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PubMed1980

Substance P, bethanechol, 4-aminopyridine, and potassium antagonize the depressing effects of low-frequency stimulation, tetrodotoxin, procaine, and of magnesium on the field-stimulated guinea-pig vas deferens.

The twitch-response enhancing potencies of (the agonists) substance P, bethanechol, 4-aminopyridine and of potassium chloride were compared in the field-stimulated guinea-pig vas deferens. The agonists were tested after the twitching activity of the isolated organ had been reduced to an equal extent by (the antagonists) tetrodotoxin, procaine, magnesium chloride, and by decreased stimulation frequency. Further experiments were performed in the functionally denervated organ. The potencies differed with the type of antagonism of the twitch-response. This pointed at different modes of action and/or sites of mechanism of the response-enhancing compounds. The pharmacological nature of agonists and antagonists as well as the results in the denervated organ indirectly suggested a predominantly neuronal point of mechanism of the agonists. This was most obvious for substance P.

4-Aminopyridine↗
PubMed1978

Cholinergic receptor mechanisms in amphibian vasoconstrictor responses.

The four choline esters, namely acetylcholine, carbachol, methacholine and bethanechol, produced constriction of frog's perfused systemic blood vessels, acetylcholine and carbachol being more potent than methacholine and bethanechol. Pentolinium and dihydroergotamine, in submaximal receptor-blocking doses, also produced a uniform partial inhibition of all choline esters and other agonists including the direct-acting barium chloride. On the other hand atropine markedly inhibited the responses of the four choline esters without affecting the adrenaline and barium responses. Compound AHR-602, a specific ganglionic muscarinic excitatory receptor stimulant, did not produce any effect in these experiments. Eserine in higher doses produced slight vasoconstriction and markedly potentiated acetylcholine responses, but it inhibited partially those of the other three choline esters without significantly affecting adrenaline and barium responses. The results provide strong evidence in favor of involvement of the postganglionic muscarinic receptors only in vasoconstriction after choline esters. There seems to be a considerable nonspecific inhibitory activity in ganglionic and alpha-adrenergic blockers in their submaximal receptor-blocking doses. It may be that in frog the adrenergic and nicotinic receptors are not as well differentiated as muscarinic receptors are. The ganglionic muscarinic receptors also seem to be absent in the frog.

Acetylcholine↗
PubMed1985

Characterization of cholinoreceptors in the rat urinary bladder by the use of agonists and antagonists of the cholinergic system.

The effects of stimulatory and inhibitory compounds acting on both nicotinic and muscarinic receptors have been evaluated in the isolated urinary bladder from adult and immature (14-18 days old) rats. Acetylcholine and bethanechol were found to induce concentration-dependent contractions which were inhibited by atropine and pirenzepine; compound McN-A-343 had a negligible contractile activity whereas DMPP had no effect at all. Responses to electrical field stimulation were abolished by tetrodotoxin (3 X 10(-8) M), enhanced by eserine (10(-8) M) and scarcely affected by hexamethonium (10(-3) M), trimethaphan (10(-3) M) and d-tubocurarine (10(-3) M). Atropine, pirenzepine and DMPP induced only a partial inhibition (50%) of the twitch response, whereas compound McN-A-343 caused a concentration-dependent inhibitory effect which was maximum (100% inhibition) at 10(-2) M. No significant differences were found between results obtained in immature and adult animals as regards either the stimulatory or the inhibitory compounds tested. It was concluded that postjunctional muscarinic receptors were responsible for the stimulatory responses observed, whereas an additional involvement of unknown mechanisms, probably not related to the cholinergic system, was suggested by the peculiar results obtained with DMPP and compound McN-A-343 on electrically-stimulated urinary bladder. Whatever the mechanisms involved, however, they are already present at the first stage of postnatal development.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1985

The relative potencies of some agonists at M2 muscarinic receptors in guinea-pig ileum, atria and bronchi.

