Cholecystokinin CCK 2 receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway

Background and purpose: Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK 1 ). However, the role played by cholecystokinin 2 (CCK 2 ) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK 2 receptors on the contractile activity of human distal colon. Experimental approach: The effects of compounds acting on CCK 2 receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl‐induced contractions or transmural electrical stimulation. Key results: Cholecystokinin octapeptide sulphate induced concentration‐dependent contractions which were enhanced by GV150013 (CCK 2 receptor antagonist; +57% at 0.01 μM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by N ω ‐propyl‐L‐arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by N ω ‐nitro‐L‐arginine methylester (L‐NAME, non‐selective nitric oxide synthase inhibitor). In the presence of KCl‐induced contractions, cholecystokinin octapeptide sulphate elicited concentration‐dependent relaxations (‐36%), which were unaffected by NPA, but were counteracted by GV150013 or L‐NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 μM). Conclusions and implications: CCK 2 receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK 2 receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform. British Journal of Pharmacology (2007) 151 , 1246–1253; doi: 10.1038/sj.bjp.0707339