Cholecystokinin CCK2 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 (CCK1). However, the role played by cholecystokinin 2 (CCK2) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK2 receptors on the contractile activity of human distal colon.Experimental approach:The effects of compounds acting on CCK2 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 (CCK2 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 Nω-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by Nω-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:CCK2 receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK2 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; published online 18 June 2007 [ABSTRACT FROM AUTHOR]