ABSTRACT
Neuropeptide Y (NPY) has been shown to mimic the effects of some sigma receptor agonists in the brain and to possess the same proabsorptive effect as these agonists in the isolated mouse jejunum. The aim of present study was to investigate the effect of NPY on duodenal alkaline secretion in the rat and to define its mode of action. NPY (0.01 to 3 micrograms/kg i.v.) induced a dose-related increase in duodenal bicarbonate secretion, the maximal effect being obtained at 1 micrograms/kg. This response was significantly inhibited by the i.v. administration of haloperidol, BMY 14802, devazepide, hexamethonium, tetrodotoxin and by bilateral truncal vagotomy, but not by SCH 23390, sulpiride, prazosin or atropine, whereas i.c.v. devazepide had no effect. This pharmacological profile is identical to that reported for sigma receptor agonists. The results suggest that NPY and sigma ligands act through a common pathway to stimulate duodenal alkaline secretion in the rat.
Subject(s)
Bicarbonates/metabolism , Duodenum/drug effects , Neuropeptide Y/pharmacology , Receptors, sigma/drug effects , Animals , Duodenum/metabolism , Injections, Intravenous , Male , Neuropeptide Y/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , VagotomyABSTRACT
BACKGROUND: The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats. METHODS: Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied. RESULTS: JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784. CONCLUSION: These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.
Subject(s)
Bicarbonates/metabolism , Cinnamates/pharmacology , Cyclopropanes/pharmacology , Duodenal Ulcer/prevention & control , Duodenum/drug effects , Duodenum/metabolism , Receptors, sigma/drug effects , Stomach Ulcer/prevention & control , Animals , Cysteamine , Gastric Acid/metabolism , Guanidines/pharmacology , Male , Rats , Rats, Sprague-DawleyABSTRACT
An extraluminal strain gage force transducer has been developed for recording gastrointestinal motility in small animals such as rats. Two commercial strain gages are bonded and wires attached to form half a Wheatstone bridge. The device is placed between silicone sheeting and prepared for implantation. As many as six implanted transducers can record simultaneously contractions and tone variations of circular or longitudinal gastrointestinal muscles. The transducers have been implanted in more than 20 rats, with some units lasting up to 4 mo. Furthermore, good relationships exist between intraluminal pressure waves registered by a small intraluminal balloon and gut contractions registered by the transducer. The transducers are a useful and accurate tool for rodent gut motility studies.
Subject(s)
Gastrointestinal Motility , Muscle Contraction , Muscle, Smooth/physiology , Animals , Rats , TransducersABSTRACT
Time-response and dose-response curves for acid output to continuous infusion of histamine (HIST) and pentagastrin (PG) were determined by two techniques in conscious rats provided with chronic gastric fistula. With the step-dose technique the dose of the stimulant was increased each hour; with the single-dose technique only one dose of the stimulant was administered on each test day. The observed maximum acid output (OMAO) was obtained either by infusion of PG at a rate of 6 microgram/kg/h using both techniques or HIST at a rate of 1 mg/kg/h with the single-dose and 2 mg/kg/h with the step-dose technique. These OMAO were in the order: single PG greater than single HIST greater than step Hist greater than step PG in ratios 100--99--83--82. The dose-response curves were also analyzed by application of the Michaelis-Menten equation. For each stimulant there was no difference between the calculated maximum acid output (CMAO) whatever the technique used, but PG gave lower CMAO than HIST (p less than 0.05). For both stimulants the calculated doses for half the calculated maximal response (CD 50) are significantly higher with the step-dose than with the single-dose technique. These results are compared with those previously described in the literature for cats, dogs and man.
