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PubMed1989

Inhibitory effects of DF 594, a new antispasmodic agent, on intestinal motility in the dog.

DF 594, 11-(N-methylnipecotyl)-6,11-dihydro-5H-pyrido[2,3-b]-1,5-benzod iazepin-5-one hydrochloride, is a new antimuscarinic compound endowed with high affinity for intestinal muscarinic receptors and showing potent inhibitory effects on intestinal motility. This study investigated the intestinal motor effects of DF 594 in fasting, conscious dogs, chronically fitted with electrodes and strain gauges along the small bowel. In a first series of experiments, we assessed the antispasmodic activity of the compound by comparing the ability of intravenous DF 594 or atropine to antagonize the stimulatory effect of bethanechol (100 micrograms/kg s.c.). ED50 values for inhibition of bethanechol-stimulated contractions were 13.9 (8.8-21.8) and 4.0 (1.8-8.7) micrograms/kg for DF 594 and atropine, respectively. In a second series of experiments, we evaluated the effects of intravenous DF 594 and atropine on the migrating motor complex (MMC), monitoring heart rate as well. Similarly to atropine (30-100 micrograms/kg), DF 594 (100-300 micrograms/kg) blocked the further migration of an ongoing MMC and significantly delayed the onset of the following MMC. Unlike atropine, DF 594 had only a minor effect on heart rate at the highest dose tested (300 micrograms/kg). These data indicate that DF 594 is an effective antispasmodic agent at doses lower than those required to interfere with the MMC and is also less likely than atropine to induce cardiac side effects.

Animals↗
PubMed1985

Action of different agonists and antagonists of the cholinergic system on the rat lower esophageal sphincter.

Several compounds acting on the cholinergic system at different levels were tested for their stimulatory or inhibitory effects on the isolated lower esophageal sphincter (LES) of the rat. Results obtained with acetylcholine, bethanechol and compound McN-A343 on the one hand and atropine, pirenzepine, ganglion blocking agents and tetrodotoxin on the other, suggested that LES contraction was associated mainly with the stimulation of post-synaptic muscarinic receptors. Nicotinic receptors (both ganglionic and muscular) seem to have a minor role, if any.

Animals↗
PubMed1986

The effect of the new H2-receptor antagonist mifentidine on gastric secretion, gastric emptying and experimental gastric and duodenal ulcers in the rat: comparison with cimetidine and ranitidine.

The new H2-receptor antagonist mifentidine (DA 4577) was tested for its antisecretory and gastric motor effects in comparison with cimetidine and ranitidine. The Shay rat preparation (5 h) was used for studying gastric secretion; the gastric emptying of a liquid meal was chosen for studying gastric motility. All the three compounds inhibited acid secretion in a dose-dependent fashion. Calculated ED50s were 2.3, 12.2 and 92.8 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. Therefore, in this animal model, mifentidine was about 40 times more potent than cimetidine and 5 times more potent than ranitidine. As far as gastric emptying is concerned, the effect of equiactive antisecretory doses (i.e. the respective ED50s calculated from the previously established dose-response curves) of all the three antagonists was completely different. Cimetidine delayed emptying rate, whereas ranitidine accelerated it and mifentidine was completely ineffective. However, at higher doses, also this compound affected emptying rate by reducing it dose-dependently. Gastric and duodenal ulcers were induced in the rat by dimaprit (100 mg X kg-1 intravenously) and cysteamine (250 mg X kg-1 subcutaneously), respectively. As far as gastric ulcer is concerned, the ED50s (the effective dose which protected 50% of the animals from lesions) were 0.23, 4.40 and 9.70 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. As regards duodenal ulcer, the ED50 was 4.48 for mifentidine and 150.00 mg X kg-1 for ranitidine. In this animal model, the efficacy of cimetidine was very low. Therefore an ED50 could not be determined. In conclusion, results of the present investigation demonstrated that mifentidine is a potent antisecretory compound and an effective anti-ulcer agent in the rat.