The effects of some agonists on isolated preparations of guinea-pig ileum, atria and bronchial muscle have been compared with those of carbachol. The concentrations producing comparable responses were used to estimate the equipotent molar ratio relative to carbachol. Arecaidine propargyl ester was 4 to 5 times as active as carbachol on the ileum but more than 10 times as active as carbachol on atrial rate or atrial force, so the results confirm that this compound has a 2 to 3 fold selectivity for receptors in atria. Ethoxyethyltrimethylammonium iodide was one-quarter to one-third as active as carbachol on ileum but only one-tenth as active as carbachol on atrial rate or atrial force and so shows a 3 to 4 fold selectivity for receptors in ileum. The other compounds tested, which included acetylcholine, methacholine, n-pentyltrimethyl-ammonium iodide and bethanechol showed less selectivity. There were no obvious differences between effects on atrial rate and effects on atrial force, though with esters it was often difficult to obtain effects on atrial rate in the absence of an inhibitor of cholinesterase. Activity on bronchial muscle was generally similar to activity on ileum.

Acetylcholine↗
PubMed1988

Binding and functional characterization of the cardioselective muscarinic antagonist methoctramine.

The antimuscarinic properties of the newly synthetized polymethylene tetramine derivative, methoctramine, were investigated in binding and functional assays. Methoctramine displaced the specific binding of [3H]-N-methylscopolamine [( 3H]NMS) and [3H] pirenzepine from membranes of rat tissues with the following order of affinities: heart = cerebellum greater than cortex greater than submandibular glands, the ratio of the affinities of the compound for the heart and the glands amounting to about 130. Computer fits of binding curves generated in cardiac and cortical membranes were compatible with an interaction at one binding site, whereas those in submandibular glands and cerebellum had slopes significantly lower than 1. Experiments performed in cardiac membranes to investigate the effect of methoctramine on the dissociation kinetics of [3H]-NMS showed that concentrations of compound up to 1 microM did not affect the dissociation of [3H]-NMS elicited by an excess of NMS. At greater concentrations (10-100 microM), methoctramine dose dependently inhibited [3H]-NMS dissociation, thus revealing an allosteric interaction. In in vitro functional assays, methoctramine displayed more than 100 times greater affinity for the muscarinic receptors mediating negative inotropic and chronotropic effects in guinea pig atria than for those responsible for tracheal contraction. Similarly, the compound was a more potent antagonist of the bradycardial response to bethanechol than of the bladder tonus increase, saliva secretion and hypotension induced by the muscarinic agonist in anesthetized cats. Finally, in the pithed rat, methoctramine preferentially inhibited cardiac M2 (vagal bradycardia) over ganglionic M1 (McN-A-343-induced hypertension) responses. The evidence appears to characterize methoctramine as being the most selective M2 muscarinic antagonist described to date.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Study of the antisecretory and antiulcer mechanisms of a new indenopirydazinone derivative in rats.

The present study investigates the antisecretory and antiulcer mechanisms of a new indenopyridazinone derivative previously reported to inhibit gastric acid secretion in pylorus-ligated rats and to prevent gastric ulcerations induced by indomethacin or ethanol in the same animal species. The new compound was tested on the acid hypersecretion induced by histamine, pentagastrin and bethanechol in in vivo and in vitro experimental models. Furthermore, its influence on the mucosal layer adhering the gastric wall in indomethacin-treated rats was considered. Ranitidine was selected as a reference drug. The results obtained demonstrated that the new molecule, at variance with ranitidine, exerts antiulcer activity mainly enhancing the gastric mucosal integrity and simultaneously inhibiting the gastric acid hypersecretion evoked exclusively by cholinergic pulses. Therefore, an involvement of a neuronal rather than an effectorial mechanism has been suggested. Due to these mechanisms of action it clearly differentiates from ranitidine and its possible application in the peptic disease resistant to H2-blockers could be speculated.

Animals↗
PubMed2003

Selective activation by photodynamic action of cholecystokinin receptor in the freshly isolated rat pancreatic acini.

