Title

 

Authors

A. Adduci¹, G. Rizzo², C. Coco² and D. Currò¹.

¹Inst. of Pharmacology and ²Dept. of Surgical Sciences, School of Medicine, Catholic Univ. of the Sacred Heart, Rome, Italy

 

Abstract

The voltage-dependent K⁺ (K_V) channels form the largest family among the group of human K⁺ channels (Gutman et al., 2005). K_V channels encoded by the KCNQ gene family (K_V7.1–7.5) are delayed rectifier K⁺ channels with important functional roles in cardiomyocytes and neurons. The opening of K_V7.2-7.3 channels in neurons gives rise to the M current, that modulates excitability and firing pattern (Miceli et al., 2008). K_V7 channels also regulate smooth muscle activity in different systems (Greenwood and Ohya, 2009). The aim of the present study was to investigate the motor effects of K_V7 channel modulators in the human taenia coli. Colon specimens were obtained from patients undergoing surgical resections for colonic cancer. The study was approved by the local Ethics Committee and all patients signed an informed consent. Muscle strips prepared from the taenia coli were suspended under isotonic conditions (9.8-mN load) in Krebs solution maintained at 37° C, bubbled with carbogen and containing guanethidine (5 μM) and L-NAME (100 μM) (to obtain nonadrenergic nonnitrergic conditions) inside 5-ml organ baths. The effects of the K_V7.2-7.5 channel activators retigabine and flupirtine (Rundfeldt et al., 2000) and K_V7 blocker XE-991 (Wang et al., 1998) were investigated. XE-991 (1-100 μM) produced concentration-dependent contractions, with mean EC₅₀ and E_max of 21.0±4.1 μM and 27.8±5.4 % of the maximal contraction induced by bethanecol (100 μM), respectively (n=9). After XE-991 washout from the bath, the strips recovered to only 91.8.2±5.4 % of the XE-991-induced maximal contraction. Retigabine (10-100 μM) and flupirtine (10-100 μM) induced concentration-dependent relaxations of bethanecol (10 μM)-pre-contracted strips. Retigabine (100 μM)- and flupirtine (100 μM)-induced relaxations were 46.8±7.0 % and 38.5±8.2 % of bethanecol (10 μM)-produced pre-contraction, respectively (n=5 each). XE-991 (20 μM) reduced retigabine (100 μM)-induced relaxation to approximately 20 % of the control response (n=3). Our results seem to indicate that K_V7 channel modulators regulate the smooth muscle tone in the human taenia coli. Thus, K_V7 channel activators could be considered as useful relaxant agents of the colonic smooth muscle.
 
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