Effect of dexloxiglumide and spiroglumide, two 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 gastric motor activity has been long hampered by the lack of specific and potent nonpeptide antagonists of CCK-receptors. The availability of such compounds has stimulated a broad array of investigations into the physiological actions of this hormone and to examine its putative role in certain diseases.


OBJECTIVE
The effect of two recently developed CCK-receptor antagonists, namely dexloxiglumide and spiroglumide, on gastric emptying and secretion as well as their selectivity towards CCKA- and CCKB-receptors in vivo was studied in the rat.


METHODS
Gastric emptying 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 gastric 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, spiroglumide, proved to be capable of inhibiting dose-dependently pentagastrin-induced acid hypersecretion, its ID50 being 20.1 (8.67-46.4) mg/kg. On the other hand, dexloxiglumide, at doses able to almost completely block CCKA mediated effects (i.e. delay of gastric emptying), was ineffective against pentagastrin-induced acid hypersecretion. Similarly, 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 demonstrate in vivo that dexloxiglumide is a selective antagonist for CCKA-receptors whereas spiroglumide is selective for CCKB-gastrin-receptors. These compounds are therefore useful tools for discriminating between different subclasses of CCK-receptors in vivo and might have a therapeutic potential in motility or acid-related disorders.
Scarpignato
C
C
Institute of Pharmacology, School of Medicine and Dentistry, University of Parma, Italy.
Kisfalvi
I
I
D'Amato
M
M
Varga
G
G
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005746:Gastric Emptying / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology*; D007651:Keto Acids / Q000494:pharmacology*; D008297:Male; D010418:Pentagastrin / Q000494:pharmacology; D010421:Pentanoic Acids / Q000494:pharmacology*; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*
D006727:Hormone Antagonists; D007651:Keto Acids; D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; D013141:Spiro Compounds; C103490:dexloxiglumide; C053737:loxiglumide; D010418:Pentagastrin; D011377:Proglumide; C076954:spiroglumide; D012844:Sincalide