Gustatory effects on intestinal motility of dogs

Trained, unanaesthetised dogs with jejunal fistula and adapted to 2 h meal-time showed transient taste-correlated changes in pressure (mm H2O) but not in frequency of intestinal motility. Intestinal pressure was increased on bitter taste both before meal-time (4.7 +/- 0.2 mm) and after it (13.1 +/- 0.9 mm) over respective basal pressure (before meal 3.2 +/- 0.4 mm), after meal 10.6 +/- 1.4 mm), whereas it was decreased on sweetness of saccharin (before meal 1.1 +/- 0.1 mm, after meal 4.8 +/- 0.5 mm), and glucose (before meal 1.7 +/- 0.2 mm; after meal 8.8 +/- 0.9 mm). Taste-induced motility changes were more pronounced on starvation than on fed state.     

Acute effects of morphine on rat intestinal motility

Systemic injection of morphine (0.5–16 mg/kg) caused dose-related increases in intestinal intraluminal pressure in anesthetized rats. Injection of morphine into cerebral ventricles was no more effective than the intravenous (i.v) route. Decapitation of the animals did not prevent the intestinal stimulatory effect of i.v. morphine. The intestinal stimulation induced by i.v. morphine and 5-hydroxytryptamine (5-HT), but not that induced by cholecystokinin octapeptide, was antagonized by methysergide. Morphine appears to stimulate contractions of intestinal circular muscle in the rat by release of local, endogenous 5-HT.     

Time-related effects of benzodiazepines on intestinal motility in conscious dogs

The effects of diazepam and GABA on intestinal motility were investigated in fasted dogs fitted with strain-gauge transducers. Injected intravenously at 9.00 and 16.00 h, diazepam (0.5 mg kg-1) affected intestinal motility only during darkness i.e. from 19.00 to 7.00 h. These jejunal motor effects which were mimicked by GABA, (0.3 mg kg-1 i.v.) corresponded to a disruption of the migrating myoelectric complex (MMC) with an increased contractile activity. These results demonstrate that benzodiazepines affect the intestinal motility in dog and suggest that the effects are related to sleep-stages.     

The calcium channel antagonist, verapamil, potentiates the inhibitory action of morphine on intestinal and biliary motility

The effects of morphine and verapamil have been assessed on the gastrointestinal propulsion of charcoal meal and egg yolk-induced gall bladder emptying in mice. Each drug significantly inhibited these functions. In combination, an additive effect was seen on the inhibition of gastrointestinal transit, whilst verapamil potentiated the morphine-induced inhibition of gall bladder emptying. It is concluded that calcium ion channel antagonists may potentiate the activity of opiate drugs.     

Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450

The use of common formulation ingredients (categorized into six groups) for preclinical animal studies has been assessed with respect to cytochrome P450 (CYP) inhibition, specifically CYP3A inhibition, in expressed human CYP3A4, human liver microsomes, dog- and cynomolgus monkey intestinal microsomes. Results indicated a wide range of inhibition potentials and there appeared to be species differences with inhibition of CYP3A activity. Generally, greater inhibition of CYP3A activity was observed with amphiphilic ingredients (for example mixed micellar solutions, Tween 80, and oleic acid). From the data presented, it can be predicted that the majority of the ingredients tested would not have a significant impact on the potential inhibition, by the formulation, on any apparent first pass metabolism in the intestinal tract for new drug entities being tested in the preclinical environment. However a number of common ingredients will require further investigation based on the estimated concentration within the gastrointestinal tract.     

Inhibitory effects of calcium channel blockers on intestinal motility in the dog

Calcium channel blockers are now widely used for the treatment of cardiovascular disorders. However, data concerning their effects on intestinal motility in vivo are still rather fragmentary. Therefore, we evaluated the effects of three prototype calcium channel blockers (nifedipine, verapamil and diltiazem) on intestinal motility in five fasting, conscious dogs fitted with electrodes and strain-gauges along the small bowel. The myoelectric data were analyzed by a recently developed and validated computer program which allows accurate monitoring of intestinal spike activity. The mechanical data were analyzed by calculating a motility index. After recording of at least two migrating motor complexes (control), an i.v. infusion of one of the following calcium channel blockers was maintained for 3 h: 0.29 or 0.87 mumol/kg per h nifedipine, 1.02 or 2.04 mumol/kg per h verapamil and 1.11 or 2.22 mumol/kg per h diltiazem. Nifedipine 0.29 mumol/kg per h significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. The higher dose suppressed migrating motor complex cycling and almost completely abolished both spike and mechanical activities. The two doses of verapamil had effects similar to those of the two doses of nifedipine. Both doses of diltiazem significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. We conclude that all the agents tested, apart from their well known cardiovascular effects, also have a profound inhibitory effect on intestinal motility in vivo, the order of potency being nifedipine greater than verapamil greater than diltiazem. The search for more selective calcium channel blockers for the treatment of intestinal motor disorders with minimal cardiovascular effects is warranted.     

