The rebound excitation triggered by anticholinergic drugs from ovine pyloric antrum, small bowel and gallbladder.

The effect of anticholinergic drugs on gastrointestinal motility is complex and incompletely recognized. Accordingly, in 6 adult sheep bipolar electrodes and strain gage force transducers were surgically attached to the antral, small intestinal and gallbladder wall at the serosal side. During chronic experiments the myoelectric and mechanical recordings were performed in fasted and non-fasted animals before and after various doses of hexamethonium, atropine and pirenzepine given intravenously. Hexamethonium administration triggered rebound excitation after an inhibitory period almost in all the recording sites. Administration of atropine and pirenzepine evoked these secondary contractions mostly in the small intestine and gallbladder. No rebounds were observed when the anticholinergic drugs were given during feeding. In fasted animals, rebound excitation arrived later but more frequently than in non-fasted animals. The excitatory changes were dose-dependent. In the gallbladder, these values were lower than in the small intestine. The frequency of the recurrent pattern was dependent upon the dose of the anticholinergic drug used. It is concluded that nicotinic receptors are more important than muscarinic receptors in the initiation of the rebound excitation in pyloric antrum while in the small bowel and gallbladder the role of both cholinergic receptors is similar. The anticholinergic drugs should be used with caution in all these clinical situations, where the enhancement of gastrointestinal motility must be avoided.     

Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine

Pacemaker potentials were recorded in situ from myenteric interstitial cells of Cajal (ICC-MY) in the murine small intestine. The nature of the two components of pacemaker potentials (upstroke and plateau) were investigated and compared with slow waves recorded from circular muscle cells. Pacemaker potentials and slow waves were not blocked by nifedipine (3 µM). In the presence of nifedipine, mibefradil, a voltage-dependent Ca²⁺ channel blocker, reduced the amplitude, frequency, and rate of rise of upstroke depolarization (dV/dt_max) of pacemaker potentials and slow waves in a dose-dependent manner (1–30 µM). Mibefradil (30 µM) changed the pattern of pacemaker potentials from rapidly rising, high-frequency events to slowly depolarizing, low-frequency events with considerable membrane noise (unitary potentials) between pacemaker potentials. Caffeine (3 mM) abolished pacemaker potentials in the presence of mibefradil. Pinacidil (10 µM), an ATP-sensitive K⁺ channel opener, hyperpolarized ICC-MY and increased the amplitude and dV/dt_max without affecting frequency. Pinacidil hyperpolarized smooth muscle cells and attenuated the amplitude and dV/dt_max of slow waves without affecting frequency. The effects of pinacidil were blocked by glibenclamide (10 µM). These data suggest that slow waves are electrotonic potentials driven by pacemaker potentials. The upstroke component of pacemaker potentials is due to activation of dihydropyridine-resistant Ca²⁺ channels, and this depolarization entrains pacemaker activity to create the plateau potential. The plateau potential may be due to summation of unitary potentials generated by individual or small groups of pacemaker units in ICC-MY. Entrainment of unitary potentials appears to depend on Ca²⁺ entry during upstroke depolarization. pacemaker activity; slow waves; gastrointestinal motility; calcium channel     

Spatiotemporal electrical and motility mapping of distension-induced propagating oscillations in the murine small intestine

Since the development of knockout animals, the mouse has become an important model to study gastrointestinal motility. However, little information is available on the electrical and contractile activities induced by distension in the murine small intestine. Spatiotemporal electrical mapping and mechanical recordings were made from isolated intestinal segments from different regions of the murine small intestine during distension. The electrical activity was recorded with 16 extracellular electrodes while motility was assessed simultaneously by tracking the border movements with a digital camera. Distension induced propagating oscillatory contractions in isolated intestinal segments. These propagating contractions were dictated by the underlying propagating slow wave with superimposed spikes. The frequencies, velocities, and direction of the propagating oscillations strongly correlated with the frequencies (r = 0.86), velocities (r = 0.84), and direction (r = 1) of the electrical slow waves. N(omega)-nitro-L-arginine methyl ester decreased the maximal diameter of the segment and reduced the peak contraction amplitude of the propagating oscillatory contractions, whereas atropine and verapamil blocked the propagating oscillations. Tetrodotoxin had little effect on the maximal diameter and peak contraction amplitude. In conclusion, distension in the murine small intestine does not initiate peristaltic reflexes but induces a propagating oscillatory motor pattern that is determined by propagating slow waves with superimposed spikes. These spikes are cholinergic and calcium dependent.     