Animals↗
PubMed1979

Potentiation and inhibition of ganglionic transmission by ruthenium red.

The effect of ruthenium red, 2.5 to 5 muM, on ganglionic transmission in rat superior cervical ganglia and frog abdominal ganglia were studied in vitro. In rat ganglia, ruthenium red caused a spontaneous firing of ganglia cells, and an increase in the amplitude and duration of the compound action potential following a single stimulus volley. However, transmission following a conditioning volley or a repetitive stimulus train to the preganglionic nerve was depressed up to 60 sec. The asynchronous firing caused by bethanechol was potentiated by ruthenium red. In the frog, ruthenium red caused repetitive firing of ganglion neurons following either orthodromic or antidromic stimulation. It is suggested that the potentiation of the single potential and the spontaneous firing are due to a ruthenium red-induced increase in intracellular calcium concentration. The depression of transmission may be due to a temporary depletion of readily releasable acetylcholine. It is also suggested that ruthenium red has an effect on the postsynaptic membrane.

Action Potentials↗
PubMed1977

Effects of membrane stabilizers on pancreatic amylase release.

Compounds with membrane stabilizing activity were studied as to their ability to affect pancreatic amylase release and the steps in the stimulus-secretion coupling process. Chlorpromazine, propranolol, and thymol were all found to inhibit bethanechol-stimulated amylase release and at slightly higher concentrations to induce release regardless of the presence of the secretagogue. This biphasic effect was similar to that found previously for the local anesthetic tetracaine. Release by high concentrations of propranolol and tetracaine was accompained by ultrastructural evidence of cell damage. Membrane stabilizers at concentrations which inhibited amylase release were shown to block bethanechol-induced depolarization and stimulation of 45Ca++ efflux although the drugs alone partially depolarized pancreatic cells. Release of amylase induced by Ca++ introduced by the ionophore A23187 was also abolished. The findings indicate that membrane stabilizers independently inhibit the steps leading to a rise in intracellular Ca++ and the subsequent Ca++-activated amylase release.

Amylases↗
PubMed1986

Effect of omeprazole on gastric acid secretion by the rat isolated stomach.

The inhibitory effect of omeprazole has been investigated on the isolated gastric fundus from immature rats. Omeprazole (10(-7)-10(-5) M) inhibited basal acid secretion, conversely from H2-receptor antagonists, antimuscarinic compounds and calcium antagonists; the effect was mimicked only by KSCN (3 X 10(-4)-3 X 10(-2) M). Omeprazole (10(-6)-10(-5) M) caused an insurmountable antagonism of the hypersecretion induced by histamine and bethanechol, whereas it competitively antagonized the secretory response to isoprenaline and dibutyryl cAMP. Experiments carried out in low calcium media showed that calcium ions did not significantly affect the inhibitory potency of omeprazole when tested on basal acid secretion, whereas low calcium solutions enhanced the action of omeprazole against histamine-induced hypersecretion. The above data confirmed the potent antisecretory activity of omeprazole in different experimental conditions in which the common antisecretagogues are without effect and pointed out the novel site of action in the control of gastric acid secretion at intracellular level.

Animals↗
PubMed1993

Effect of a new colonic prokinetic compound, T-1815, on gastrointestinal motility in anesthetized and conscious fasted dogs.

