (Evans et al. 1996). Several of its properties, including low voltage threshold for activation, slow activation and absence of inactivation, are similar to the neuronal M-current, which is encoded by genes of the KCNQ family. This led us to investigate the possible contribution of KCNQ channel subunits to the background K⁺ conductance, membrane potential and contractile function of PASMC. At least three KCNQ channel subunits (KCNQ1, KCNQ4 and KCNQ5) were identified in pulmonary arteries, from humanely killed rat and mouse, by RT-PCR analysis of mRNA. A functional role for these channels is suggested by the finding that two blockers of KCNQ channels, linopirdine and XE991, caused rat and mouse pulmonary arteries to constrict at concentrations similar to those causing inhibition of recombinant KCNQ channels. The action was mediated by a direct effect on PASMC, because it was essentially unaffected by removal of the endothelium or by inhibiting the action of nerve-released noradrenaline with phentolamine. Moreover, the constrictor effect was abolished in the absence of extracellular calcium or in the presence of the calcium antagonist, nifedipine, or the K⁺-channel opener, levcromakalim. This implies that pulmonary vasoconstriction caused by KCNQ blockers is mediated by membrane depolarisation and activation of voltage-dependent, L-type calcium channels. Thus KCNQ channel blockers appear to inhibit the background K⁺ conductance, suggesting a role for these channels in maintaining the resting membrane potential. We have identified several molecular candidates for the resting K⁺ conductance in PASMC. Nevertheless, multiple K⁺ channels are probably involved in regulating the resting membrane potential and their nature remains controversial.