Central and peripheral inhibitory effects of morphine on intestinal transit in mice

In the present study, intestinal motility was measured by the transit of charcoal meal through the small intestine in mice. Morphine, given subcutaneously, caused a dose-dependent slowing of the rate of intestinal transit. This inhibitory effect of morphine was antagonised by prior subcutaneous administration of naloxone hydrochloride or its quaternary analog naloxone methylbromide. However, on a weight basis, naloxone methylbromide was only about half as potent as naloxone hydrochloride. Morphine given centrally, either intracerebroventricularly or intracisternally, caused a dose-related inhibition of intestinal transit, the intracerebroventricular route appearing to be more effective. The effects of centrally administered morphine were antagonised by prior subcutaneous administration of naloxone hydrochloride but not by naloxone methylbromide. The narcotic antagonists administered centrally were effective in suppressing the inhibitory effect of subcutaneously administered morphine. When given intracerebroventricularly naloxone methylbromide was as effective as naloxone hydrochloride, while by intracisternal route, it was about half as potent as naloxone hydrochloride. These results provide evidence that peripherally administered morphine inhibits intestinal transit by both central and peripheral mechanisms. Of the central routes of administration studied, it appears that the sites around the lateral ventricles play a more significant role in the intestinal inhibitory actions of morphine.     

Inhibitory effects of daidzein on intestinal motility in normal and high contractile states

Context: Daidzein is a naturally occurring compound and has various health benefits. However, its effects on intestinal smooth muscle contractility remain unknown.

Aims: The present study was to characterize the effects of daidzein on the contractility of isolated jejunal smooth muscle and its underlying mechanisms.

Methods: Ex vivo assay was selected as the major method to determine the effects of daidzein on the contractility of isolated jejunal smooth muscle fragment (JSMF).

Results: Daidzein (5–160 µmol/L) inhibited the contractility of JSMF in normal contractile state and in a dose-dependent manner. Daidzein also inhibited the contractility of JSMF induced by ACh, histamine, erythromycin and high Ca²⁺, respectively, and decreased charcoal propulsion in the small intestine in vivo. The inhibitory effects of daidzein were partially blocked by phentolamine or propranolol and were abolished in the presence of varapamil or at Ca²⁺-free assay condition. However, the inhibitory effects of daidzein on jejunal contraction were not significantly influenced by nitric oxide (NO) synthase inhibitor L-NG-nitro-arginine (l-NNA). Daidzein was also found to directly inhibit the phosphorylation and Mg²⁺-ATPase activity of smooth muscle myosin.

Discussion and Conclusion: The results implicated that α- and β-adrenergic receptors were involved in the inhibitory effects produced by daidzein rather than via NO pathway. As a phytoestrogen, daidzein has shown its potential value in relieving the hypercontractility of small intestine.     

The involvement of opiate receptors in the effects of trimebutine on intestinal motility in the conscious dog

The effects of intravenous (i.v.) vs intracerebroventricular (i.c.v.) administration of trimebutine on the motility of the small intestine and colon of fasted dogs were assessed using chronic electromyography. Trimebutine, injected intravenously, stimulated small intestinal motility, by inducing a propagated phase of regular spike activity, and inhibited colonic motility for some 4 h. These effects were not reproduced by i.c.v. administration which disrupted the cyclic motor profile of the small intestine for about 2.5 h and did not modify colonic motility. The stimulation of the small intestine motility induced by i.v. administration of the drug was blocked by previous i.v. but not by i.c.v. administration of naloxone. It was concluded that in the dog, the effects of trimebutine on the small intestine but not on the colon, involve peripheral opiate receptors.     