Effect of T-1815, a new colonic prokinetic compound, on gastrointestinal motility was studied in anesthetized and conscious dogs fasted for 24 hr before experiment. In anesthetized dogs, intravenous injection of T-1815 in doses of 0.3-3.0 mg/kg caused a biphasic effect on the gastric motility, a slight decrease followed by a slight increase. While the compound elicited only an increase in motility of the duodenum, jejunum and colon. In the colon, high-amplitude contractions were observed in 2 out of 5 animals at 1 mg/kg, i.v. of T-1815 and 4 out of 5 animals at 3 mg/kg. Bethanechol at 0.01 mg/kg, i.v. produced only a potentiation of the motility in all of the sites, but never induced high-amplitude contractions in the colon. During the interdigestive state in conscious dogs, intravenous T-1815 at 1 and 3 mg/kg caused contractions similar to the interdigestive phase III contractions at the stomach and duodenum in only 2 out of 7 experiments, and colonic motility was slightly depressed at 3 mg/kg. Oral administration of T-1815 at 30 and 50 mg/kg did not elicit the phase III-like contractions but produced persistent contractions at the stomach and duodenum in 2 out of 4 conscious animals during the interdigestive state. In the proximal and middle colon, high-amplitude contractions were observed in 5 out of 7 animals by 10-50 mg/kg, p.o. of T-1815. From the above results, it is concluded that the pharmacological effect of T-1815 on gastrointestinal motility is different from that of the cholinergic agonist. In addition, T-1815 seems to have a characteristic to induce high-amplitude contractions which are known to be closely related to defecation.

Administration, Oral↗
PubMed1994

Ventricular arrhythmias induced by chemically modified intrinsic cardiac neurones.

OBJECTIVE: The aim was to investigate whether intrinsic cardiac neurones can be involved in the genesis of ventricular arrhythmias. METHODS: Nicotinic, muscarinic, beta adrenergic, peptidergic, and amino acidergic agonists, as well as purinergic compounds, were individually administered in microliter quantities adjacent to spontaneously active in situ right atrial neurones in 57 anaesthetised dogs before and after acute decentralisation. RESULTS: Ventricular arrhythmias were induced in one third of the dogs following neurochemical administration. Ventricular arrhythmias are induced much less frequently when intrathoracic extracardiac neurones are modified chemically. Salvos of ventricular premature contractions or ventricular tachycardias were elicited when intrinsic cardiac neurones were modified locally applied nicotine, bethanechol, isoprenaline, angiotensin II, bradykinin, substance P, vasoactive intestinal polypeptide, glutamate, or adenosine. In 60% of those instances in which intrinsic cardiac neuronal activity was modified by a neurochemical, ventricular arrhythmias were elicited. When arrhythmias were induced, activity generated by chemically modified intrinsic cardiac neurones increased from 0.7(SD 0.2) to 2.2(0.4) impulses.s-1 (p < 0.05). Following decentralisation of the intrinsic cardiac nervous system, repeat administration of the same neurochemicals into the same loci elicited ventricular arrhythmias in 42% of those dogs in which ventricular arrhythmias had been elicited previously. Neuronal activity increased [0.8(0.5) to 2.1(0.6) impulses.s-1; p < 0.05] in 86% of these instances. CONCLUSIONS: Intrinsic cardiac neurones can be involved in the genesis of ventricular arrhythmias.

Adenosine↗
PubMed1990

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat.

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.

Animals↗
PubMed1990

Hexocyclium derivatives with a high selectivity for smooth muscle muscarinic receptors.

1. The affinity of a number of derivatives of the muscarinic antagonist, hexocyclium, containing an amidine cationic head, for guinea-pig cardiac and ileal receptors was investigated. 2. All the compounds studied displayed a greater affinity for muscular than for cardiac muscarinic receptors. 3. The 5 fold ileal selectivity of hexocyclium was increased by a number of chemical substitutions. The largest discrimination between receptors (about 200 fold) was found for the formamidine derivative. 4. The selectivity displayed by the hexocyclium derivatives stemmed from a greater decrease in affinity towards cardiac as compared to ileal receptors.

Animals↗
PubMed1991

[Effects of NIK-228 on gastric acid secretion in rats using the congo red sprayed method].

