Motor effects of KV7 channel modulators in the rat gastric fundus

Valeria Ipavec, Maria Martire, Diego Curro. D Curro, Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

The voltage-dependent type 7 K+ (KV7.1-7.5) channels are well known for their functional roles in neurons, in which KV7.2-7.3 channels mediate the M current, and cardiomyocytes. They also regulate smooth muscle activity. The aim of our study was to evaluate whether KV7 channel modulators affect the motor activity of the proximal stomach. Longitudinal muscle strips were prepared from the gastric fundus of rats killed by decapitation and were suspended under isotonic conditions (10-mN load) in Krebs solution maintained at 37°C, bubbled with carbogen and containing atropine (1 μM) and guanethidine (5 μM) (to obtain nonadrenergic noncholinergic (NANC) conditions) inside 5-ml organ baths. The effects of the KV7.2-7.5 channel activators retigabine and flupirtine and KV7 blockers XE-991 (Wang et al., 1998) and DMP-543 were investigated. XE-991 (0.5-100 μM) produced concentration-dependent contractions, with mean pD2 and Emax of 5.40±0.09 and 63.2±3.3 % of U46619 (0.1 μM)-induced contraction, respectively (n = 9). Retigabine (1-100 μM) and flupirtine (4-144 μM) induced concentration-dependent relaxations of U46619 (0.1 μM)-pre-contracted strips, with pD2s of 4.73±0.05 and 4.41±0.06 and Emaxs of 93.6±2.3 % (n = 6) and 90.9±2.1 % (n = 6) of the maximal relaxation induced by papaverine (300 μM), respectively. XE-991 blocked retigabine- and flupirtine-induced relaxations. Tetrodotoxin (1 μM) and ω-conotoxin GVIA (30 nM) did not affect any motor responses produced by the channel modulators. XE-991 (10 μM) and DMP-543 (20 μM) significantly increased electrical field stimulation (EFS, 2 Hz)-induced relaxation (by 12.7±2.1 %, n = 8, P<0.001, and 24.8±3.9 %, n = 7, P<0.001, of controls, respectively). XE-991 (20 μM) and DMP-543 (20 μM) reduced the area under the curve (AUC) of EFS (13 Hz)-evoked response (by 15.6±2.9 %, n = 8, P<0.01, and 21.2±4.1 %, n = 7, P<0.01, of controls, respectively). Higher XE-991 concentrations did not produce any greater effects. XE-991 (20 μM) also reduced the AUC of vasoactive intestinal polypeptide-produced relaxation (by 39.7±3.6 %, n = 7, P<0.001, of controls). Thus, in the rat gastric fundus, KV7 channel modulators appear to regulate smooth muscle tone and the NANC relaxations evoked by low- and high-frequency EFS.

Wang H-S et al. (1998). Science 282: 1890-1893.