Effect of metoclopramide in guinea-pig ileum longitudinal muscle: evidence against dopamine-mediation.

Abstract

SUMMARY The investigation examines the hypothesis that metoclopramide-induced potentiation of gastrointestinal motility is mediated through dopamine receptors. In vitro studies on the longitudinal muscle of the guinea-pig ileum were performed. Metoclopramide, in concentrations comparable with those seen in plasma after therapeutic doses in man, selectively potentiated the cholinergic response. Metoclopramide can block dopamine, and its antiemetic effect probably involves antagonism of dopamine centrally.5 6 The presence of dopamine in gastrointestinal nerve7, raises the possibility tested here that metoclopramide acts peripherally by antagonising dopamine. MethodsExperiments were carried out on longitudinal muscle strips from guinea-pig ileum. Male guinea-pigs, 300-500g, were killed by a blow on the back of the head, bled out, and the terminal 30-40 cm ileum after discarding the last 20 cm was removed.Received for publication 22 June 1981 gastrointestinal motility does not involve local Longitudinal muscle strips 4-5 cm long, were prepared from the terminal ileum.8 Each strip was suspended under a load of 0.25 g in a 5 ml organ bath with built-in platinum electrodes. The bath contained Krebs-Henseleit solution: (mM) (NaCl, 113; KC1, 4.7; CaC12, 2.5; MgSO4, 1.2; KH2PO4, 1.2; NaHCO3, 25; glucose, 11.5), maintained at 37°C and bubbled with 95%0 2 and 5% CO2. Electrical stimulation was delivered from an electronic stimulator9, through the built-in platinum electrodes with a pulse duration of 0.2 ms, frequency 0 1 Hz and supramaximally effective voltage. Longitudinal muscle tone was monitored continuously using an isometric transducer and a pen-recorder. All experiments were performed a minimum of three times. DRUGSThe following drugs were dissolved in distilled water: acetylcholine chloride, atropine sulphate, dopamine hydrochloride, hexamethonium bromide, histamine chloride (Sigma); metoclopramide hydrochloride (Beecham Pharmaceuticals); phentolamine mesylate (Ciba); tetrodotoxin (Sigma).Bromocriptine methansulphonate (Sandoz) was dissolved in 30% ethyl alcohol to make 1.3 mM stock solution; further dilutions were made in Krebs solution. Pimozide (Janssen Pharmaceuticals) was dissolved in citric acid solution to make 5.5 mM stock solution and further diluted with distilled water. 66 on 10 May 2018 by guest. Protected by copyright.

TSH and PRL Responses to Domperidone and TRH in Men with Insulin-Dependent Diabetes Mellitus of Different Duration

“…33, 41, 42], IDDM seems to alter TSH and PRL secre tion simultaneously in euthyroid subjects; modifications of these hormones have been studied as an associated phenomenon and an altered dopaminergic control of pituitary function has been proposed as the likely cause of their disorder [18]. TSH and PRL responses to metoclopramide, an antidopaminergic agent, have been tested to prove this hypothesis [ 18], However, because of its interactions with other ncurotransmitters such as serotonin [20,21,26,34] or acetyl choline [3,12,19,25,26,43], mctoclopramide does not seem to be just an antagonist of dopamine. Furthermore, data in the litera ture describing TSH and PRL alterations in IDDM are scant and often contradictory, since decreased [9,18], increased [1,22] or unchanged [6,10,13,15,24,30,32,33,38,40,42] circulating levels of these hormones have been reported.…”

Pharmacological Bases of the Medical Treatment of Gastroesophageal Reflux Disease

“…Of the various possible mechanisms capable of altering gastrointestinal motor activity, almost all have been claimed for metoclopramide. A critical analysis of all studies sug gests that mctoclopramidc-induced potentia tion of gastrointestinal motility does not in volve local dopamine receptors [Zar et al, 1982] and is consistent with the idea that the drug may act as a preferential, prejunctional muscarinic antagonist thus inhibiting the negative feedback inhibition of acetylcholine release [Fernandez and Massingham, 1985]. Finally, it is known that metoclopramide is an effective, albeit weak, antagonist of 5-HTj receptors which have been found onlyassociated with peripheral autonomic, affer ent and enteric neurones.…”

Effect of TKS159, a novel 5‐hydroxytryptamine4 agonist, on gastric contractile activity in conscious dogs

“…These agents exert their effects through several mechanisms of action. For instance, metoclopramide has been reported to activate the intramural cholinergic neurones responsible for modifying gastric motility, 5 to enhance gastric emptying through an antidopaminergic effect 6 and to increase acetylcholine (ACh) release from nerve terminals 7 . Cisapride has been shown to enhance endogenous ACh release without affecting dopamine receptors 8 and to stimulate gastric motility via a mechanism involving 5‐hydroxytryptamine (5‐HT) 4 receptors 9 .…”