We have reported the antiulcer activities of a new compound that we named NIK-228 (3-hydroxy-methyl-2-methylimidazo [2, 1-b] benzothiazole). In the present report, we studied the antisecretory effects of NIK-228 on basal and stimulated gastric acid secretion using the Congo red sprayed method. Male Wistar rats (200 to 250 g) were used after 24 hr of fasting (without water). NIK-228, atropine and cimetidine were administered orally or intravenously 1 hr before operation for Congo red spraying. NIK-228 (100 mg/kg, p.o.), atropine (5 mg/kg p.o.) and cimetidine (100 mg/kg, p.o.) all inhibited basal gastric acid secretion. Oral administration of NIK-228 and atropine inhibited gastrin, 2-deoxy-D-glucose (2-DG) and bethanechol-induced acid secretion, but didn't inhibit histamine-induced acid secretion. Cimetidine inhibited all of histamine, gastrin, 2-DG and bethanechol-induced acid secretion. In vagotomized rats, oral and intravenous administration of atropine both inhibited bethanechol-induced acid secretion, but NIK-228 was not inhibited. These results suggested that antisecretory effects of NIK-228 were caused by the central vagal systems.

Animals↗
PubMed1975

Acid-secretory effects of pentagastrin, histamine, urecholine, DBcAMP, and cBMP in isolated stomachs of fed and fasted rats.

Pentagastrin, histamine, urecholine, DBcAMP, and cGMP were all potent stimulants of acid secretion in the isolated stomach of the fed rat. With the exception of histamine and cGMP, all of these compounds were inactive when the stomach of the fasted rat was used. Pentagastrin was most effective when given on the serosal surface while histamine was equally potent whether it was added to the mucosal or serosal surface of the isolated stomach. The test would appear to be a relatively simply, but effective system for studying the basic mechanisms of action of several important secretagogues in the rat.

Animals↗
PubMed1982

Cholinergic pharmacology of mammalian hippocampal pyramidal cells.

Responses of CAl pyramidal cells to cholinergic compounds were recorded with intracellular microelectrodes in guinea-pig hippocampal slices. Perfusion of slices with medium containing the muscarinic antagonists atropine or scopolamine (10(-7)-10(-6)M) blocked all actions of acetylcholine. Properties of control neurons and those from separate populations of neurons impaled in slices exposed to muscarinic blocking agents were compared. 1-2 h of perfusion with atropine-containing media significantly decreased membrane input resistance from 37.6 +/- 8.7 (S.D.) M omega (n = 74) to 21.9 +/- 7.7 (S.D.) M omega (n = 24) without producing significant changes in membrane potential. Muscarinic antagonists also reduced or eliminated the anomalous inward rectification normally seen in hippocampal pyramidal neurons. Exposure of slices to 10(-5)-10(-6)M eserine for about 1 h produced changes in neuronal membrane input resistance and potential and slow after hyperpolarizations similar to those elicited by application of acetylcholine. Bethanechol mimicked the actions of acetylcholine but was effective at lower concentrations and had longer lasting effects on afterhyperpolarizations. Nicotine produced an excitatory response in only one of 7 neurons. These experiments demonstrate that the actions of acetylcholine on hippocampal CAl neurons result from interaction with muscarinic receptors. Acetylcholine has modulatory effects on cell membrane properties which may be mediated through tonic release mechanisms.

Acetylcholine↗
PubMed1992

Effect of pinacidil on spontaneous and evoked contractile activity.