1 Sulphonated aluminium phthalocyanine (SALPC) photodynamic action induces amylase secretion and permanent calcium oscillation in rat pancreatic acinar cells, because of the activation of phospholipase C or signalling proteins upstream. The aim of the present study was to investigate the involvement of muscarinic acetylcholine and cholecystokinin (CCK) receptors. 2 Muscarinic receptor antagonist atropine (10 micro M) blocked amylase secretion induced by bethanechol (100 micro M), and CCK(1) receptor antagonist (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydor-4-oxo-pyrrolo-[3,2,1-jk][1,4] benzodiazepine-3yl]-1H-indole-2-carboxamide (FK480) (1 micro M) blocked amylase secretion induced by CCK (100 pM). 3 Amylase secretion induced by SALPC photodynamic action was not inhibited when atropine and FK480 were present during photodynamic action. However, addition of FK480 1 micro M after initiation of photodynamic action inhibited photodynamic amylase secretion. Bethanechol (10, 100 micro M) added after photodynamic action resulted in a full secretory response. 4 Atropine (10 nM) abolished calcium oscillation induced by bethanechol (5 micro M), and FK480 (10 nM) blocked calcium oscillation induced by CCK (10 pM). 5 Atropine up to 10 micro M was without effect on Ca(2+) oscillation triggered by photodynamic action, but these oscillations were abolished by FK480 (10 nM). FK480 (10 nM) had no effect on calcium oscillations induced by bethanechol (5 micro M). Bethanechol 5 micro M, added after FK480 blockade of photodynamic calcium oscillation, still triggered regular calcium oscillation. 6 It is concluded that SALPC photodynamic action selectively and permanently activates CCK receptor in rat pancreatic acini. Such permanent and selective modulation of signalling proteins has important implications for the treatment of pancreatitis, prion diseases, and neurodegenerative disorders.

Amylases↗
PubMed1975

Cholinomimetic teratogens: studies with chicken embryos.

The cholinomimetic compounds carbachol, decamethonium, neostigmine, succinylcholine, trimethylphenylammonium, and others were tested for their interference with normal chick development. All these compounds led to abnormalities of the cervical vertebrae; at higher dosage interference with normal morphogenesis involved the whole vertebral column. Hypoplasia of the leg muscles occurred with lower incidence. Responses, tested with carbachol, rose from 24 to 72 and 96 h, then declined to 120 h of incubation. Two of the cholinometic compounds used in combined treatment produced a high degree of synergism. Gallamine, benzoquinomium, butyrylcholine, and bethanechol had protective effects. Acetylcholine, at high dosage, caused defects different from the above. It is suggested that the cholinomimetic teratogens interfere with normal development by displacing acetylcholine from its receptors or by forming complexes with it.

Acetylcholine↗
PubMed1987

Muscarinic receptor subtypes mediating the mucosal response to neural stimulation of guinea pig ileum.

Muscarinic receptors involved in the secretory response evoked by electrical stimulation of submucosal neurons were investigated in muscle-stripped flat sheets of guinea pig ileum set up in flux chambers. Neural stimulation produced a biphasic increase in short-circuit current due to active chloride secretion. Atropine and 4-diphenylacetoxy-N-methylpiperadine methiodide (4-DAMP) (10(-7) M) were more potent inhibitors of the cholinergic phase of the response than was pirenzepine. Dose-dependent increases in base-line short-circuit current were evoked by carbachol and bethanechol; 4-hydroxy-2-butynyl trimethylammonium chloride (McN A343) produced a much smaller effect. Tetrodotoxin abolished the effects of McN A343 but did not alter the responses of carbachol and bethanechol. McN A343 significantly reduced the cholinergic phase of the neurally evoked response and caused a rightward shift of the carbachol dose-response curve. All muscarinic compounds inhibited [3H]quinuclidinyl benzilate binding to membranes from mucosal scrapings, with a rank order of potency of 4-DAMP greater than pirenzepine greater than McN A343 greater than carbachol greater than bethanechol. These results suggest that acetylcholine released from submucosal neurons mediates chloride secretion by interacting with muscarinic cholinergic receptors that display a high binding affinity for 4-DAMP. Activation of neural muscarinic receptors makes a relatively small contribution to the overall secretory response.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1993

Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs.

