K(V)7 channels regulate muscle tone and nonadrenergic noncholinergic relaxation of the rat gastric fundus

Voltage-dependent type 7 K(+) (K(V)7) channels play important physiological roles in neurons and muscle cells. The aims of the present study were to investigate the motor effects of K(V)7 channel modulators in the rat gastric fundus and the expression of K(V)7 channels in this tissue. Muscle tone and electrical field stimulation (EFS)-evoked relaxations of precontracted longitudinal muscle strips of the rat gastric fundus were investigated under nonadrenergic noncholinergic conditions by organ bath studies. Gene expression was studied by real-time PCR and tissue localization of channels was investigated by immunohistochemistry. The K(V)7 channel blocker XE-991 induced concentration-dependent contractions, with mean pD(2) and E(max) of 5.4 and 48% of the maximal U46619-induced contraction, respectively. The K(V)7 channel activators retigabine and flupirtine concentration-dependently relaxed U46619-precontracted strips, with pD(2)s of 4.7 and 4.4 and E(max) of 93% and 91% of the maximal relaxation induced by papaverine, respectively. XE-991 concentration-dependently inhibited retigabine-induced relaxation with a pIC(50) of 6.2. XE-991 and DMP-543, another K(V)7 channel blocker, increased by 13–25% or reduced by 11–21% the relaxations evoked by low- or high-frequency EFS, respectively. XE-991 also reduced the relaxation induced by vasoactive intestinal polypeptide (VIP) by 33% of controls. Transcripts encoded by all K(V)7 genes were detected in the fundus, with 7.4 and 7.5 showing the highest expression levels. K(V)7.4 and 7.5 channels were visualized by confocal immunofluorescence in both circular and longitudinal muscle layers. In conclusion, in the rat proximal stomach, K(V)7 channels appear to contribute to the resting muscle tone and to VIP- and high-frequency EFS-induced relaxation. K(V)7 channel activators could be useful relaxant agents of the gastric smooth muscle.