Use of a microelectrode array to record extracellular pacemaker potentials from the gastrointestinal tracts of the ICR mouse and house musk shrew (Suncus murinus)

BackgroundThe rhythmic contraction and relaxation of smooth muscles in the gastrointestinal (GI) tract is governed by pacemaker electrical potentials, also termed slow waves, which are calcium currents generated by interstitial cells of Cajal (ICCs). Malfunction of pacemaker rhythms contributes to a number of clinically challenging gastrointestinal motility disorders.MethodA microelectrode array (MEA) was used to record slow waves in vitro from intact GI tissues freshly isolated from the ICR mouse and Suncus murinus. The effects of temperature, extracellular calcium and potassium concentrations on pacemaker potentials were quantified using spatiotemporal metrics.ResultsPacemaker frequency decreased from the duodenum to the ileum in the mouse, but this phenomenon was less significant in Suncus murinus. In both the mouse and Suncus murinus, the stomach had a much lower pacemaker frequency than the intestine. Propagation velocity and amplitude were highest in the proximal intestine. Temperature significantly increased pacemaker frequency in the intestinal tissues of both species. Removal of Ca²⁺ from the medium inhibited pacemaker potential and increasing the Ca²⁺ concentration increased pacemaker frequency in the mouse ileum. Increasing K⁺ concentration decreased pacemaker frequency in the absence of nifedipine.ConclusionsThe MEA allows efficient investigation of gut pacemaker frequency and propagation.     

Y-27632 inhibits gastric motility in conscious rats

Y-27632, a highly selective inhibitor of p160ROCK, desensitizes the smooth muscle to Ca2+ and inhibits smooth muscle contraction. While this drug has the potential to become a novel drug for hypertension, it might also affect other smooth muscle, including that of gastrointestinal tract. We studied the effects of Y-27632 on gastric contractions in conscious rats. Strain gauge force transducers were sutured onto the serosal side of the gastric antrum and contractions were recorded before and after the intravenous injection of Y-27632. Doses of 1.0 mg/kg to 10 mg/kg significantly decreased contraction amplitude and the motility index in a dose dependent manner. With 10 mg/kg, the mean amplitude was decreased by up to 69 +/- 14% and the motility index by up to 81 +/- 7%. The change occurred immediately after drug infusion and lasted for 3.5h. Contraction frequency showed only a slight decrease. No signs of bowel obstruction were observed. These results indicate that Rho-mediated Ca sensitization has a role in the physiologic contractions of gastric smooth muscle in rats. Y-27632 is useful to investigate the physiology of gastrointestinal motility.     

Influence of Various Feeding Conditions,the Migrating Myoelectric Complex and Cholinergic Drugs on Antral Slow Waves in Sheep

