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Biomedical subjects

M Pairet

Publications and source records attributed to M Pairet.

29 records · Page 2Linked to original sources
PubMed1986

Cholinergic modulation of the release of serotonin in the gastric interstitial fluid. An in vivo study in rabbits.

Dialysis fibers chronically implanted into the gastric submucosa of rabbits allowed us to simultaneously (a) collect an interstitial fluid dialysate in which 5-hydroxytryptamine concentrations were measured, and (b) locally perfuse drugs such as acetylcholine, neostigmine, and atropine, which stimulated the release of 5-hydroxytryptamine. The effect of acetylcholine was not blocked by atropine but was blocked by hexamethonium. Furthermore, 5-hydroxytryptamine concentrations in the interstitial fluid were lower when acetylcholine and hexamethonium were injected together than when hexamethonium was injected alone. We conclude that acetylcholine stimulates the release of 5-hydroxytryptamine into the gastric interstitial fluid by acting on nicotinic receptors, and has inhibitory effects by stimulating the muscarinic receptors.

Acetylcholine↗
PubMed1986

Colonic formation of soft feces in rabbits: a role for endogenous prostaglandins.

Rabbits produce hard and soft feces in a circadian rhythm. The motor activity of the haustrated proximal colon is inhibited during the formation of soft feces, whereas the spiking activity of the distal colon is stimulated. A potential role for endogenous prostaglandins (PG) in the control of the soft-feces elaboration by the rabbit colon was investigated in conscious animals by using PGE2 and PGF2 alpha and by inhibiting them with indomethacin. The infusion of both PGE2 and PGF2 alpha induced typical electromechanical events consisting of inhibition of the proximal and stimulation of the distal colon and was followed by soft-pellet defecation. Rabbits accustomed to be fed twice daily produced soft feces at fixed intervals of 252 +/- 32 min after the evening meal, with a soft-to-hard feces ratio of 1.45. After indomethacin treatment, this ratio was significantly (P less than 0.01) reduced to 0.92. These results are consistent with the concept that endogenous prostaglandins play a major role in the motor function involved in soft-feces formation by the rabbit.

Animals↗
PubMed1986

[Physico-chemical stimulation of dietary origin and digestive motility in the rabbit].

The effects on gastrointestinal motility of two different diets, one containing dehydrated lucerne and the other dehydrated beet pulp (both being either coarsely or finely ground before pelleting) were studied in 16 unanesthetized 50-60-day old rabbits fed ad libitum. The rabbits fed with lucerne had better antroduodenal and ileo-caecal coordination, a higher level of electrical activity on the duodenum, and more frequent migrating myoelectric complexes on the jejunum and ileum than those fed with beet pulp. Furthermore, the rabbits fed the finely ground pellets showed weak electrical activity on the ileum and poor ileo-caecal coordination irrespective of fiber source, suggesting a unique effect of size per se on these portions of the digestive tract.

Animals↗
PubMed1985

Origin and characterization of migrating myoelectric complex in rabbits.

Myoelectric activity patterns of the upper gastrointestinal tract were recorded using chronically implanted electrodes in conscious rabbits. A cyclical pattern of intense spiking activity occurring on almost every slow wave for 10-15 min, corresponding to the regular spiking phase or phase III of the migrating myoelectric complex (MMC), was recorded. This activity was detected by electrodes implanted distal to the ligament of Treitz on the proximal jejunum at a frequency of 9.4-10.6/24 hr. The MMC pattern occurred in both fed and fasted animals, regardless of the presence of cecotrophy. Initiation of phase III activity on the jejunum persisted after transplantation of the pancreatic duct opening to the proximal duodenum 5 cm from the pylorus and when gastric contents emptied directly into the proximal jejunum through a large gastrojejunostomy. It is concluded that the MMC pattern of the rabbit small intestine is persistently initiated in the proximal jejunum distal to the pancreatic and biliary ducts. The jejunal origin of the MMC in the rabbit is reminiscent of that seen transiently 8-10 hr after a meal in dogs during the change from fed to the fasted pattern of gastrointestinal motor activity.

