Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) patients experience exaggerated pain during movements such as walking. Anti-nerve growth factor (NGF) antibodies have recently shown analgesic effects in OA patients. We examined the effect of a single dose of anti-NGF antibody on pain during motion, joint edema and lesion in a rat model of OA to determine whether the analgesic effect demonstrated in clinical studies can be translated to a preclinical model. METHODS: Sodium monoiodoacetate (MIA)-induced arthritic rats that develop a right-left gait imbalance when walking as an index of pain during motion. This imbalance was assessed using a gait analysis system called "CatWalk". Edema size and lesion score in the relevant knee joint were also measured. The effect of a single intravenous injection of an anti-NGF monoclonal antibody AS2886401-00 on these parameters was assessed. RESULTS: AS2886401-00 administered at 0.3 or 1 mg/kg on Day 3 post-MIA injection resulted in a statistically significant improvement in gait imbalance even on Day 35. When gait measurement was set on Week 3 post-MIA administration, administration of the antibody at a timing close to the gait measurement, i.e., 1 or 24 h prior to the measurement, was less effective. AS2886401-00 did not suppress either edema or lesion. CONCLUSIONS: A single dose of anti-NGF antibody exerts a long-lasting analgesic effect on pain during motion in a rat model of OA. This finding could be associated with the analgesic efficacies that anti-NGF antibodies have exhibited in clinical studies. It appears unlikely that analgesia is secondary to inhibition of joint edema and lesion.

Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats.

Serotonin (5-HT) and norepinephrine (NE) have been implicated in the mediation of endogenous analgesic mechanisms via the descending inhibitory pain pathway in the brain, and dysfunction in both the 5-HT and NE systems has been suggested as an etiology of fibromyalgia (FM). Given that 5-HT reuptake inhibition in the brain appears to be associated with pain reduction, this mechanism might exert an analgesic effect also on pain associated with FM. In this case, it would be of interest to investigate the correlation of 5-HT transporter (SERT) occupancy with in vivo analgesic effect on pain associated with FM. Here, we investigated the relationship between SERT occupancies and the analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine, which are both 5-HT and NE reuptake inhibitors (SNRIs), on muscular pain in reserpine-induced myalgia (RIM) rats, an animal model of FM-like chronic pain. We also investigated the SERT occupancy level necessary for AS1069562 and duloxetine to exert analgesic effects on muscular pain. AS1069562 and duloxetine attenuated muscular hyperalgesia in RIM rats, representing the first findings to be reported regarding the analgesic effect of AS1069562 on pain associated with FM. SERT occupancy levels of AS1069562 and duloxetine increased in both dose- and plasma and brain concentration-dependent manners. SERT occupancy levels of AS1069562 and duloxetine were significantly correlated with efficacy on muscular pain thresholds in RIM rats. This finding concerning the precise correlation of SERT occupancy with in vivo analgesic effect on pain associated with FM is reported here for the first time. SERT occupancy level above 70% was necessary for AS1069562 and duloxetine to exert significant analgesic effects on muscular pain. These results suggest that SERT occupancy level is useful in determining appropriate analgesic doses of AS1069562 and duloxetine for treating pain symptoms in FM patients.

Effects of ingesting milk fermented by Lactococcus lactis H61 on skin health in young women: a randomized double-blind study.

We conducted a randomized double-blind trial to evaluate the effects of fermented milk produced using only Lactococcus lactis strain H61 as a starter bacterium (H61-fermented milk) on the general health and various skin properties of young women. Healthy female volunteers (n=23; age=19-21r) received H61-fermented milk (10(10) cfu of strain H61/d) or conventional yogurt (10(10) cfu of both Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus per day), as a reference food, daily for 4 wk. Before and at the end of 4 wk, blood samples were taken, and skin hydration (inner forearms and cheek) and melanin content, elasticity, and sebum content (cheek only) were measured. Skin hydration at the inner forearm was higher at wk 4 than at wk 0 in both groups. Sebum content in cheek rose significantly after intervention in the H61-fermented milk group, but not the conventional yogurt group. Other skin parameters did not differ in either group. Serum analysis showed that total protein concentration and platelet count were elevated and reactive oxygen species decreased in both groups after the intervention. Although H61-fermented milk and conventional yogurt had similar effects on skin status and some blood characteristics of participants, an increase of sebum content in cheek is preferable to H61-fermented milk. As skin lipids contribute to maintaining the skin barrier, H61-fermented milk would provide beneficial effects on skin for young women.