The presented study was designed to elucidate whether the cholinergic mechanisms control ovine antral slow waves in various physiological conditions, including feeding and various phases of migrating myoelectric complex (MMC). The investigations were carried out on six adult sheep of Polish Merino breed with seven bipolar electrodes surgically implanted onto the antral and small intestinal wall. In the course of chronic experiments, the myoelectric activity was recorded from these regions using the multichannel electroencephalograph. Experiments were performed on 48h fasted and non-fasted animals. During some of these experiments, sheep were fed with standard fodder. During control experiments 0.15M NaCl was slowly administered i.v. through the indwelling catheter and during other experiment, hexamethonium bromide (2.0 and 5.0mg/kg), atropine sulfate (0.02; 0.1; 0.5 and 1.5mg/kg) and pirenzepine dihydrochloride (0.02; 0.5 and 2.0mg/kg) were administered i.v. during phase 1-2a or 2b MMC. The drugs were also given in combinations. The recordings were analysed and the antral slow wave amplitudes and frequencies were calculated. Unlike the slow wave amplitude, either feeding or the anticholinergic drugs significantly increased slow wave frequency, especially when the given procedure was started during phase 2b MMC. The most pronounced effects were observed after hexamethonium given alone or in combinations. Thus, the cholinergic system modulates antral slow wave frequency in sheep.     

A gastrointestinal function bioassay evaluation of the mycotoxin,T-2 trichothecene

The Fusarium-produced mycotoxin T-2 trichothecene toxin was administered to two groups of young CD-1 mice to test the effects on three parameters of intestinal motility. The criteria selected included composite motility (cm²/min), peak amplitude (mm) and contraction frequency (recorded peaks/min). T-2 treated mice showed an increase in composite motility in response to low dosage (0·085 mg/kg), and at the higher dosage (0·250 mg/kg) a decreased motility. In the lowest treatment group there was a mean decrease of 39·54% in contraction amplitude while contraction frequency increased by 24·84%. The motility measurements were obtained by perfusing 2 cm sections of small intestine, including the entire duodenum excised from mice pre-treated with mycotoxin. Contractions were recorded with a physiograph and the composite motility measurements were taken using a computer program to determine the area of the data curves. T-2 toxin caused an alteration in the amplitude and frequency of motility measurements, but no overall concentration-related changes were noted. T-2 toxin causes measurable responses in the duodenum which may be one of the sites-of-action for this mycotoxin.     

Spatiotemporal Mapping of Motility in Ex Vivo Preparations of the Intestines

Multiple approaches have been used to record and evaluate gastrointestinal motility including: recording changes in muscle tension, intraluminal pressure, and membrane potential. All of these approaches depend on measurement of activity at one or multiple locations along the gut simultaneously which are then interpreted to provide a sense of overall motility patterns. Recently, the development of video recording and spatiotemporal mapping (STmap) techniques have made it possible to observe and analyze complex patterns in ex vivo whole segments of colon and intestine. Once recorded and digitized, video records can be converted to STmaps in which the luminal diameter is converted to grayscale or color [called diameter maps (Dmaps)]. STmaps can provide data on motility direction (i.e., stationary, peristaltic, antiperistaltic), velocity, duration, frequency and strength of contractile motility patterns. Advantages of this approach include: analysis of interaction or simultaneous development of different motility patterns in different regions of the same segment, visualization of motility pattern changes over time, and analysis of how activity in one region influences activity in another region. Video recordings can be replayed with different timescales and analysis parameters so that separate STmaps and motility patterns can be analyzed in more detail. This protocol specifically details the effects of intraluminal fluid distension and intraluminal stimuli that affect motility generation. The use of luminal receptor agonists and antagonists provides mechanistic information on how specific patterns are initiated and how one pattern can be converted into another pattern. The technique is limited by the ability to only measure motility that causes changes in luminal diameter, without providing data on intraluminal pressure changes or muscle tension, and by the generation of artifacts based upon experimental setup; although, analysis methods can account for these issues. When compared to previous techniques the video recording and STmap approach provides a more comprehensive understanding of gastrointestinal motility.     