Animals↗
PubMed1984

Opioid control of the ruminant stomach motility: functional importance of mu, kappa and delta receptors.

In sheep, the subcutaneous (SC) or intracerebroventricular (ICV) administration of the mu-type opioid agonists, fentanyl and morphine, evokes a blockade of the cyclic contractions of the reticulum. A similar inhibition of forestomach motility was recorded following the administration of the two enkephalin analogs, D-Ala2-Met5-enkephalinamide (DAMA) and D-Ala2-D-Leu5-enkephalin (DADLE) which are mixed mu - delta opioid agonists. In contrast, the reticular contractions were enhanced by the SC or ICV administration of the kappa type agonist, ethylketazocine (EKC) and U - 50 488 H. The proximal duodenum motor activity was transiently increased resulting in the occurrence of a phase III-like activity by these opioid agonists, regardless of the subtypes. The effects of the opioid agonists on reticular motility were prevented by the injection of naloxone but not by the quaternary parent compound methylnaloxone which does not cross the blood-brain barrier. The duodenal motor effects elicited by the opioid agonists were antagonized by both naloxone and methylnaloxone. The results suggest that the inhibition of the ruminant stomach motility is centrally mediated by mu - delta type opioid agonists and are consistent with opposite effects from kappa type opioid agonists. The stimulatory effect of peptide and non-peptide opioid agonists on the duodenum may result in part from direct opioid receptor-mediated actions on smooth muscle.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1984

Opioid receptor agonists in the rabbit colon: comparison of in vivo and in vitro studies.

Myoelectrical activity was recorded in the proximal and distal colon of rabbits using chronically implanted electrodes. The motility in both the proximal and distal colon was inhibited by the intravenous (IV) administration of the following opioid agonists for mu receptors: morphine and fentanyl, kappa receptors: ethylketazocine (EKC) and U 50 488 H, and delta receptors: D-Ala2 D-Leu5-enkephalin (DADLE) and D-Ser2 Leu-enkephalin-Thr6 (DSLET). In contrast, the myoelectric activity in the distal colon was increased during the infusion of an endogenous kappa opioid agonist, dynorphin (DYN). All of these effects were prevented by naloxone pretreatment. During in vitro studies using extraluminal force transducers, fentanyl, U 50 488 H and DSLET inhibited spontaneous contractions of the proximal colon, but U 50 488 H and DSLET caused a substantial increase in the motility of the distal colon. The observed motor responses in the proximal and distal colon following opioid agonist administration indicate that the control of these two intestinal segments may be different. It is suggested that the stimulatory effect of dynorphin on the distal colon is peripherally-mediated while inhibition of the whole colon by opioid agonists regardless of subtypes seems to be centrally-mediated.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

Continuous assessment of multiple vital physiological functions in conscious freely moving rats using telemetry and a plethysmography system.

The general pharmacologist in the pharmaceutical industry is challenged to generate physiologically relevant data on possible safety liabilities or on secondary therapeutic uses as early as possible in drug development. This implies the need for efficient use of usually only small supplies of test article. For this reason, we have developed a new animal model combining various elements to provide a broad spectrum of data focussing on the so-called vital physiological functions: cardiovascular, respiratory, and central nervous system. This system uses rats chronically implanted with transmitters for the measurement of arterial pressure, ECG, and body temperature. Modification of the transmitters also allows for the simultaneous assessment of locomotor activity. Studies are performed with these rats in plethysmographs placed directly over the antenna units thus allowing for the additional assessment of respiratory function in the same studies. Using this system, we can generate simultaneously a wide range of relevant physiological parameters in conscious rats with a modest requirement for test article. Such an approach is highly useful for getting early safety readouts of potential drug development candidates as well as for detecting possible secondary therapeutic actions of a drug.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMedDate not supplied

Effects of telmisartan on renal excretory function in conscious dogs.