FRG-8813, a new histamine H2 receptor antagonist, was examined for antisecretory effects and compared with famotidine and cimetidine in rats and dogs. In pylorus-ligated and lumen-perfused rats, FRG-8813 given i.v. reduced basal gastric acid secretion and the acid secretion evoked by histamine, tetragastrin, bethanechol, and 2-deoxy-D-glucose in a dose-dependent manner. The i.v. antisecretory activity of FRG-8813 was equivalent to or slightly less than that of famotidine and the intraduodenal (i.d.) activity was greater than that of cimetidine. The duration of action of FRG-8813 was substantially longer than that of farmotidine and cimetidine for both i.v. and i.d. routes. The i.v. ED40 values for the histamine- and tetragastrin-evoked responses and the i.v. ED30 value for the bethanechol-evoked response were 0.15, 0.09 and 0.43 mg2kg, respectively. In Heidenhain pouch dogs, when the three H2 antagonists were given i.v. or orally, the relative antisecretory potency of the compounds was similar to that in rats. The long-lasting antisecretory effect of FRG-8813 was also observed, and the i.v. ED50 values for histamine-, tetragastrin- and bethanechol-evoked responses were 0.1, 0.24 and 1.0 mg/kg, respectively. Comparison of the parenteral and enteral potencies indicated that FRG-8813 has a lower bioavailability than famotidine and cimetidine in rats and dogs. These data suggest that FRG-8813 has a potent and long-lasting antisecretory effect with a far greater potency than cimetidine and with a slightly lower potency than famotidine.

Acetamides↗
PubMed1997

Sensory nerve-mediated inhibitory responses in airways of F344 rats.

We recently described a sensory nerve inhibitory system that mediates relaxation in the airways of Sprague-Dawley rats. Results of several studies have shown that this system protects the lungs against injury induced by toxic stimuli. Whether a similar inhibitory system exists in the airways of Fischer 344 (F344) rats is unknown. Because this rat strain is used extensively in lung toxicological research, the purpose of this study was to determine whether a sensory nerve inhibitory system exists in intrapulmonary bronchi and tracheae isolated from F344 rats. In intrapulmonary bronchi at resting tone, substance P (1.0 microM) evoked a transient contraction that was inhibited by the 5-HT2A receptor antagonist, ketanserin. Exposing airway segments to compound 48/80 to degranulate mast cells also abolished substance P-induced contractions. Inhibition of cyclooxygenase with meclofenamate augmented markedly the contraction to substance P in the intrapulmonary bronchi. In intrapulmonary bronchi that were contracted with bethanechol, substance P evoked a biphasic response characterized by an increase in tension above that induced by bethanechol followed by relaxation. Incubation of the airways with ketanserin abolished the contractile portion of the response; relaxation responses were augmented after ketanserin. In contracted intrapulmonary bronchi that had been treated with compound 48/80, substance P and capsaicin caused relaxation responses that were inhibited markedly or were nearly abolished by the NK1 receptor antagonist, RP67580, by meclofenamate, and by denuding the epithelium. Capsaicin-induced relaxation responses also were abolished by desensitization of C-fibers with capsaicin. Only ketanserin-sensitive contractile responses were observed in response to substance P in tracheal segments. We conclude that a sensory nerve inhibitory system exists in the intrapulmonary airways of F344 rats. The presence of this inhibitory system in F344 rat airways may play a protective role against lung injury induced by inhaled toxicants.

Analgesics↗
PubMed1987

Muscarinic receptors mediate negative and positive inotropic effects in mammalian ventricular myocardium: differentiation by agonists.

The concentration-dependence of the negative and positive inotropic effect of choline esters and of oxotremorine was studied in isometrically contracting papillary muscles of the guinea-pig. The preparations were obtained from reserpine-pretreated animals and were electrically driven at a frequency of 0.2 Hz. In the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine (IBMX, 100 mumol l-1), choline esters and oxotremorine produced concentration-dependent negative inotropic effects. Oxotremorine exhibited the highest negative inotropic potency (with a half-maximal effective concentration, EC50, of 20 nmol l-1) followed by carbachol (139 nmol l-1), methacholine (490 nmol l-1), acetylcholine in the presence of 10 mumol l-1 physostigmine (1.36 mumol l-1) and bethanechol (10 mumol l-1). Atropine was a competitive antagonist of the negative inotropic effects. Carbachol and oxotremorine decreased Vmax, overshoot and duration of slow Ca2+-dependent action potentials which had been elicited in the presence of 100 mumol l-1 IBMX. Choline esters produced a concentration-dependent positive inotropic effect. With an EC50 of 32 mumol l-1, carbachol was the most potent compound, followed by methacholine (35 mumol l-1), acetylcholine in the presence of 10 mumol l-1 physostigmine (46 mumol l-1) and bethanechol (142 mumol l-1). Compared to carbachol and methacholine which increased force by 100% of control, the increase induced by acetylcholine and bethanechol was only 64 and 58%, respectively. Atropine shifted the concentration-effect curves of all choline esters to higher concentrations. Choline esters caused intracellular Na+ activity to increase in the quiescent papillary muscle. This effect was reversed by atropine. Oxotremorine produced a small concentration-dependent positive inotropic effect (about 30% of the maximal effect of carbachol) which was resistant to atropine. Oxotremorine was a potent inhibitor of the positive inotropic effect of choline esters, and did not cause an increase in intracellular Na+ activity in the quiescent papillary muscle. The results show that muscarinic receptors of the ventricular myocardium mediate two inotropic effects, which are opposite in direction and differ in their concentration-dependence by a factor of 100. Although agonists differentiate between both inotropic effects, it is unknown whether the receptors involved represent receptor states or separate receptor subpopulations. The negative inotropic effect of choline esters and of oxotremorine can be best explained by adenylate cyclase inhibition. While stimulation of phosphoinositide hydrolysis might have been responsible for the positive inotropic effect of choline esters via modulation of cation-fluxes across the cell membrane, such a mechanism was not involved in the positive inotropic effect of oxotremorine.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Dual synaptic effects of activating M1-muscarinic receptors, in superior cervical ganglia of rabbits.

