Pharmacologic characterization of excitatory and inhibitory cholecystokinin receptors of the cat gallbladder and sphincter of Oddi.

The pharmacologic properties and specificity of cholecystokinin (CCK) receptors of the biliary tract were investigated by testing various sulfated and desulfated CCK fractions and by using specific CCK-gastrin antagonists. Sulfated CCK-7 (5-80 pmol/kg) caused gallbladder contraction and sphincter of Oddi relaxation. Denervation with tetrodotoxin decreased the gallbladder response by 50% and changed the sphincter of Oddi response from relaxation to contraction. Desulfated CCK-7 (80-400 pmol/kg) caused a weak gallbladder contraction that was unaffected by tetrodotoxin. The gallbladder did not respond to CCK-3 (10-80 nmol/kg) or to CCK-2 (10-160 nmol/kg) in doses that completely relaxed the sphincter of Oddi. These doses, however, were 5-2000 times higher than the maximal dose of sulfated CCK-7. After denervation with tetrodotoxin, desulfated CCK-7 (10-400 pmol/kg) induced a weak sphincter of Oddi contraction even with doses five times greater than the maximal dose of sulfated CCK-7. The denervated sphincter of Oddi did not respond to CCK-3 (10-80 nmol/kg) or CCK-2 (10-160 nmol/kg). Furthermore, a continuous proglumide infusion (5-20 mg/kg X min) and bolus doses of dibutyryl cyclic guanosine monophosphate (250-1000 micrograms/kg) blocked the effect of sulfated CCK-8 on the gallbladder and sphincter of Oddi. Higher doses of these antagonists were needed, however, to block the CCK effect on the sphincter of Oddi than on the gallbladder. In contrast, high doses of desulfated CCK-7 (100 pmol/kg) or CCK-3 (200 nmol/kg) did not antagonize the effect of sulfated CCK-8 (10-80 pmol/kg) on the gallbladder. These findings suggest the existence of three sets of specific CCK receptors with molecular configuration requirements determined by the type of cell where these receptors are located: on the postganglionic cholinergic neurons, on the smooth muscle cells of the gallbladder, and sphincter of Oddi, or on the postganglionic noncholinergic, nonadrenergic inhibitory neurons.