In pulmonary artery (PA), compelling evidence have suggested that TWIK-related Acid Sensitive K+ -1 (TASK-1) channel contribute to the background K+ current that support the membrane potential (Em) of the smooth muscle cells. However, due to poor selectivity of its modulators, the role of TASK-1 channel in the functional regulation of tone in pulmonary arteries remains elusive. The purpose of this study was to investigate the properties of PA isolated from mice in which the TASK-1 and TASK-3 genes have been deleted (TASK1/3 knockout, KO), compared with their wild type controls (C57BL/6 mice, WT).
Intra-PAs were isolated from adult male WT and KO mice. Vessels were mounted on a wire myograph for isometric tension recordings. PAs were also processed for gene expression studies using RT-PCR. The addition of 10mM KCl, the K+ channel modulators 4-AP (1mM) and levcromakalim (10μm), or the L-type calcium channel blocker nifedipine (1μm), did not elicit any significant contractile response in PAs from either KO (N=3) or WT mice (N=3), suggesting that the Em is not depolarised and that artery is fully dilated in both groups. The contractile response of PA to phenylephrine, serotonin and PGF2⍺ did not show any difference between the two strains. Potency (pEC50) of the prostacyclin analog treprostinil to induce relaxation on preconstricted vessels was significantly higher in KO mice (6.7±0.1, N=3) than in WT mice (7.2±0.1N=4).
RT-PCR confirmed TASK-1 expression in PA from WT but not KO mice whereas TASK-3 was not expressed in either WT or KO mouse PA. TASK-2, TASK-5, TWIK-2, Kv1.5 and Kv2.1 RNA levels did not show any significant alteration between WT (N=3) or KO mice (N=3).
The PA isolated from KO mice does not display any resting tone or altered responses to the studied agonists. Surprisingly, response to treprostinil was increased, and TASK-1 absence in PA was not compensated by alteration of other K+ channels expression. The results thus far do not support a major physiological role for TASK-1 in mouse PA.Le texte complet de cet article est disponible en PDF.