EFFECT OF LOXIGLUMIDE (CR-1505) ON CCK-INDUCED CONTRACTIONS AND H-3 ACETYLCHOLINE-RELEASE FROM GUINEA-PIG GALLBLADDER

Release of [H-3]-acetylcholine (H-3-ACh) and muscle contractions in re sponse to cholecystokinin (CCK) were measured and recorded simultaneou sly from isolated guinea-pig gallbladder. Cholecystokinin octapeptide (CCK8) (10(-10)-10(-7) M) enhanced the release of [H-3]ACh and the con tractions of the muscle. TTX (10(-6) M) inhibited the CCK-induced rele ase of H-3-ACh by only 30%. In Ca2+-free medium CCK8 had no effect. Lo xiglumide, (CR 1505), a newly synthesized nonpeptide CCK-A-receptor an tagonist, D.L- (3,4-dichlorbenzoilamino) -5 - / N - (3 -methoxypropyl) -pentylamino-5-oxo-pentanoic acid, antagonized both the ACh-releasing effect of CCK and the contractions in a dose-dependent manner. The aff inity (pA2) of CR 1505 to CCK-receptors, determined by the shift of th e concentration-response curves for CCK8 was 8.36. It was 5 logarithmi c orders higher than the pA2 of proglumide. The IC50 value of CR 1505 calculated by the CCK-induced release of H-3-ACh was 10 nM. The result s suggest the existence not only of muscular CCK receptors but also ne uronal receptors for CCK probably located on cholinergic nerves.