Automated measurement of spontaneous pain-associated limb movement and drug efficacy evaluation in a rat model of neuropathic pain.

BACKGROUND: The withdrawal response elicited by a nociceptive stimulus, i.e., evoked pain measure, is commonly used as an efficacy endpoint in neuropathic pain animal models. It, however, has several limitations, which highlight the importance of examining spontaneous pain. The present study describes an automated method for measuring spontaneous pain behaviour in a rat model of neuropathic pain caused by chronic constriction injury (CCI) of sciatic nerve. METHODS: After CCI surgery, a small magnet was implanted into the operated limb. The rat was placed in a test chamber that was surrounded by wire coil. Limb movements, including lifting/guarding, flinching/shaking, licking and walking in the operated limb, caused changes in the electromagnetic field, including a change in voltage and transformed into a signal via an amplifier. RESULTS: CCI rats consistently showed more frequent limb movement than sham rats. There was no significant correlation between the frequency of spontaneous pain behaviour and the evoked pain symptoms. Treatment with duloxetine (30 mg/kg p.o.) and amitriptyline (30 and 100 mg/kg p.o.) significantly reduced this frequency. Pregabalin at 30 mg/kg p.o. tended to reduce the frequency, and diclofenac up to 10 mg/kg p.o. had no effect. CONCLUSION: A non-subjective automated method for measuring spontaneous pain behaviour in an animal model of neuropathic pain was established. It is expected that the current system will greatly enhance the analysis of spontaneous pain-related behaviour, which is a predominant symptom in patients with neuropathic pain. The current system may also be valuable in the screening of potential analgesic treatments.

Reserpine causes biphasic nociceptive sensitivity alteration in conjunction with brain biogenic amine tones in rats.

The present study investigated the precise relationship between brain biogenic amine (dopamine, noradrenaline, and serotonin) tones and nociception. Nociceptive sensitivities to multimodal (muscle pressure, tactile, cold, and heat) stimuli were assessed in acute phase (up to 24 h after reserpine or tetrabenazine injection) and chronic phase (on day 2 or later) in rats. A single injection of reserpine (3 mg/kg s.c.) significantly decreased biogenic amines in the spinal cord (SC), thalamus (THA), and prefrontal cortex (PFC) in both acute and chronic phases, but significantly increased a dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the SC and a serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the SC and THA in acute phase. The content of all biogenic amine metabolites was at low level in chronic phase. Animals exhibited hypersensitivities to tactile and heat stimuli and hyposensitivity to muscle pressure stimulus in acute phase. In chronic phase, they manifested hypersensitivities to all modes of stimuli. Tetrabenazine (20 mg/kg i.p.) significantly decreased brain biogenic amines for a short time, although it did not significantly affect the nociceptive sensitivities. In conclusion, a single injection of reserpine causes a biphasic alteration of nociceptive sensitivities, which is in conjunction with the dynamic change of brain biogenic amine tones, in rats. Cold and heat hypersensitivities in addition to mechanical ones are induced by the reserpine treatment. Sustained modification of brain biogenic amine tones would be critical to induce a robust change in nociceptive sensitivities based on the different effects between reserpine and tetrabenazine.

Purinergic P2X receptor activation induces emetic responses in ferrets and Suncus murinus (house musk shrews).

