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The Effect of CCKB/Gastrin Antagonists on Stimulated Gastric Acid Secretion in the Anaesthetized Rat 1N.J

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The Effect of CCKB/Gastrin Antagonists on Stimulated Gastric Acid Secretion in the Anaesthetized Rat 1N.J Br. J. Pharmacol. (1991), 104, 973-977 q:) Macmillan Press Ltd, 1991 The effect of CCKB/gastrin antagonists on stimulated gastric acid secretion in the anaesthetized rat 1N.J. Hayward, M. Harding, S.A.C. Lloyd, A.T. McKnight, J. Hughes & G.N. Woodruff Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Hills Road, Cambridge CB2 2QB 1 The urethane-anaesthetized, vagotomised rat preparation was used to investigate the effects of the histamine H2-antagonist ranitidine, the proton pump inhibitor omeprazole and the CCKB/gastrin antago- nists CI-988, PD 136450 and L-365,260 on pentagastrin-, histamine- and bethanechol-induced gastric acid secretion. 2 The novel CCKB/gastrin antagonists CI-988 and PD 136450, and L-365,260 dose-dependently inhib- ited pentagastrin-induced secretion. The ED50 value for PD 136450 was 0.05 pmol kg ',the same follow- ing intravenous or subcutaneous administration. 3 CI-988 and PD 136450 administered subcutaneously at dose levels highly effective for antagonism of pentagastrin responses had no effect on basal acid secretion. 4 Ranitidine inhibited pentagastrin-, bethanechol-, and histamine-induced acid secretion, whereas the CCKB/gastrin antagonists inhibited only the secretory response to pentagastrin. 5 The selective CCKA antagonist, devazepide, was inactive at up to 300 pmolkg- i.p. against the three stimulants of acid secretion. 6 CI-988 and PD 136450 will be useful research tools with which to investigate the role of CCKB/gastrin receptors in gastric acid secretion and the trophic activities of gastrin and cholecystokinin (CCK) on the gastrointestinal tract. Keywords: CCKA receptor; CCKB receptor; gastrin receptor; vagotomised; gastric acid secretion; cholecystokinin Introduction for the CCKA class of receptor found predominantly, though not exclusively in peripheral organs, and L-365,260 (Lotti & The primary endogenous mediators of gastric acid secretion Chang, 1989; Bock et al., 1989) which is relatively selective for are acetylcholine, gastrin and histamine. Each of these secre- the CCKB ('brain') receptor and the gastrin receptor, no tagogues acts through its own receptor to trigger unique series antagonist is known that discriminates between the CCKB of biochemical events within the parietal cell but the final step and gastrin receptor. More recently, non-peptide, non- involves activation of the enzyme, H', K+-ATPase, located in benzodiazepine compounds, CI-988 (PD 134308) and PD the membrane of intracellular tubulovesicles. As a result of 136450 have been described that have affinity at the this activation, potassium ions are reabsorbed from the lumen CCKB/gastrin receptor comparable to that seen with L-365, into the cytosol in exchange for the hydrogen ions that are 260, but are more selective for the CCKB receptor over the excreted into the lumen of the canaliculi. CCKA receptor (Hughes et al., 1990; Horwell et al., 1991). The interrelationship of the three physiological gastric While the antisecretory effects of L-365,260 have been secretagogues in the stimulation of gastric acid secretion described in several animal models of acid secretion (Lotti & remains unresolved. The physiological problem is in the Chang, 1989), the activity of the more selective compounds relationship between gastrin and histamine, both being power- has not yet been reported. The importance of such studies ful stimulants of gastric acid secretion and both synthesized in with the CCKB/gastrin antagonists is not only for an exami- the mucous membrane of the stomach. As early as 1938, nation of their potential utility as anti-secretory agents, but MacIntosh had proposed that stimulation of the vagus also as possible adjuncts to therapies with currently available resulted in the release of histamine, and Code (1965), and later agents that carry the attendant risk of hypergastrineamia that Kahlson & Rosengren (1972) extended that idea to gastrin, is a consequence of the achlorhydria produced by long-term making histamine the final common chemostimulant. antisecretory therapy. However, many believe gastrin to be a direct hormone of In the present study, an in situ perfused stomach prep- secretion in its own right; thus, the question of the function aration of the rat has been used for the quantitative investiga- and interrelationship of the three secretagogues in the tion of the effect of the selective CCK/gastrin receptor stomach remains unsettled. The pharmacological problem at antagonists devazepide, L-365,260, CI-988 and PD 136450 on the basis of this has been the lack of antagonists for the gastric acid secretion evoked by pentagastrin, histamine or gastrin receptor that have sufficient affinity and selectivity. bethanechol. A preliminary account of these findings has been Proglumide, a non-selective CCK receptor antagonist, blocks presented to the British Pharmacological Society (Hayward et gastrin