Effect of the novel cholecystokinin receptor antagonist CR-1392 on cholecystokinin-induced antroduodenal and pyloric motor activity in vivo.

The effects of i.a. injected cholecystokinin (CCK)-octapeptide on pyloric and antroduodenal motility, measured with strain gauges and combined side hole-sleeve manometry, were investigated in 16 dogs in vivo. CCK-octapeptide (OP) induced strong pyloric contractions when injected into the pylorus (threshold of 2 x 10(-13) mol; ED50, 8 x 10(-13) mol). Similar responses were obtained in the distal antrum (threshold, 6 x 10(-13) mol; ED50, 3 x 10(-12) mol) and the proximal duodenum (threshold, 5 x 10(-13) mol; ED50, 3 x 10(-12) mol). The nonsulfated form of CCK-OP was about 2 to 3 log units less potent in eliciting these excitatory responses in the pylorus (threshold, 9 x 10(-10) mol). Atropine shifted the dose-response curve of CCK-OP in pylorus, duodenum and antrum to the right suggesting a neural action of CCK-OP. However, an excitatory effect of CCK-OP was still present after neural blockade with tetrodotoxin i.a. Therefore, there was probably a muscular as well as a neural site of action of CCK-OP in these tissues. Systemic application of the novel CCK-antagonist CR-1392 in a dose of 1.2 mg/kg i.v. plus 100 micrograms i.a. shifted the dose-response curve of CCK-OP 1 log unit to the right without affecting the dose-response curve to acetylcholine. This dose of CR-1392 did not interfere with the pyloric motor responses to duodenal field stimulation or to intraduodenal acid infusion. These results demonstrate the dual peripheral action on nerve and muscle of CCK-OP in the pylorus in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)