BACKGROUND AND PURPOSE: Despite the rapid progress made in understanding the significant role played by signalling via extracellular ATP in physiology and pathology, there has been no clear information generated on its involvement in the emetic response. EXPERIMENTAL APPROACH: In the present study, the emetogenic potential of extracellular ATP signalling in mammalian species was examined using ferrets and Suncus murinus (house musk shrews). A slowly degradable ATP analogue, alpha,beta-methyleneATP (alpha,beta-meATP), was used to activate the P2X receptors, and either the non-selective P2 receptor antagonist, pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), or the specific P2X(3) homomer and P2X(2/3) heteromer antagonist, A-317491, were tested against the agonist-induced response. KEY RESULTS: Intraperitoneal injection of alpha,beta-meATP produced significant emetic responses in ferrets (1 - 30 mg kg(-1)) and in Suncus murinus (5 - 50 mg kg(-1)). The responses occurred frequently within the first 10 min after administration, much less frequently from 11 to 60 min and no responses occurred later than 60 min. The emetic responses were completely inhibited by intraperitoneal pre-treatment with PPADS (100 mg kg(-1)) or A-317491 (100 mg kg(-1)). Abdominal surgical vagotomy did not reduce the emetic response in Suncus murinus significantly. CONCLUSIONS AND IMPLICATIONS: These results for the first time indicate that the activation of P2X receptors evokes emetic responses in mammalian species. The P2X(3) homomer and.or P2X(2/3) heteromer in the area postrema could be responsible for the emetic response. This finding contributes to the elucidation of the roles played by extracellular ATP signalling in various emetic symptoms.

Energy expenditure during walking in amputees after disarticulation of the hip. A microprocessor-controlled swing-phase control knee versus a mechanical-controlled stance-phase control knee.

We have compared the energy expenditure during walking in three patients, aged between 51 and 55 years, with unilateral disarticulation of the hip when using the mechanical-controlled stance-phase control knee (Otto Bock 3R15) and the microprocessor-controlled pneumatic swing-phase control knee (Intelligent Prosthesis, IP). All had an endoskeletal hip disarticulation prosthesis with an Otto Bock 7E7 hip and a single-axis foot. The energy expenditure was measured when walking at speeds of 30, 50, and 70 m/min. Two patients showed a decreased uptake of oxygen (energy expenditure per unit time, ml/kg/min) of between 10.3% and 39.6% when using the IP compared with the Otto Bock 3R15 at the same speeds. One did not show any significant difference in the uptake of oxygen at 30 m/min, but at 50 and 70 m/min, a decrease in uptake of between 10.5% and 11.6% was found when using the IP. The use of the IP decreased the energy expenditure of walking in these patients.

%VO2max as an indicator of prosthetic rehabilitation outcome after dysvascular amputation.

In this study, independent ambulation of at least 100 metres with/without a cane was regarded as successful prosthetic rehabilitation. The subjects were classified into two groups according to this criterion at the time of discharge. The successful group attained this performance, the other group failed to reach this level. The successful group included 8 unilateral trans-femoral amputees aged 72.2 +/- 2.1 years who underwent amputation at more than 70 years, and succeeded in walking with a prosthesis. The group which failed included 9 unilateral trans-femoral amputees aged 63.2 +/- 2.1 years who underwent amputation between the ages of 60-65 years, and had great difficulty in walking with a prosthesis. The purpose of this research was to investigate whether or not %VO2max as an indicator of physical fitness is useful in predicting prosthetic rehabilitation outcome after dysvascular amputation by comparing these two groups. Evaluation of physical fitness was conducted before the subjects began prosthetic rehabilitation. Information about each subject before fitting with a prosthesis was collected retrospectively from clinical charts made during admission. The successful group were capable of strenuous exercise, reaching the intensity of 50% VO2max or more. In the group which failed only one reached the intensity of 50% VO2max. The working capacity of 50% VO2max or greater would appear to be a valid initial guideline level of physical fitness at which an amputee can expect to succeed in walking with a prosthesis. Apart from physical fitness, a lesser number of comorbidity, good ability to stand on the remaining leg, and a strong will to walk were found to be important factors contributing to successful prosthetic rehabilitation. This study also showed that age alone was not an important factor.

Effect of endurance training program based on anaerobic threshold (AT) for lower limb amputees.