Postsynaptic potentials elicited by various muscarinic agonists and by preganglionic stimuli in the presence of such agonists were recorded from rabbit superior cervical ganglia using sucrose-gap and air-gap methods. While methacholine and bethanechol (both at 10(-4) M) induced biphasic potential changes, McN-A-343 and a novel synthetic compound AF-102B (10(-7) M-10(-5) M) produced only a depolarizing response which was depressed by the M1-antagonist pirenzepine (10(-7) M), but not by the M2 antagonist AF-DX 116 (same concentration), indicating that these compounds act purely as M1-muscarinic agonists in this system. These agonists selectively depressed the orthodromic slow excitatory postsynaptic potential (EPSP) in a dose-dependent manner without substantially affecting the fast EPSP; this is in accord with the view that their depolarizing action is on the same postsynaptic muscarinic receptor that mediates the slow EPSP. The slow inhibitory post synaptic potential (IPSP), on the other hand, was found potentiated in the presence of these agonists. This potentiation was antagonized not only by pirenzepine but also by yohimbine; the potentiation was itself enlarged by nomifensine (a dopamine-uptake inhibitor). We postulate that M1-muscarinic receptors are present not only on the postganglionic principal cells but also on the interneurons; the former were already known to be responsible for the generation of slow EPSP, but the latter may be on terminals of dopamine-containing small intensely fluorescent cells and regulate the orthodromic release of dopamine and are to be distinguished from the M2-receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMedDate not supplied

An improved method of evaluation of drug-evoked changes in gastric emptying in mice.

INTRODUCTION: The increased availability of transgenic mice prompts a need for the adaptation to mice of whole-animal assays traditionally performed in larger laboratory animals. Gastric emptying studies are frequently conducted in dogs and rats. Mouse-based gastric emptying models currently available often use inert, nonnutrient liquid meals containing nonabsorbable markers or radionuclides. We have developed a mouse gastric emptying assay that features a favorable throughput and the use of a semisolid, high-calorie meal. METHODS: A carbohydrate- and protein-rich semisolid test meal was prepared from common laboratory reagents. Gastric emptying was determined by subtracting the mass of test meal remaining in the stomach from the mass of test meal administered. A time-course study of basal emptying of a semisolid, paste-like test meal high in carbohydrate and protein from the stomachs of overnight-fasted mice was conducted. Agents known to either inhibit (propantheline, 0.3-10 mg/kg sc; corticotropin-releasing factor [CRF], 3-100 nmol/kg ip) or accelerate (metoclopramide, 1-10 mg/kg ip; bethanechol, 1-30 mg/kg ip) gastric emptying were tested. A single time-point variation of the assay can be used for quickly screening compounds for effects on gastric emptying. RESULTS: In time-course studies, the test meal emptied from the stomach with a half-emptying time of 30.6 min (95% CI: 27.3-34.7). The gastric emptying data were successfully modeled by a two-parameter exponential decay function. No lag phase was observed, indicating that the meal empties from the stomach as a liquid. The anticholinergic agent propantheline increased gastric half-emptying time (t(1/2)) approximately threefold, while metoclopramide decreased gastric half-emptying time approximately twofold compared to basal emptying. Single time-point screening studies correctly detected the gastrokinetic activity of bethanechol and the inhibitory effect of CRF. DISCUSSION: The mouse gastric emptying assay reported here is simple, inexpensive, and not labor-intensive. It is capable of detecting either stimulation or inhibition of gastric motor activity. This assay should prove useful for identifying drug-evoked changes in gastric emptying as well as for assessing the gastric motility effects of altered gene expression in genetically modified mice.