RS67506对肠道运动的影响

目的研究5-羟色胺(5-HT)4受体激动剂RS67506对小鼠肠推进运动和对大鼠离体小肠肌条运动的影响。方法应用炭末法和张力换能器分别观察RS67506对小鼠肠推进运动和对大鼠离体小肠肌条的平均收缩幅度、收缩频率和静息张力的影响,并与Cisapride的作用相比较。结果 RS67506在小剂量时对小鼠肠推进运动无明显作用,中剂量和大剂量时作用明显,并且RS67506剂量依赖性增强肌条的收缩幅度,但对肌条收缩频率和静息张力无明显作用。结论 RS67506在剂量稍大的条件下,具有与Cisapride相当的对小鼠肠推进运动的作用。它对大鼠离体小肠肌条的收缩幅度与Cisapride相似,具有剂量依赖性增强作用,如果事先加入5-HT4受体拮抗剂RS23597-190,RS67506无明显作用,这表明RS67506对平滑肌肌条的作用是通过5-HT4受体完成的。     

Interaction between the inhibitory effects of morphine and clonidine on intestinal transit in mice

Both clonidine and morphine dose-dependently inhibited intestinal transit in mice. This inhibitory effect of clonidine was antagonized by prior administration of yohimbine but not by naloxone, while morphine's effect was antagonized by both yohimbine and naloxone. Morphine pretreatment did not induce any apparent tolerance to the effect of clonidine and morphine tested 4 h later. However, yohimbine became more potent in antagonizing the effect of clonidine while naloxone remained ineffective. Morphine pretreatment enhanced the antagonistic effectiveness of both yohimbine and naloxone against morphine. Clonidine pretreatment at a dose that did not induce any tolerance slightly enhanced the antagonistic effects of yohimbine and naloxone against morphine. Yohimbine also became more effective against clonidine but naloxone remained ineffective. At higher doses of clonidine pretreatment tolerance to the effects of morphine and clonidine were observed. These results suggest that both alpha 2-adrenoceptors and opioid receptors are involved in the inhibitory action of morphine on intestinal transit, while clonidine mainly acts through the alpha 2-adrenoceptors. In addition, there is a close interaction between the alpha 2-adrenoceptors and opioid receptors in the intestine.     

The effects of proglumide on morphine induced motility changes

Proglumide (0.02 mg/kg), a cholecystokinin antagonist, was administered to rats either together with or without morphine (0, 5, 15, or 45 mg/kg). Whereas proglumide in the absence of morphine showed a trend towards enhanced behavioral activation, it potentiated the hy[okinesia induced by morphine. These results are consistent with the hypothesis that endogenous cholecystokinin tonically antagonizes opiate modulation of motility, irrespective of whether such modulation is produced by opiates and endogenous or exogenous origin.     

Antibiotic-associated colitis: an in vitro investigation of the effects of antibiotics on intestinal motility.

1 Nine antibiotic compounds in common use were studied to determine their ability to affect intestinal motility in vitro, in the guinea-pig ileum and rabbit colon. 2 Ampicillin, doxycycline, mecillinam and metronidazole were without effect over a concentration range which included typical serum levels found when these drugs are used therapeutically. 3 Clindamycin, gentamicin, kanamycin, pivmecillinam and trimethoprim were all found to inhibit evoked and reflex responses of the guinea-pig ileum but only clindamycin and trimethoprim also affected evoked responses of the rabbit colon. 4 Kanamycin and gentamicin appeared to have a predominantly pre-junctional action, pivmecillinam and trimethoprim a predominantly post-junctional action. Clindamycin had a pre-junctional action at low concentrations and long exposure times, and a post-junctional action at high concentrations and short exposure times. 5 The concentration of each antibiotic required to inhibit the peristaltic reflex of the guinea-pig ileum was less than that required to inhibit its responses to electrical stimulation or exogenous acetylcholine or histamine but greater than the serum levels associated with their respective use in therapeutic doses. 6 A sequence of events whereby antibiotic-induced alterations in gastro-intestinal motility could lead to the development of pseudomembranous colitis is proposed.     