Uninhibited bladder contractions have been associated with a variety of bladder dysfunctions including outlet obstruction, neurogenic bladder, incontinence, and other neurologic and nonneurogenic bladder disorders. One class of compounds that is gaining popularity and support for the treatment of hyperreflexia is potassium channel openers, such as pinacidil and cromakalim. In general, these agents act by hyperpolarizing the smooth muscle membrane, resulting in an increase in membrane stability which in turn would be expected to inhibit spontaneous and evoked contraction. It is the purpose of this study to compare the potency and selectivity of pinacidil at inhibiting both hyperreflexia in vivo, and several forms of in vitro contractile stimulation in the rabbit. The following is a summary of the results. (1) Pinacidil is an effective inhibitor of hyperreflexia in the in vivo rabbit model. (2) Pinacidil is a substantially more potent inhibitor of the amplitude of the hyperreflexia than the frequency. (3) Pinacidil was substantially more potent at inhibiting the contractile response to 2-Hz stimulation than to 32-Hz stimulation, but was equally effective at inhibiting field stimulation of the bladder base and body. (4) Pinacidil was significantly more potent at inhibiting the peak response to field stimulation than the rate of tension generation. (5) Pinacidil was equally potent and effective at inhibiting the phasic and tonic components of the response to field stimulation. (6) Pinacidil was a more potent inhibitor of methoxamine stimulation of the bladder base than bethanechol stimulation of the bladder body. (7) Pinacidil was a noncompetitive or mixed inhibitor of both methoxamine and bethanechol stimulation, whereas it was a competitive inhibitor of KCl stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Anti-ulcer effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl) phenyl] propionic acid hydrochloride (TEI-5103).

The anti-ulcer effects of the newly synthesized compound 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)-phenyl]propionic acid hydrochloride (TEI-5103) on experimentally induced ulcers in rats were studied. TEI-5103 at doses of 25 to 400 mg/kg p.o. prevented formation of ulcers induced by serotonin, indomethacin, acetylsalicylic acid or stress (acute ulcer models), its effect being greater against gastric ulcers induced by serotonin. On acetic acid ulcer (chronic ulcer model), TEI-5103 at a daily dose of 200 mg/kg p.o. accelerated the healing of ulcers. TEI-5103 at doses of 100 to 400 mg/kg i.d. did not inhibit gastric acid secretion in pylorus-ligated rats. It markedly increased gastric blood flow in anesthetized rats (at 10-20 mg/kg i.v., measured by the aminopyrine clearance method), and also increased gastric blood flow in anesthetized dogs (at 2.5-10 mg/kg i.v., measured by the cross thermocouple method). These results indicate that TEI-5103 is effective as an anti-ulcer agent increasing gastric mucosal blood flow and possibly promoting the healing process of peptic ulcers.

Acetates↗
PubMed1994

Pharmacological profile of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo- 5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), a new potent and selective gastrin/cholecystokinin-B receptor antagonist, in vitro and in vivo.

(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) is an extremely potent and highly selective gastrin/cholecystokinin (CCK)-B receptor antagonist. We compared the gastrin/CCK-B receptor-blocking properties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365, 260 and Cl-988 in vitro and in vivo. YM022 replaced specific binding of [125I]CCK-8 to rat brain gastrin/CCK-B receptors in a stereoselective and competitive manner. The Ki value of YM022 for gastrin/CCK-B receptors in brain were estimated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 and Cl-988 also replaced gastrin/CCK-B receptor binding, with Ki values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, such as benzodiazepine. In vivo, intravenous (i.v.) administration of YM022 inhibited pentagastrin-induced gastric acid secretion in anesthetized rats, with an ED50 value of 0.0078 mumol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mumol/kg i.v. L-365,260 (1-10 mumol/kg i.v.) and Cl-988 (0.3-3 mumol/kg i.v.) also antagonized acid secretion induced by pentagastrin, with ED50 values of 4.23 and 1.01 mumol/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Progressive isolated segmental anhidrosis.

A patient had progressive segmental anhidrosis, which proved after extensive neurologic and autonomic workup to be an isolated abnormality. Intradermal acetylcholine produced localized sweating in areas of thermoregulatory anhidrosis five months after the onset of symptoms but failed to do so at two years. These findings are consistent with a preganglionic sympathetic lesion affecting a functionally defined subset of sympathetic cells and/or fibers. The alteration of the sudomotor response to intradermal acetylcholine during the course of the illness suggests that the diagnostic utility of pharmacologic sweat tests may be time dependent, limited to a relatively early period following onset of anhidrosis.

Acetylcholine↗