We have already reported that the one-leg cycling test driven by the subject's sound leg as the exercise load test is effective in measuring the anaerobic threshold (AT) of unilateral lower limb amputees. The aim of this research is to investigate whether or not endurance training based on each subject's AT gained from the one-leg cycling test is useful in improving the physical fitness of lower limb amputees. The test subjects were all unilateral transfemoral amputees comprising a group of 14 undertaking endurance training and a control group of 10. The form of endurance training is driving an ergometer with the sound limb only in the same way as the load test. The training program was designed so that the subjects would exercise at a target heart rate corresponding to AT point for 30 minutes per day, 3-5 days each week for 6 weeks. After the training periods, in the training subjects the AT and maximum oxygen uptake (__O2max) increased significantly. The rate of increase averaged 36.5%, 26.0%, respectively, compared to their levels before the training. On the contrary, no changes occurred in the control subjects. These results suggest that our chosen training program based on each subject's AT is effective in improving the physical fitness of lower limb amputees.

Neurometer measurement of current stimulus threshold in rats.

We examined the current stimulus threshold in rats with the Neurometer, a device used clinically for measuring perception and pain thresholds. Although many studies have indicated the usefulness of this device in the quantification of nerve dysfunction in patients, we have found no published reports on the use of the Neurometer in animals. Transcutaneous nerve stimuli of the three sine-wave pulses produced by the Neurometer (at 2000, 250, and 5 Hz) were applied to plantar surface of rats. The intensity of each stimulation at which rats vocalized or were hardly startled was defined as the current stimulus threshold. With repeated stimulation, the thresholds were almost constant. Repeated topical application to the area around the stimulating electrode of a high concentration of capsaicin, which acts on small-diameter fibers, increased the thresholds at 250 and 5 Hz, but did not affect the 2000-Hz threshold. Intravenous morphine (2-5 mg/kg) increased all three thresholds, whereas intrathecal morphine (20 or 80 microg) increased only the 5-Hz threshold. Intravenous injection of a minor tranquilizer, diazepam, at 1 mg/kg raised the thresholds at 2000 and 250 Hz, but did not affect the 5-Hz threshold. Higher dose of diazepam increased all three thresholds. These results suggest that the Neurometer makes possible selective examination of subsets of nerve fibers that differ in diameter not only in humans but also in animals. The present study in rats, in which we established a method of measurement, may provide helpful suggestions for the interpretation of data in humans.

Adenosine A1 receptor blockade reverses dysmotility induced by ischemia-reperfusion in rat colon.

This study was designed to assess whether adenosine A1 receptor antagonists [(R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] reverse dysmotility induced by ischemia-reperfusion in the rat colon. The gene of adenosine A1 receptor was expressed in the colon. Clamping (30 min) of the colonic marginal vessels was followed by reperfusion, and the propulsive colonic motility was evaluated. Propulsion was significantly slowed by ischemia-reperfusion, while FK352 and DPCPX abolished this delay. In contrast, the non-selective adenosine receptor antagonist, 8-phenyltheophylline, failed to affect the dysmotility. Thus, adenosine A1 receptor antagonists have potent therapeutic potential against ischemia-reperfusion-induced dysmotility in the colon.

Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro.

We investigated the in vitro pharmacological profile of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate). In cloned human 5-HT3A receptors, YM-31636 had a pKi value of 9.67 vs. ramosetron and pKi values for other 5-HT3 receptor agonists were less than 7. YM-31636 showed very low affinities for other receptors. YM-31636 induced contraction of isolated guinea pig distal colon. The intrinsic activity was approximately 0.90 compared with 5-hydroxytryptamine's (5-HT) 1.0, and the potency was 26 times greater than that of 5-HT. YM-31636 increased short-circuit current (Isc) in the isolated guinea pig distal colon. In this case, the relative intrinsic activity was approximately 0.19. In isolated guinea pig right atrium, YM-31636 induced tachycardia with the relative intrinsic activity of approximately 0.23. All these effects of YM-31636 were antagonized by ramosetron, a selective 5-HT3 receptor antagonist. These results suggest that YM-31636 is a potent and selective 5-HT3 receptor agonist, preferentially acting on the contraction of the colon.

The role of 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in the regulation of gut motility in the ferret.