Aging and intestinal motility: a review of factors that affect intestinal motility in the aged

Normal aging is associated with significant changes in the function of most organs and tissues. In this regard, the gastrointestinal tract is no exception. The purpose of this review is to detail the important age-related changes in motor function of the various parts of the gastrointestinal tract and to highlight some of the important motility changes that may occur, either in relation to common age-related disorders, or as a result of certain drugs commonly prescribed in the aged. A major confounding factor in the interpretation of motor phenomena throughout the gastrointestinal tract in this age group is the frequent coexistence of neurological, endocrinological and other disease states, which may be independently associated with dysmotility. Overall, current data are insufficient to implicate normal aging as a cause of dysmotility in the elderly. Normal aging is associated with various changes in gastrointestinal motility, but the clinical significance of such changes remains unclear. More important is the impact of various age-related diseases on gastrointestinal motility in the elderly: for example, long-standing diabetes mellitus may reduce gastric emptying in up to 50% of patients; depression significantly prolongs whole-gut transit time; hypothyroidism may prolong oro-caecal transit time; and chronic renal failure is associated with impaired gastric emptying. In addition, various, frequently used drugs in the elderly cause disordered gastrointestinal motility. These drugs include anticholinergics, especially antidepressants with an anticholinergic effect, opioid analgesics and calcium antagonists.     

The inhibitory effects of alpha(2)-adrenoceptor agonists on gastrointestinal transit during croton oil-induced intestinal inflammation.

1. The peripheral effects of alpha(2)-adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric administration of croton oil (CO). Our hypothesis was that inflammation would 'sensitize' adrenoceptors in peripheral and/or central terminals of myenteric and submucous plexus neurones, and enhance systemic effects of alpha(2)-adrenoceptor agonists. 2. Male swiss CD-1 mice, received intragastrically CO (0.05 ml), castor oil (CA, 0.1 ml) or saline (SS) 3 h before the study: gastrointestinal transit (GIT) was evaluated 20 min afterwards with a charcoal meal. The presence of inflammation was assessed by electron microscopy. 3. The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced an inflammatory response. Both clonidine (imidazoline1/alpha(2)-agonist) and UK-14304 (alpha(2)-agonist) produced dose-related inhibitions of GIT in all groups. During inflammatory diarrhoea (CO), potencies of systemic (s.c.) clonidine and UK-14304 were significantly increased 3.5 and 2.1 times, respectively, while potencies remained unaltered in the presence of diarrhoea without inflammation (CA). The effects were reversed by administration (s.c.) of receptor-specific adrenoceptor antagonists, but not by naloxone. 4. Clonidine was 8.3 (SS) and 2.8 (CO) times more potent when administered intracerebroventricularly (i.c.v.), than when administered s.c. Inflammation of the gut did not alter the potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammation, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED20 and ED50S), but partially reversed ED80S, further supporting the peripheral effects of the agonists in CO treated animals. 5. The results demonstrate that inflammation of the gut enhances the potency of alpha(2)-adrenoceptor agonists by a peripheral mechanism. The results also suggest that the inflammatory response induces an up-regulation or sensitization of alpha(2)-adrenoceptors and/or imidazoline receptors.     

The effect of cannabinoids on intestinal motility and their antinociceptive effect in mice

1. After oral administration to mice, pethidine, Delta(8)-tetrahydrocannabinol (THC), Delta(9)-THC, a cannabis extract and cannabinol had a dose-dependent antinociceptive effect when measured by the hot-plate method. Cannabidiol was inactive at 30 mg/kg. Delta(8)-THC, Delta(9)-THC and pethidine did not differ significantly in potency, but Delta(9)-THC was 6.5 times more active than cannabinol.2. After oral administration, three different cannabis extracts, Delta(8)-THC, Delta(9)-THC and morphine produced dose-dependent depressions of the passage of a charcoal meal in mice. Delta(8)-THC and Delta(9)-THC were equipotent and were about five times less potent than morphine. Cannabidiol was inactive up to 30 mg/kg. The effect of the three cannabis extracts on intestinal motility could be accounted for by their Delta(9)-THC content.3. The antinociceptive effect of pethidine and the effect of morphine on intestinal motility were antagonized by nalorphine whilst the effects of the cannabis extracts and the pure cannabinoids were not.4. From these results it is concluded that although cannabis and the narcotics share several common pharmacological properties, the mode of action of each is pharmacologically distinct.