Pacemaking activity is regulated by membrane stretch via the CICR pathway in cultured interstitial cells of Cajal from murine intestine

Membrane stretch is an important stimulus in gastrointestinal (GI) motility regulation, but the relationship between membrane stretch and the pacemaking activity of GI smooth muscle is poorly understood. We examined the effect of intestinal distension on slow waves and the effect of membrane stretch on pacemaker currents in cultured intestinal interstitial cells of Cajal (ICCs) from murine small intestine. At organ level, intestinal distension significantly increased amplitude of slow and fast waves, and enhanced frequencies of fast but not slow waves. At the cellular level, membrane stretch-induced by hyposmotic cell swelling (MSHC) depolarized membrane potential and activated large inward holding current, but suppressed amplitude of pacemaker potential or pacemaking current. External Ca²⁺-free solution abolished pacemaker current and blocked MSHC-induced inward holding current. However, a sustained inward holding current was activated and the amplitude of pacemaker current was increased by high ethylene glycol tetraacetic acid (EGTA) in pipette. Then MSHC also potentiated the inward holding current. MSHC significantly increased amplitude of rhythmic Ca²⁺ transients and basal intracellular Ca²⁺ concentration ([Ca²⁺]_i). 2-APB blocked both pacemaker current and Ca²⁺ transients but did not alter the effect of MSHC on pacemaker current and Ca²⁺ transients. In contrast, ryanodine inhibited Ca²⁺ transients but not pacemaker current, and completely blocked MSHC-induced inward holding current and MSHC-induced increase of basal [Ca²⁺]_i. These results suggest that intestinal distension potentiates intestinal motility by increasing the amplitude of slow waves. Membrane stretch potentiates pacemaking activity via releasing Ca²⁺ from calcium-induced calcium release (CICR) in cultured intestinal ICCs.     

十二指肠内胆盐对胃肌电和运动的影响及其神经...

Changes of gastric myoelectric fast wave, slow wave and gastric motility were studied after intraduodenal infusion of sodium taurocholate (ST) in an attempt to search the concerned neuromechanism. Frequency and total amplitude of the fast wave and slow wave of gastric myoelectric activity and of gastric contractile wave were recorded every five minutes before and after intraduodenal infusion of ST under the background action of various drugs. The frequency and amplitude were expressed in percentage change of the respective premedication value. After intraduodenal infusion of ST (n = 10) the frequency and the amplitude of fast wave and gastric contractile wave were suppressed. Blocking anesthesia of celiac plexus, reserpinization and intravenous infusion of carbachol could eliminate the inhibition induced by ST, which could be partly eliminated by intravenous infusion of propranolol but not affected by phentolamine at all. The results demonstrate that intraduodenal infusion of bile salt suppresses the fast wave of gastric myoelectric activity and gastric motility, most probably controlled by efferent sympathetic adrenergic fibres through beta-receptor.     

Spatial localization and properties of pacemaker potentials in the canine rectoanal region

The present study investigated the spatial organization of electrical activity in the canine rectoanal region and its relationship to motility patterns. Contraction and resting membrane potential (E(m)) were measured from strips of circular muscle isolated 0.5-8 cm from the anal verge. Rapid frequency [25 cycles/min (cpm)] E(m) oscillations (MPOs, 12 mV amplitude) were present across the thickness of the internal anal sphincter (IAS; 0.5 cm) and E(m) was constant (-52 mV). Between the IAS and the proximal rectum an 18 mV gradient in E(m) developed across the muscle thickness with the submucosal edge at -70 mV and MPOs were replaced with slow waves (20 mV amplitude, 6 cpm). Slow waves were of greatest amplitude at the submucosal edge. Nifedipine (1 micro M) abolished MPOs but not slow waves. Contractile frequency changes were commensurate with the changes in pacemaker frequency. Our results suggest that changing motility patterns in the rectoanal region are associated with differences in the characteristics of pacemaker potentials as well as differences in the sites from which these potentials emanate.     

