J Physiology (1993) 87. 291-300 291 © Elsevier, Paris Effect of CCK and its antagonists on gastric emptying C Scarpignato a, G Varga b, C Corradi a Institute of Pharmacology School of Medicine & Dentisttw Maggiore University" Hospital University qf Parma, 43100 Parma, Italy; blnstitute of Experimental Medicine," Hungarian Academy of Sciences, Budapest. Hungary (Received 1 May 1993; accepted 8 June 1993) Summary - Cholecystokinin (CCK) belongs to the group of substances known as brain-gut peptides: it functions both as a neuropeptide and a gut hormone. The peptide and its synthetic derivatives (like for instance CCK-8 and the amphibian counterpart caerulein) significantly delay emptying of gastric contents in both animals and humans. The fact that CCK, in doses mimicking postprandial plasma levels, strongly affects emptying rate suggests the peptide to be a physiologic regulator of gastric emptying. Unfortunately, clear definition of the role of CCK in the physiology of gastric motor activity has long been hampered by the lack of specific and potent non-peptide antagonists of CCK-receptors. The availability of such com- pounds has stimulated a broad array of investigations into the physiological actions of this hormone and examination of its putative role in certain diseases. This paper summarizes the available data concerning the effect of CCK and its antagonists on gastric emptying. The use of selective CCK-antagonists has allowed to establish that the gastric motor effect of the peptide is direct and mediated through the stimulation of CCK-A receptors. As a consequence. CCK-A antagonism results in acceleration of emptying rate under certain experimental and clinical conditions. This peculiar pharmacologic effect of CCK-A antagonists, which could be useful in the treatment of functional dyspepsia (idiopathic or diabetic), gastroparesis and gastro-esophageal reflux disease (where patients often display a delayed emptying rate of solid food) needs to be further investigated, in order to fully explore their potential as gastrokinetic drugs. CCK / CCK-receptors / CCK-antagonists / gastric emptying Introduction Many receptor types are now known to modulate the function of the gut (Burks et al, 1983; Ruoff et al, 1991), and new agents are being developed that enhance gastrointestinal motor function and accelerate transit. These drugs will offer a wider variety of therapeutic approaches for the numer- ous conditions in which gut hypomotility plays a pathophysiological role. Functional alterations of dopaminergic (inhibitory) and muscarinic (stimu- latory) receptors are thought to be implicated in the pathogenesis of gut hypomotility. Con- sequently, gastrointestinal motility has been stimulated through the use of dopamine antago- nists (such as metoclopramide, domperidone and L-sulpiride) or by substances which release acetylcholine (such as metoclopramide or cisa- pride), or even directly by cholinergic drugs which bind and act on muscarinic receptors of the smooth muscle cell, for example bethanechol (Scarpignato, 1988). Recent evidence strongly suggests that blockade of CCK-receptors is also a promising avenue. This paper will summarize the available data concerning the effect of cholecystokinin (CCK) and its antagonists on gastric emptying and dis- cuss the potential of CCK-A antagonists as gastrokinetic drugs. Cholecystokinin and gastric emptying Gastric emptying is one of the most important motor functions in the gastrointestinal tract (Heading et al, 1992). It limits the rate of absorp- tion of nutrients and drugs by controlling delivery into the small intestine (McHugh, 1983). The rate of delivery is modulated by feedback from nutrients and other receptors in the small in- testine, by the central nervous system via the vagus and sympathetic nerves and by release of a variety of hormones (Meyer, 1991). CCK clearly belongs to the group of substances known as brain-gut peptides: it functions both as a neuropeptide and a gut hormone (Docray, 1989). The peptide and its synthetic derivatives (like for instance CCK-8 and the amphibian counterpart