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 (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 microM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by N(omega)-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 microM). 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.