Melatonin effects on gut motility are independent of the relaxation mediated by the nitrergic system in the goldfish

Melatonin is a key neuroendocrine transducer in the circadian organization of vertebrates. However, its role in gastrointestinal physiology has not been explored in depth. In goldfish, a role for melatonin as a modulator of intestinal motility has been reported, whereby it attenuates the cholinergic contraction. The aim of the present work was to investigate this relaxation induced by melatonin in the gut smooth muscle of the goldfish, studying the possible involvement of nitric oxide. An in vitro model of isolated goldfish intestine was used to test the effects on intestinal motility. The addition of melatonin (10 pM-100 μM) to the organ bath relaxed acetylcholine- and serotonin-stimulated gut strips, but no effect was observed on KCl-contracted preparations. The addition of L-NAME (nitric oxide synthase inhibitor) increased the amplitude of the spontaneous slow waves, while sodium nitroprusside (SNP, nitric oxide donor) abolished them. All these results support a role for the nitrergic system in goldfish gut motility. However, neither L-NAME, nor SNP nor the nitric oxide precursor, l-arginine, modified the melatonin relaxing effect. These results highlight the existence of a basal nitrergic tone in the gut of goldfish, where melatonin would exert a calcium-dependent, nitric oxide-independent relaxing effect on serotonergic and cholinergic contraction.     

Effects of intracerebroventricular injections of thyrotropin releasing hormone on gastrointestinal propulsive motility in rats

The effect of intracerebroventricular (ICV) injections of thyrotropin releasing hormone (TRH) on the propulsive motility of the gastrointestinal tract was examined in rats. The distance travelled by charcoal meal through the small intestine, measured in terms of percentage of its total length, was recorded as the index of propulsive motility. The results were as follows: (1) The propulsive distance of charcoal meal was significantly reduced in a dose-dependent manner after ICV injections of TRH (1 microgram/10 microliters, 5 micrograms/10 microliters or 10 micrograms/10 microliters) (P less than 0.01-0.001) The effects were abolished by injection of atropine (5 micrograms/10 microliters ICV). (2) The gastrointestinal propulsive motility decreased markedly (P less than 0.01) after injection of a larger dose of TRH (50 micrograms/100 g) into the hypodermis. The effects were not completely blocked by subcutaneous injections of propranolol (5 mg/kg). (3) No effects (P greater than 0.05) were found on the inhibition of gastrointestinal propulsive motility after ICV injections of regitine (2.5 mg/kg im, 50 micrograms/50 microliters ICV) or propranolol (5 mg/kg im, 50 micrograms/50 microliters ICV). The results indicate that TRH has an inhibitory effect on the propulsive motility of gastrointestinal tract, which may be mediated via the non-adrenergic inhibitory nerve of the vagal nerves.     

Spatial and temporal coupling between slow waves and pendular contractions

In contrast to the mechanisms of segmental and peristaltic contractions in the small intestine, not much is known about the mechanism of pendular contractions. High-resolution electrical and mechanical recordings were performed from isolated segments of the rabbit ileum during pendular contractions. The electrical activities were recorded with 32 extracellular electrodes while motility was assessed simultaneously by video tracking the displacements of 20-40 serosal markers. The electrical activities consisted of slow waves, followed by spikes, that propagated in either the aboral or oral direction. The mechanical activity always followed the initial electrical activity, describing a contraction phase in one direction followed by a relaxation phase in the opposite direction. Pendular displacements were always in rhythm with the slow wave, whereas the direction of the displacements was dictated by the origin of the slow wave. If the slow wave propagated aborally, then the pendular displacement occurred in the oral direction, whereas if the slow wave propagated in the oral direction, then the displacement occurred in the aboral direction. In the case of more complex propagation patterns, such as in the area of pacemaking or collision, direction of displacements remained always opposite to the direction of the slow wave. In summary, the direction and pattern of propagation of the slow wave determine the rhythm and the direction of the pendular motility. The well-known variability in pendular movements is caused by the variability in the propagation of the underlying slow wave.     