The role of 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptors in the regulation of gut motility in the ferret was investigated. The selective 5-HT3 receptor antagonist ramosetron (1 - 10 microg/kg s.c.) prolonged the interval of gastric antral migrating motor complex, but had only slight effect on small intestinal and colonic motility in unfed animals. The selective 5-HT4 receptor antagonist SB 204070 did not affect motility throughout gut in unfed animals. Neither ramosetron nor SB 204070 affected the motility throughout gut in fed animals. In conclusion, neither 5-HT3 nor 5-HT4 receptors tonically regulate ferret gut motility except that 5-HT3 receptors have a key role in the occurrence of migrating motor complex specifically in the stomach. The role of 5-HT3 and 5-HT4 receptor system in the regulation of gut motility in ferrets is similar to that in other mammalian species studied, including humans. This similarity suggests that the ferret is a suitable model animal to study gut motor functions in humans.

Stimulation of gastric acid secretion by progesterone metabolites as neuroactive steroids in anesthetized rats.

The effect of neuroactive progesterone metabolites, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, and their stereoisomers at the 3 C site, 5alpha- and 5beta-pregnan-3beta-ol-20-one, on gastric acid secretion was investigated in urethane-anesthetized rats. Both 5alpha- and 5beta-pregnan-3alpha-ol-20-one dose-dependently (0.3-3 mg x kg(-1), i.v.) stimulated gastric acid secretion with an early onset of action. Their potency and efficacy were almost the equivalent of one another. In contrast, their stereoisomers did not have a significant effect even at 10 mg x kg(-1) (i.v.). The 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion was remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg x kg(-1), i.v.). An antagonist of the GABA(A) receptor, picrotoxin, at 3 and 6 mg x kg(-1) (i.v.), significantly inhibited the 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion. These results indicate that naturally occurring neuroactive steroids, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, stimulate gastric acid secretion in a stereoselective and dose-dependent manner in urethane-anesthetized rats. It is likely that the action of these neuroactive steroids is of central origin and that interaction with GABA(A) receptors and stimulation of vagal pathway are involved in its mechanism of action.

The efficacy of physiological cost index (PCI) measurement of a subject walking with an Intelligent Prosthesis.

The Intelligent Prosthesis may enable lower limb amputees to walk faster than with conventionally damped prostheses and as a result the physical burden involved in walking could be expected to be considerably higher. The aim of this study was to investigate whether or not physiological cost index (PCI) is applicable as an indicator for monitoring the amount of exercise load involved in walking with an Intelligent Prosthesis. The method used a treadmill and monitored gas exchange, ventilation and heart rate (HR) in 6 unilateral trans-femoral amputees, ages were between 17 and 34 with an average age of 23.1. The exercise protocol was as follows: for each person speeds at 0.8 times the subject's free level walking speed, 1.0 times, 1.2 times, 1.4 times and for some 1.6 times were applied. In each case the index of correlation between PCI and oxygen uptake in response to walking speed was calculated. A significant correlation was observed between PCI and oxygen uptake in each case, which indicated a close relationship between cardiopulmonary factor and energy consumption while walking. These results suggest that PCI is of use as an indicator for ascertaining the amount of exercise load in walking with an Intelligent Prosthesis.

Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor.

Binding properties of gastrointestinal prokinetic benzamides for both cloned human 5-hydroxytryptamine (5-HT)3 receptors and cloned human 5-HT4 receptors were examined and pharmacological properties of YM-53389{(+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2, 4-oxadiazol-3-yl]aniline monohydrochloride} were characterised in animals. Cisapride, renzapride and zacopride inhibited specific binding of [3H]ramosetron to cloned human 5-HT3 receptors, with Ki values of 684, 7.64 and 0.38 n m, respectively. YM-53389, however, slightly replaced that (Ki>10,000 n m). YM-53389, cisapride, renzapride and zacopride replaced specific binding of [3H]GR 113808 to cloned human 5-HT4 receptors, with Ki values of 54.6, 41.5, 115 and 373 n m, respectively. The potency for inhibitory effect of YM-53389 on 5-HT3 receptor-mediated contraction in the guinea-pig isolated colon was very low with pIC50 of 4.7. YM-53389 exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat isolated oesophagus with pEC50 of 6.3. In mice, YM-53389 at 10 and 30 mg kg-1, s.c. significantly shortened whole gut transit time, in contrast to cisapride, renzapride and zacopride which were reported to delay that. YM-53389 had no significant effect on upper gastrointestinal propulsion at doses up to 30 mg kg-1, s.c. Based on these results, YM-53389 may surpass existing benzamides in facilitating lower intestinal propulsion and benefit patients with gastrointestinal disorders associated with impair of intestinal propulsion, such as constipation, based on the selective interaction with human 5-HT4 receptors vs human 5-HT3 receptors.

