Involvement of endogenous CCK and CCK1 receptors in colonic motor function

Abstract

Cholecystokinin (CCK) is a brain-gut peptide; it functions both as a neuropeptide and as a gut hormone. Although the pancreas and the gallbladder were long thought to be the principal peripheral targets of CCK, CCK receptors are found throughout the gut. It is likely that CCK has a physiological role not only in the stimulation of pancreatic and biliary secretions but also in the regulation of gastrointestinal motility. The motor effects of CCK include postprandial inhibition of gastric emptying and inhibition of colonic transit. It is now evident that at least two different receptors, CCK(1) and CCK(2) (formerly CCK-A and CCK-B, respectively), mediate the actions of CCK. Both localization and functional studies suggest that the motor effects of CCK are mediated by CCK(1) receptors in humans. Since CCK is involved in sensory and motor responses to distension in the intestinal tract, it may contribute to the symptoms of constipation, bloating and abdominal pain that are often characteristic of functional gastrointestinal disorders in general and irritable bowel syndrome (IBS), in particular. CCK(1) receptor antagonists are therefore currently under development for the treatment of constipation-predominant IBS. Clinical studies suggest that CCK(1) receptor antagonists are effective facilitators of gastric emptying and inhibitors of gallbladder contraction and can accelerate colonic transit time in healthy volunteers and patients with IBS. These drugs are therefore potentially of great value in the treatment of motility disorders such as constipation and constipation-predominant IBS.

Figure 1

Structural similarities of members of the CCK/gastrin peptide family: CCK, gastrin and the amphibian skin peptide caerulein. All of these peptides share a common feature, the same amidated tetrapeptide Trp-Met-Asp-Phe-NH₂ at the C-terminal. The characteristic CCK-like activity depends on the sulfated Tyr residue at the seventh position.

Figure 2

Predicted membrane topology of CCK₁ and CCK₂ receptors. Both belong to the family of G-protein-coupled receptors with seven transmembrane domains. A large portion of the amino-acid sequence is conserved. EC=extracellular side of the membrane.

Figure 3

Chemical structures of CCK₁ receptor antagonists: devazepide, lorglumide, loxiglumide and lintitript.

Figure 4

Inhibition of CCK-induced contractions of human gallbladder by CCK₁ receptor blockade. Effects of dexloxiglumide at 0.1 μM (red), 1 μM (green), 3 μM (purple) on the contractile responses produced by CCK-OP (blue) in isolated human gallbladder. Each point represents the mean and standard error of the values obtained from 35 individual experiments. Adapted from Maselli et al. (2001).

Figure 5

Effect of CCK₁ receptor blockade on gastric emptying of liquids in rats. (a) Inhibitory action of 7.5 mg kg⁻¹ dexloxiglumide, administered intravenously 15 min before the agonist, on the CCK-induced delay in gastric emptying. (b) Dose-dependent inhibition of the CCK-induced delay in gastric emptying by dexloxiglumide (DEXLOX). Each column or point represents the mean and standard error of the values obtained from 8 to 10 individual experiments (^*P<0.05). The curve shows a computer-generated logarithmic plot of percentage inhibition as a function of the antagonist dose. Adapted from Scarpignato et al. (1996).

Figure 6

Concentration-dependent effect of CCK-8 (red) and JMV-180 (blue) on amylase release from rat pancreatic acini (solid line, left axis) and on contractile activity of isolated rat pyloric rings (broken line, right axis). Amylase release is calculated as a percentage of the initial amylase content. Values for the contractile activity are expressed as a percentage of the contractile effect of 10⁻⁵ M acetylcholine on the same preparation. Each point represents the mean and standard error of the values obtained from at least five to six individual experiments. Adapted from Kisfalvi et al. (2001).