Effect of ghrelin on gastric myoelectric activity and gastric emptying in rats

Ghrelin is a recently discovered peptide in the endocrine cells of the stomach, which may stimulate gastric motility via the vagal nerve pathway. However, the mechanism of ghrelin-induced changes in gastrointestinal motility has not been clearly defined. The purpose of this study was to investigate the pharmacological effects of ghrelin on gastric myoelectrical activity and gastric emptying in rats, and to investigate whether cholinergic activity is involved in the effects of ghrelin. The study was performed on Sprague-Dawley rats implanted with serosal electrodes for electrogastrographic recording. Gastric slow waves were recorded from fasting rats at baseline and after injection of saline, ghrelin, atropine, or atropine+ghrelin. Gastric emptying of non-caloric liquid was measured by the spectrophotometric method in conscious rats. Intravenous administration of rat ghrelin (20 microg/kg) increased not only dominant frequency, dominant power and regularity of the gastric slow wave but also the gastric emptying rate when compared with the control rats (P<0.01, P<0.05, P<0.05, P<0.001 respectively). These stimulatory actions of ghrelin on both gastric myoelectrical activity and gastric emptying were not fully eliminated by pretreatment with atropine sulphate. These results taken together suggest that ghrelin may play a physiological role in the enteric neurotransmission controlling gastric contractions in rats.     

Peripheral pacemakers and patterns of slow wave propagation in the canine small intestine in vivo

In an anesthetized, open-abdomen, canine model, the propagation pattern of the slow wave and its direction, velocity, amplitude, and frequency were investigated in the small intestine of 8 dogs. Electrical recordings were made using a 240-electrode array from 5 different sites, spanning the length of the small intestine. The majority of slow waves propagated uniformly and aborally (84%). In several cases, however, other patterns were found including propagation in the oral direction (11%) and propagation block (2%). In addition, in 69 cases (3%), a slow wave was initiated at a local site beneath the electrode array. Such peripheral pacemakers were found throughout the entire intestine. The frequency, velocity, and amplitude of slow waves were highest in the duodenum and gradually declined along the intestine reaching lowest values in the distal ileum (from 17.4+/-1.7 c/min to 12.2+/-0.7 c/min; 10.5+/-2.4 cm/s to 0.8+/-0.2 cm/s, and 1.20+/-0.35 mV to 0.31+/-0.10 mV, respectively; all p<0.001). Consequently, the wavelength of the slow wave was strongly reduced from 36.4+/-0.8 cm to 3.7 +/- 0.1 cm (p<0.001). We conclude that the patterns of slow wave propagation are usually, though not always, uniform in the canine small intestine and that the gradient in the wavelength will influence the patterns of local contractions.     

Changes in serotonin levels and 5-HT receptor activity in duodenum of streptozotocin-diabetic rats

Few previous studies have discussed the changes in serotonin receptor activity in the small intestine of diabetic animals. Therefore, we examined serotonin content in duodenal tissue and dose-dependent effects of serotonin agonists and antagonists on the motor activity of ex vivo vascularly perfused duodenum of streptozotocin (STZ)-diabetic rats. Serotonin content was significantly increased in enterochromaffin cells but not altered in serotonin-containing neurons in STZ-diabetic rats. Motor activity assessed by frequency, amplitude, and percent motility index per 10 min of pressure waves was reduced in the duodenum of diabetic rats, and this reduction was reversed by insulin treatment. Serotonin dose dependently increased the motor activity in control rat duodenum but only a higher concentration of serotonin increased the motor activity in diabetic rats. The 5-hydroxytryptamine (5-HT) receptor subtype 4 (5-HT(4)) antagonist SB-204070 dose dependently reduced motor activity in both control and diabetic rats, whereas the 5-HT(3) receptor antagonist azasetron, even at a higher concentration, failed to affect motor activity in diabetic rat duodenum but dose dependently reduced motor activity in control rat duodenum. These results suggest that 5-HT(3) receptor activity was impaired but 5-HT(4) receptor activity was intact in STZ-diabetic rat duodenum. Such an impairment of 5-HT(3) receptor activity may induce the motility disturbance in the small intestine of diabetes mellitus.     

Catalepsy induced by morphine or haloperidol: effects of apomorphine and anticholinergic drugs.