Synthesis of the selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist (+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-y l]aniline.

In a search for novel 5-hydroxytryptamine 4 (5-HT4) agonists focusing on the linker group of benzamide derivatives, 2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl]a niline (2) was prepared and its optical isomers were separated. The S isomer 2(S) showed high affinity for the human 5-HT4 receptor without affinity for the human 5-HT3 receptor, and potent 5-HT4 agonistic activity in longitudinal muscle myenteric plexus (LMMP) preparations of guinea pig ileum. The R isomer 2(R) showed opposite selectivity. As a result of other receptor binding studies, 2(S) (YM-53389) was shown to be a highly selective 5-HT4 agonist.

The efficacy of the one-leg cycling test for determining the anaerobic threshold (AT) of lower limb amputees.

The aim of this study was to investigate whether or not the one-leg cycling test driven by the subject's sound leg as the exercise load method is an applicable method for determining the anaerobic threshold (AT) of lower limb amputees. To evaluate physical fitness, a graded exercise test that monitored gas exchange, ventilation and heart rate (HR) was performed in 51 unilateral lower limb amputees. AT was successfully measured for 42 out of 51 subjects, an 82.3% success rate. The average AT was 12.7 +/- 2.2 ml/kg/min, and the average HR at AT points was 117.7 +/- 16.2 beats/min. The average peak oxygen uptake was 20.1 +/- 5.6 ml/kg/min, and the average peak HR was 145.1 +/- 22.4 beats/min. The peak HR exceeded the HR at AT by an average 27.4 beats/min, which indicates that a comparatively intense exercise load above the AT level is possible. The average AT was 40.9% of the predicted maximum oxygen uptake, which seems reasonable when compared to the reports of other researchers. These results suggested that the one-leg cycling test driven by the sound limb is of use as a method for determining the AT of lower limb amputees.

Effects of gastroprokinetic agents on gastroparesis in streptozotocin-induced diabetic rats.

The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. A slight decrease in gastric emptying was observed in the diabetic rats from 2 to 52 weeks after the diabetes induction. We also investigated the influence of gastroprokinetic agents on STZ-induced diabetic gastroparesis and subdiaphragmatic vagotomy-induced gastroparesis in rats. The selective 5-HT3 receptor antagonists ramosetron (YM060), YM114 (KAE-393), granisetron and ondansetron, and the substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride mosapride and SC-53116 dose-dependently enhanced gastric emptying in normal rats. These compounds also reversed the impairment of diabetic gastroparesis rats at 7 days after the STZ injection, but higher doses were required. The solid gastric emptying in subdiaphragmatic vagotomized rats was also delayed. Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.

The selective 5-hydroxytryptamine (5-HT)4-receptor agonist RS67506 enhances lower intestinal propulsion in mice.

Interactions of gastrointestinal prokinetic benzamides with 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptors and the relation to their effects on gastrointestinal propulsion were investigated. Renzapride and zacopride potently inhibited 5-HT3-receptor-mediated contractions in the guinea pig colon, whereas RS67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride), a selective 5-HT4-receptor agonist, showed no inhibition. RS67506, renzapride and zacopride all exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat oesophagus. In mice, RS67506 shortened the whole gut transit time, whereas renzapride and zacopride were reported to prolong it. Gastrointestinal prokinetic benzamides, which are selective for 5-HT4-receptor agonistic over 5-HT3-receptor antagonistic action, may be useful in treating gastrointestinal disorders associated with impaired lower intestinal propulsion such as constipation.