Contractile mechanisms of action of gastroprokinetic agents: cisapride, metoclopramide, and domperidone

Abstract

We investigated the contractile mechanisms of action of three putative gastroprokinetic agents (cisapride, metoclopramide, and domperidone) on the linear phase of gastroduodenal emptying of solid meals in six healthy conscious dogs. The spatial and temporal parameters of gastric, pyloric, and duodenal contractions during the entire period of gastroduodenal emptying, during the 60-min period of drug infusion (ti), and during the postdrug infusion period (tpi) were analyzed by a computer method. Cisapride accelerated the total gastroduodenal emptying time (tfull), metoclopramide had no significant effect, and domperidone delayed the tfull. None of the drugs had a significant effect on gastroduodenal emptying during ti. Both cisapride and metoclopramide enhanced the rate of gastroduodenal emptying during tpi. Cisapride enhanced pyloric and duodenal motor activity but had no significant effect on antropyloroduodenal coordination during tfull and ti. During tpi, cisapride significantly enhanced both the pyloric and duodenal motor activity and antropyloroduodenal coordination. Metoclopramide exhibited only a few significant effects on the frequency, amplitude, duration, and area under contractions in the antrum, pylorus, and duodenum, but it enhanced antropyloroduodenal coordination during tfull and tpi. Domperidone decreased the frequency of corporeal, pyloric, and duodenal contractions and deteriorated antropyloroduodenal coordination by decreasing the frequency of contractions propagating from the antrum or the pylorus to the duodenum. Cisapride and metoclopramide, but not domperidone, increased the mean distance of propagation of duodenal contractions during tfull, ti, and tpi. We conclude that cisapride is more effective in accelerating gastroduodenal emptying because it stimulates the largest number of parameters of gastropyloroduodenal contractions that enhance gastric emptying. Most enhancement of gastric emptying rate with both cisapride and metoclopramide occurs during tpi.

Molecular, functional, and pharmacological targets for the development of gut promotility drugs

“…However, the regulation of gastric emptying is multifactorial and complex. It depends on coordination among several mechanisms, including pyloric contractions and tone, antro-pyloro-duodenal coordination, fundic adaptive relaxation followed by gradual increase in tone, and propagating RPCs in the body of the stomach (25,46). It is, therefore, critical that the stimulation of gastric RPCs by promotility drugs does not adversely affect the other regulatory mechanisms so as to negate their beneficial effects (65).…”

Pharmacological Characterization of 5-Hydroxytryptamine-Receptor Subtypes in Circular Muscle from the Rat Stomach

“…7) In addition, the stimulation of 5-HT 4 receptors elicits gastrointestinal contractile activity and increases the rate of gastric emptying in humans 8,9) and dogs. [10][11][12] With regard to gastric smooth muscle activity, it is generally accepted that the 5-HT 1B/1D and 5-HT 7 receptors are relaxant whereas the 5-HT 2 , 5-HT 3 and 5-HT 4 receptors are contractile. Although the gastric contractility of 5-HT has been reported in a variety of species and stomach regions, regional and functional differences of 5-HT-receptor subtypes have been fully investigated only in the guinea pig stomach.…”

Macrophage Fcγ Receptors Expression Is Altered by Treatment with Dopaminergic Drugs

“…Chlorpromazine has a predominant D1 and D2 dopaantagonist action, while benzamides (metochlopramide, sulpiride, veralipride, alizapride, and cisapride) have a more selective D2 dopa-antagonist effect (27)(28)(29)(30)(31)(32). A selective D1 dopa-antagonist would help to differentiate the relative contribution of D1 and D2 dopa-antagonists action on the expression of macrophage Fc␥ receptors.…”

“…M, S, V, A, and Cs are dopa-antagonists of the benzamide family. Metochlopramide has been widely used in the symptomatic treatment of digestive disorders (29). Sulpiride has been mainly prescribed for the treatment of minor psychiatric disorders (30).…”