KV7 channels regulate muscle tone and nonadrenergic noncholinergic relaxation of the rat gastric fundus

Voltage-dependent type 7 K+ (KV7) channels play important physiological roles in neurons and muscle\r\ncells. The aims of the present study were to investigate the motor effects of KV7 channel modulators in\r\nthe rat gastric fundus and the expression of KV7 channels in this tissue.\r\nMuscle tone and electrical field stimulation (EFS)-evoked relaxations of precontracted longitudinal\r\nmuscle strips of the rat gastric fundus were investigated under nonadrenergic noncholinergic conditions\r\nby organ bath studies. Gene expression was studied by real-time PCR and tissue localization of channels\r\nwas investigated by immunohistochemistry.\r\nThe KV7 channel blocker XE-991 induced concentration-dependent contractions, with mean pD2 and\r\nEmax of 5.4 and 48% of the maximal U46619-induced contraction, respectively. The KV7 channel activators\r\nretigabine and flupirtine concentration-dependently relaxed U46619-precontracted strips, with pD2s of\r\n4.7 and 4.4 and Emax of 93% and 91% of the maximal relaxation induced by papaverine, respectively. XE-991\r\nconcentration-dependently inhibited retigabine-induced relaxation with a pIC50 of 6.2. XE-991 and DMP-\r\n543, another KV7 channel blocker, increased by 13–25% or reduced by 11–21% the relaxations evoked\r\nby low- or high-frequency EFS, respectively. XE-991 also reduced the relaxation induced by vasoactive\r\nintestinal polypeptide (VIP) by 33% of controls. Transcripts encoded by all KV7 genes were detected in the\r\nfundus, with 7.4 and 7.5 showing the highest expression levels. KV7.4 and 7.5 channels were visualized\r\nby confocal immunofluorescence in both circular and longitudinal muscle layers.\r\nIn conclusion, in the rat proximal stomach, KV7 channels appear to contribute to the resting muscle tone\r\nand to VIP- and high-frequency EFS-induced relaxation. KV7 channel activators could be useful relaxant\r\nagents of the gastric smooth muscle.