Functional comparisons of gastrin/cholecystokinin receptors in isolated preparations of gastric mucosa and ileum

1 The gastrin cholecystokinin (CCK) receptors mediating stimulation of acid secretion in rat isolated gastric mucosa (RGM) and contraction in guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus (GPI) have been characterized by use of peptide agonists and the non‐peptide antagonists, lorglumide, devazepide and L‐365,260. 2 In RGM, gastrin peptides (sulphated gastrin heptadecapeptide (G‐17), non‐sulphated (ns) G‐17 and pentagastrin) were potent agonists of acid secretion (EC50 values of 4.3, 16 and 27 nm respectively). Sulphated CCK octapeptide (CCK‐8) was also a potent agonist, (EC50 = 0.9 nm), but was less efficacious, producing a lower maximal response. In contrast, in GPI, CCK‐8 was a potent full agonist (EC50= 1.4 nm) and was more than 1000 times more potent than the gastrin peptides in producing a sustained contractile response. 3 In GPI, CCK‐8 (0.1 to 100 nm) produced sustained contractile responses, whilst CCK‐4 (3 to 1000 nm) produced transient responses. These responses had different sensitivities to atropine (1 μm), suggesting that more than one receptor may mediate contraction in this tissue. 4 In RGM, L‐365,260 was the most potent antagonist of pentagastrin‐stimulated acid secretion (pA2 = 7.6). This functional affinity estimate was similar to that for L‐365,260 as an antagonist of excitatory responses in rat ventromedial hypothalamic slices (Kemp et al., 1989) but differed from binding affinity estimates in guinea‐pig cortex and gastric glands (Freidinger, 1989). 5 In GPI, devazepide, L‐365,260 and lorglumide yielded different affinity estimates when compared against CCK‐8 and CCK‐4 or pentagastrin respectively. These studies were consistent with the view that the sustained response produced by CCK‐8 was mediated by CCKA receptors and the transient response produced by CCK‐4 and pentagastrin was mediated by CCKB receptors. 6 Affinity estimates for L‐365,260 and lorglumide against CCK‐4 or pentagastrin in GPI were significantly different from corresponding estimates against pentagastrin in RGM. These studies are consistent with the view that gastrin/CCKB receptors in GPI may differ from those in RGM.