Gastrointestinal Motility In Rats Research Articles

PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist.

Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimer's disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 142676, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676 decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases, and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.

Epidural Anesthesia Accelerates the Recovery of Postischemic Bowel Motility in the Rat

Intestinal ischemia is associated with derangement of gastrointestinal motility. Uncontrolled clinical observations that bupivacaine injected into the epidural space causes faster recovery of bowel motility after various abdominal operations led us to assess the hypothesis that epidural anesthesia can hasten the recovery of gastrointestinal motility in the immediate postischemic period. Gut motility studies were performed in rats in which epidural anesthesia and intestinal ischemia could be initiated without the need to provoke surgical trauma. Epidural lidocaine was compared to epidural saline in their effect on intestinal motility after a 30-min period of bowel ischemia. Total ischemia to the small bowel resulted in pronounced postischemic adynamic ileus as evidenced by only 0.7% of the total length of the small bowel filled with a marker meal at the end of the study period (transit index) compared with 84.4% in the control group. Lidocaine epidural anesthesia caused significantly more rapid resolution of the adynamic ileus (60.3% of the bowel filled with the marker meal vs. 30.9% in the controls in which saline was injected). Epidural lidocaine compared to epidural saline hastens the recovery of gastrointestinal motility in rats after a 30-min period of bowel ischemia. This effect may be elicited by attenuation of sympathetic efferent inhibitory pathways or by vasodilatation caused by the sympathetic block. These results suggest that lidocaine epidural block not only alleviates pain in situations of ischemic injury to the bowel but may also hasten the recovery from postischemic paralytic ileus.

Central administration of Tyr-MIF-1 stimulates gastrointestinal motility in rats: Evidence for the involvement of dopamine, sigma and CCK receptors

The effect of central administration of the endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH 2) on the gastrointestinal myoelectric activity and its mechanism of action were studied in rats. Tyr-MIF-1 (40 & 80 μg/kg i.c.v.) stimulated antral and duodenal myoelectric activity in a multiphasic manner. On the antrum it induced a primary increase of the frequency of antral spike bursts followed by a consecutive return to control value and a second rise of the frequency. Likewise duodenal migrating myoelectric complexes (MMCs) were initially disrupted and replaced by an irregular spiking activity followed by a reaparition of the phase III of the MMCs with increased amplitude and frequency. Haloperidol (1 mg/kg i.p.) blocked all the effects of Tyr-MIF-1 whereas sulpiride (5 mg/kg s.c.) blocked only the duodenal stimulation without affecting that on the antrum. Similarly BMY-14802 (0.5 mg/kg s.c.) antagonized selectively the primary antral stimulation and the initial disruption of duodenal MMC induced by Tyr-MIF-1. L365 260 (10 μg/kg i.c.v.) has also antagonized only the initial disruption of duodenal MMCs. DTG and JO 1784 (100 μg/kg i.c.v. each) reproduced fully the effect of Tyr-MIF-1 on the duodenum but not that on the antrum. Domperidone, (+)SCH 23390, devazepide, PK 11–195 and flumazenil did not have effect on the action of Tyr-MIF-1. It is concluded that Tyr-MIF-1 stimulates the antrum involving haloperidol sensitive but non-dopamine, probably sigma receptors, and the duodenum via a pathway where central D 2 dopamine, sigma and CCK B receptors are implied.

Influence of urethane anesthesia and abdominal surgery on gastrointestinal motility in rats.

The influence of various experimental treatments on propulsive gastrointestinal motility was examined in rats, using inulin as a marker. In unanesthetized rats without any surgery, the distribution center of inulin, which was expressed as a dimensionless distance normalized by the length of the small intestine, reached 0.587 down the intestinal tract from the pylorus 60 min after the intragastric administration of inulin. However, the distribution center of inulin moved only 0.061 in 60 min in unanesthetized rats with minimial abdominal surgery for intraduodenal administration of inulin, and did not move in unanesthetized rats with cannulas for perfusion or in the rats anesthetized with urethane and treated with abdominal surgery. In urethane-anesthetized rats without surgery, almost 100% of the inulin was recovered from the stomach 60 min after intragastric administration. These results suggest that gastrointestinal motility is extensively suppressed by minimal abdominal surgery as well as by anesthesia.

Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) inhibits pentagastrin-stimulated gastric acid secretion in conscious rats

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel neuropeptide and has two amidated forms, PACAP-27 and PACAP-38. Its chemical structure is similar to that of vasoactive intestinal peptide (VIP). In our previous studies, we found that PACAP has a stimulatory effect on rat exocrine pancreas secretion and an inhibitory effect on rat gastrointestinal motility. These effects of PACAP-27 were greater than those of PACAP-38 and VIP. In the present study, we examined the effect of PACAP-27 on basal and pentagastrin (PG)-stimulated gastric acid secretion in conscious rats and compared its effect with that of VIP. Rats were equipped with a chronic gastric fistula and a permanent IV line and separately housed in metabolic cages. The effects of PACAP-27 and VIP at doses of 1.25, 2.5, 5 and 10 nmol/kg/h on basal and PG (24 μg/kg/h)-stimulated gastric acid secretion were tested. Our results showed that: (1) VIP had no significant effect on basal and PG-stimulated gastric acid secretion at the tested doses. (2) PACAP-27 had no effect on basal acid secretion but had a dose-dependent inhibitory effect on PG-stimulated gastric acid secretion. The highest inhibition by PACAP-27, 68.2 + 8.1%, was achieved at 5 nmol/kg/h. We suggest that PACAP may have a regulatory role in gastric acid secretion.

Antispasmodic Effects of 9-[(N-Methyl-3-piperidyl) methyl] Thioxanthene Hydrochloride

A new compound, 9-[( N -methyl-3-piperidyl)methyl] thioxanthene hydrochloride (methixene hydrochloride) 1 has shown parasympatholytic properties, strong inhibition of gastrointestinal motility in rats, mice, and guinea pigs and less active inhibition of salivation and pupil dilation. Its oral toxicity is low.