EFFECT OF DEXLOXIGLUMIDE AND SPIROGLUMIDE, 2 NEW CCK-RECEPTOR ANTAGONISTS, ON GASTRIC-EMPTYING AND SECRETION IN THE RAT - EVALUATION OF THEIR RECEPTOR SELECTIVITY IN-VIVO

Background: Clear definition of the role of CCK in the physiology of g astric motor activity has been long hampered by the lack of specific a nd potent nonpeptide antagonists of CCK-receptors. The availability of such compounds has stimulated a broad array of investigations into th e physiological actions of this hormone and to examine its putative ro le in certain diseases. Aims: The effect of two recently developed CCK -receptor antagonists, namely dexloxiglumide and spiroglumide, on gast ric emptying and secretion as well as their selectivity towards CCKA- and CCKB-receptors in vivo was studied in the rat. Methods: Gastric em ptying was quantified by using a liquid noncaloric meal labelled with phenol red. Acid secretion was measured by titration in conscious rats . Results: The putative CCKA-antagonist, dexloxiglumide, administered by intravenous route, was able to inhibit CCK-8-induced delay of gastr ic emptying in a dose-dependent fashion, with an ID50 (95% CL) of 1.14 (0.84-1.53) mg/kg. Similarly, the putative CCKB-gastrin-antagonist, s piroglumide, proved to be capable of inhibiting dose-dependently penta gastrin-induced acid hypersecretion, its ID50 being 20.1 (8.67-46.4) m g/kg. On the other hand, dexloxiglumide, at doses able to almost compl etely block CCKA mediated effects (i.e. delay of gastric emptying), wa s ineffective against pentagastrin-induced acid hypersecretion. Simila rly, spiroglumide, at doses which inhibit by 55% CCKB-gastrin mediated effects (i.e. acid secretion) was inactive when tested against CCK-8 induced delay of gastric emptying. Conclusions: These results demonstr ate in vivo that dexloxiglumide is a selective antagonist for CCKA-rec eptors whereas spiroglumide is selective for CCKB-gastrin-receptors. T hese compounds are therefore useful tools for discriminating between d ifferent subclasses of CCK-receptors in vivo and might have a therapeu tic potential in motility or acid-related disorders.