The present study investigated the effects of telmisartan, a selective AT1 receptor antagonist, on renal function in dogs. Conscious female dogs were treated with (i) vehicle (controls) and three doses of telmisartan (0.03 mg/kg, 0.1 mg/kg and 0.3 mg/kg) administered intravenously; (ii) vehicle and three doses of telmisartan (0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg) administered orally; or (iii) 1.0 mg/kg per day telmisartan orally for 12 days. Eight dogs were used for each experiment. Each of the four treatments in (i) and (ii) was administered 7 days apart. During the 6 h after intravenous administration, urine volume was significantly higher in dogs treated with telmisartan 0.1 mg/kg (8.5 +/- 1.6 ml/kg) and 0.3 mg/kg (7.0 +/- 0.9 ml/kg) than controls (2.7 +/- 0.3 ml/kg; P < 0.05), and renal sodium excretion was increased significantly with telmisartan 0.03 mg/kg (803 +/- 124 micromol/kg), 0.1 mg/kg (1039 +/- 213 micromol/kg) and 0.3 mg/kg (966 +/- 161 micromol/kg) versus controls (159 +/- 21 micromol/kg; P < 0.05). Oral telmisartan at doses of 1.0 mg/kg and 3.0 mg/kg also produced significant increases in urine volume (7.2 +/- 1.1 ml/kg and 6.6 +/- 1.2 ml/kg, respectively) and renal sodium excretion (599 +/- 146 micromol/kg and 555 +/- 131 micromol/kg, respectively) compared with controls (2.8 +/- 0.5 ml/kg and 80 +/- 33 mciromol/kg; P < 0.05) over the 6-h post-dose period. Telmisartan at all intravenous doses and at 3.0 mg/kg orally increased the urinary excretion of chloride significantly over the 6-h post-dose period compared with vehicle alone. The excretion of potassium and creatinine were unchanged by any treatment. Telmisartan 1.0 mg/kg administered orally for 12 days produced similar results. In conclusion, acute intravenous or oral as well as subchronic oral administration of telmisartan to conscious dogs promotes diuresis and natriuresis without affecting potassium or creatinine excretion.

Animals↗
PubMedDate not supplied

Measurement of differential inhibition of COX-1 and COX-2 and the pharmacology of selective inhibitors.

Since the discovery of a second isoenzyme of cyclooxygenase (COX)-2, it has been hypothesized that the antiinflammatory effects of non-steroidal antiinflammatory drugs (NSAIDs) are dependent on their inhibition of COX-2, whereas inhibition of constitutive COX-1 is responsible for their gastric and renal side effects as well as for inhibition of platelet activation. Consequently, a large number of in vitro assays have been developed to characterize the COX-1 and COX-2 inhibitory activities of NSAIDs in order to look for compounds with preferential inhibition of COX-2. Depending on the test system, however, the experimental conditions may vary greatly, thereby affecting the outcome. These important variables include the source of enzymes COX-1 and COX-2 (human or animal); the cell system used (intact normal cells or transfected cell lines); the method of enzyme preparation (purified enzymes, microsomal or whole cell assays); the COX-2-inducing agent; the source of arachidonic acid and its concentration; the incubation time with drug, inducing agent or arachidonic acid; and the protein concentration in the medium. Depending on the test system employed for defining the IC(50) for COX-1 and COX-2 inhibition, the resultant ratio between these activities may lead to divergent and confusing comparisons. We review the various in vitro test systems available for the measurement of COX-1 and COX-2 inhibition. The use of human recombinant enzymes and the human whole blood assay are examined in detail. The relevance of these test systems to in vivo animal models of inflammation and the side effects of NSAIDs (e.g., gastric mucosal and renal damage) is assessed. Finally, the results of clinical studies on the effect of inhibiting COX-1 and COX-2 activity is summarized.

Journal Article↗
PubMedDate not supplied

[Selective cyclooxygenase-2 (COX-2) inhibitors: importance and limitations].

The discovery of an inducible form of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic effects and side-effects of non-steroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have demonstrated in clinical trials a significantly better gastrointestinal tolerability than classical NSAIDs, for the same anti-inflammatory activity. Their tolerability in patients with active ulcer or with a recent history of ulcer as well as in patients suffering from cardiovascular or renal diseases has still to be investigated in detail. Their therapeutic potential in several new indications, including pre-term labour, colorectal cancer and Alzheimer's disease, is currently being investigated.

Alzheimer Disease↗