receptors (Magous & Bali, 1983), and has been used in al., 1991). the treatment of peptic ulcer disease in Europe and Japan (Rovati, 1976; Weiss, 1979). However, neither the specificity Methods nor the affinity of proglumide has been sufficient to permit its use in vivo to define the role of gastrin in the regulation of Anaesthetized rat perfused stomach preparation gastric acid secretion. In recent years other CCK receptor antagonists from several chemical classes have been devel- The perfused stomach preparation was that described by oped, and although there are now available such benzodiaze- Parsons (1969) as a modification of the Ghosh & Schild (1958) pines as devazepide (MK-329, L-364,718 Chang & Lotti, method. Briefly, male Wistar rats (180-220g) were anaes- 1986; Evans et al., 1986) with high affinity and high selectivity thetized with urethane (1.5gkg-1, i.p.) and the trachea and one or both jugular veins were cannulated. The stomach was 'Author for correspondence. perfused with 5.4% (w/v) glucose in water (370C) at a rate of 974 N.J. HAYWARD et at. 3 ml min-1 via perspex cannulae in the oesophagus and Pentagastrin, histamine dihydrochloride and carbamyl-/i- pyloric antrum; the perfusate issued through a perspex funnel methylcholine chloride (bethanechol) were stored as frozen ali- in the non-secretory lumen and passed over a conventional quots of 0.lmgml-', 10mgmlP', and lmgmlP' in 0.9% pH electrode recording continuously onto a flatbed chart (w/v) NaCl respectively and diluted to the required concentra- recorder. The cannula in the oesophagus was placed below the tion with 0.9% w/v NaCl. CI-988, PD 136450, ranitidine and diaphragm and the oesophagus was cut. atropine were dissolved in 0.9% w/v NaCl with brief sonica- In preliminary experiments to determine doses of the tion. L-365,260 and devazepide were made up fresh in 10% separate agonists that produce comparable, submaximal levels (v/v) ethanol in 90% carboxymethyl cellulose/Tween 80 of acid output, the dose-effect relationship with pentagastrin, (aqueous suspension, 1% w/v with respect to carboxymethyl histamine or bethanechol was determined. Agonists were cellulose, 0.1% w/v with respect to Tween 80). Omeprazole infused intravenously at a constant rate (1ml h-1) and the was made up fresh in distilled water with brief sonication. dose increased cumulatively when the effect of the preceding CI-988, PD 136450, ranitidine, atropine and omeprazole were dose had reached a peak. The response of a given dose was administered intravenously or subcutaneously in a dose measured as hydrogen ion concentration at the peak of the volume of 1 ml kg- ', whilst L-365,260 and devazepide due to response minus basal hydrogen ion concentration. Hydrogen their poor solubility were administered via the intraperitoneal ion concentration at any time of interest was measured as the route in a dose volume of 4 ml kg-1. negative antilogarithm of the pH at that time. For the work with antagonists only one dose of blocker was tested in each preparation. Once basal acid secretion was Results stable submaximal doses of either pentagastrin (1 pugkg 1 min- 1), histamine (30opgkg- ' min- 1) or Stimulation ofgastric acid secretion bethanechol (6 pgkg- min-1) were administered intra- venously via the right jugular vein. The stimulation of acid In preliminary experiments the dose-response relationship was secretion produced by the secretagogue was allowed to reach established for the secretagogues pehtagastrin, histamine and a plateau for about 30min before the dose of antagonist was bethanechol. All three secretagogues caused a dose-dependent administered by intravenous injection via the left jugular vein, increase in gastric acid secretion. Doses of histamine or subcutaneously into the right flank. Acid secretion contin- (30pg kg-1 min 1, i.v.) and bethanechol (6,ug kg- min 1, i.v.) ued to be monitored for as long as possible after drug admin- that were on the linear portion of their log dose-response istration. Results are expressed as percentage inhibition of curves, and that produce increases in acid output comparable secretagogue-induced gastric acid secretion: to that obtained with pentagastrin (1,ug kg-1 min , i.v.) were used to determine the specificity of CI-988 and PD 136450 as / reversal-basal %i1nhibition=simlae. bsa!xX 100- 100 antagonists of pentagastrin in vivo (Figure 1). Each secre- ~stimulated-basal tagogue stimulated a maintained plateau of acid output; pen- tagastrin and histamine 1 h following the start of infusion gave where: acid output levels of 1113.1 + 413.5 and inhibition = hydrogen ion concentration ([He]) at the 1415.4 + 159.0 pmol 1-' H +, and at 3 h gave acid output levels point of maximal inhibition of stimulated acid of 866.4 + 422.1 and 1254.2 + 184.2Pmol I1 H+ respectively. secretion by the compound under test In the case of bethanechol, stable levels of acid output were stimulated = [H+] at the stable level of stimulated acid obtained only after 2 h following the start of infusion, the level secretion being 1572 + 486.6 pmol I' H+; at 4 h the acid output was basal = unstimulated [He] 1767.9 + 290.6pmol 1 H+.
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