CCK-8, CCK-4 and gastrin-induced contractions in guinea pig ileum: evidence for differential release of acetylcholine and substance P by CCK-A and CCK-B receptors

Abstract

The cholecystokinin (CCK) receptor involved in contraction of guinea pig ileal longitudinal muscle to cholecystokinin is poorly understood; some studies have suggested that contraction was mediated via a CCK-A receptor whereas other studies have implicated CCK-B receptors in ileal contraction to CCK. To clarify this, we compared the effects of CCK-8 sulfate, CCK-4 and gastrin in radioligand binding studies and longitudinal ileal contractility in vitro. Contraction to all three peptides was abolished by tetrodotoxin (3 x 10(-7)M), confirming the neuronal nature of the CCK receptors mediating contraction to all three peptides. Maximal CCK-8S contractions were inhibited by 80% in the presence of atropine (10(-6)M), and entirely by the combination of atropine and a substance P receptor antagonist (3 x 10(-5)M). CCK-4 and gastrin-induced contractions were unaffected by substance P receptor blockade, but were abolished by atropine. Two selective CCK-A and CCK-B receptor antagonists, L-364,718 and L-365,260, respectively, were used to probe further the receptors involved in ileal contraction to this peptide family. Radioligand binding studies in mouse brain, rat pancreas and guinea pig stomach confirmed the selectivity of these antagonists. The CCK-A selective antagonist, L-364,718, potently inhibited ileal contractions to CCK-8S (-log KB = 9.35) with 10-fold lower affinity at receptors mediating contraction to CCK-4 (-log KB = 8.25). In contrast, the CCK-B receptor antagonist, L-365,260, did not affect contraction to CCK-8S (-log KB less than 7) but potently inhibited contraction to CCK-4 (-log KB = 9.24).(ABSTRACT TRUNCATED AT 250 WORDS)