To investigate the extent of cholinergic involvement in opiate-induced catalepsy, the effects of three anticholinergic drugs were studied on morphine-induced catalepsy. Haloperidol-induced catalepsy was also examined. Maximum catalepsy in rats was obtained with 30 mg/kg morphine or 3 mg/kg haloperidol. The anticholinergic drugs atropine, benztropine, and scopolamine were unable to antagonize morphine-induced catalepsy, yet readily antagonized haloperidol-induced catalepsy. Low doses of apomorphine (7.5 mg/kg), on the other hand, readily antagonized morphine catalepsy, but 13-fold higher doses of apomorphine were needed to block haloperidol-induced catalepsy. The results are compatible with the idea that catalepsy can be mediated via the striatum or the amygdala; morphine-dopamine antagonism may occur in the amygdala, whereas morphine-dopamine-cholinergic interactions occur in the striatum.     

Synthesis and pharmacological evaluation of some dual-acting amino-alcohol ester derivatives of flurbiprofen and 2-[1,1'-biphenyl-4-yl]acetic acid: a potential approach to reduce local gastrointestinal toxicity

The search for safer non-steroidal anti-inflammatory drugs (NSAIDs) continues with the failure of anticipated 'ideal' anti-inflammatory agents, the coxibs, on long-term usage. Increased gastric motility and acidity due to the free carboxy group are involved in the etiology of gastric toxicity, common to conventional NSAIDs. Keeping this fact in mind, it was planned to modify some of the conventional NSAIDs to amino-alcohol ester derivatives, which satisfied the structural requirements for these compounds to possess anticholinergic activity in the intact form. Besides blocking the acidic carboxylic group, incorporation of anticholinergic acivity in these molecules was expected to reduce the gastric toxicity by decreasing gastric acid secretion and motility. Synthesis and pharmacological evaluation of six different N,N-disubstituted amino-ethyl ester derivatives, structurally resembling the amino-alcohol ester class of anticholinergic agents, each for [1,1'-biphenyl]-4-acetic acid (3) and flurbiprofen (10), have been reported as potential substitutes for these NSAIDs, with improved therapeutic profile. All the ester derivatives were found to have sufficient chemical stability in buffers (pH 2.0 and 7.4), ensuring them to be absorbed as intact moieties from the gastrointestinal tract. A significant reduction in ulcerogenic potency in comparison to the parent drugs with a slightly higher anti-inflammatory potency suggests that the majority of these candidates have an improved therapeutic profile over their parent drugs. Hence, a promising novel approach, different from the conventional prodrug concept, has been successfully worked out to overcome the local gastric toxicity, yielding therapeutically better compounds for long-term oral anti-inflammatory therapy.     

Roles of interstitial cells of Cajal in regulating gastrointestinal motility: in vitro versus in vivo studies

The aim of this article is to provide a better understanding of the roles of interstitial cells of Cajal (ICC) in regulating gastrointestinal motility by reviewing in vitro and in vivo physiological motility studies. Based on the in vitro studies, ICC are proposed to have the following functions: to generate slow waves, to mediate neurotransmission between the enteric nerves and the gastrointestinal muscles and to act as mechanoreceptors. However, there is limited evidence available for these hypotheses from the in vivo motility studies. In this review, we first introduce the major subtypes of ICC and their established functions. Three Kit mutant mouse and rodent models are presented and the loss of ICC subtypes in these mutants is reviewed. The physiological motility findings from various in vitroand in vivo experiments are discussed to give a critical review on the roles of ICC in generating slow waves, regulating gastrointestinal motility, mediating neural transmission and serving as mechanoreceptors. It is concluded that the role of ICC as pacemakers may be well established, but other cells may also be involved in the generation of slow waves; the theory that ICC are mediators of neurotransmission is challenged by the majority of the in vivo motility studies; the hypothesis that ICC are mechanoreceptors has not found supportive evidence from the in vivo studies yet. More studies are needed to explain discrepancies in motility findings between the in vitro and in vivo experiments.