Animal Feed↗
PubMed2000

Mixed nicotinic-muscarinic properties of the alpha9 nicotinic cholinergic receptor.

The rat alpha9 nicotinic acetylcholine receptor (nAChR) was expressed in Xenopus laevis oocytes and tested for its sensitivity to a wide variety of cholinergic compounds. Acetylcholine (ACh), carbachol, choline and methylcarbachol elicited agonist-evoked currents, giving maximal or near maximal responses. Both the nicotinic agonist suberyldicholine as well as the muscarinic agonists McN-A-343 and methylfurtrethonium behaved as weak partial agonists of the receptor. Most classical cholinergic compounds tested, being either nicotinic (nicotine, epibatidine, cytisine, methyllycaconitine, mecamylamine, dihydro-beta-erythroidine), or muscarinic (muscarine, atropine, gallamine, pilocarpine, bethanechol) agonists and antagonists, blocked the recombinant alpha9 receptor. Block by nicotine, epibatidine, cytisine, methyllycaconitine and atropine was overcome at high ACh concentrations, suggesting a competitive type of block. The present results indicate that alpha9 displays mixed nicotinic-muscarinic features that resemble the ones described for the cholinergic receptor of cochlear outer hair cells (OHCs). We suggest that alpha9 contains the structural determinants responsible for the pharmacological properties of the native receptor.

Animals↗
PubMed1995

Affinities of muscarinic drugs for [3H]N-methylscopolamine (NMS) and [3H]oxotremorine (OXO) binding to a mixture of M1-M4 muscarinic receptors: use of NMS/OXO-M ratios to group compounds into potential agonist, partial agonist, and antagonist classes.

The relative affinities of various muscarinic drugs in the antagonist ([3H]N-methyl scopolamine ([3H]NMS)) and agonist ([3H]Oxotremorine-m ([3H]OXO-M)) binding assays using a mixture of tissues containing M1-M4 receptor subtypes have been determined. [3H]NMS bound with high affinity (Kd = 25 +/- 5.9 pM; n = 3) and to a high density Bmax = 11.8 +/- 0.025 nmol/g wet weight) of muscarinic receptors. [3H]OXO-M appeared to bind to two binding sites with differing affinities (Kd1 = 2.5 +/- 0.1 nM; Kd2 = 9.0 +/- 4.9 microM; n = 4) and to a different population of binding sites (Bmax1 = 5.0 +/- 0.26 nmol/g wet weight; Bmax2 = 130 +/- 60 nmol/g wet weight). Well known antagonists exhibited high affinity for [3H]NMS binding but a lower affinity for [3H]OXO-M binding. The opposite was true for acetylcholine and other known agonists. However, pilocarpine and McN-A-343 had similar affinities for sites labeled by both radioligands. Using the ratios of antagonist-to-agonist binding affinities, it was possible to group compounds into apparently distinct full agonist (ratios of 180-665; e.g. carbachol, muscarine, OXO-M, OXO-S and arecoline), partial agonist (ratios of 14-132; e.g. McN-A-343, pilocarpine, aceclidine, bethanechol, OXA-22 and acetylcholine) and antagonist (ratios of 0.22-1.9; e.g. atropine, NMS, pirenzepine, methoctramine, 4-DAMP and p-fluorohexahydrosialo-difenidol) classes. These data suggest that the NMS/OXO-M affinity ratios using a mixture of M1-M4 muscarinic receptors may be a useful way to screen and group a large number of compounds into apparent agonist, partial agonist, and antagonist classes of cholinergic agents.

Animals↗
PubMed2004

Regulation of drug absorption from small intestine by enteric nervous system I: a poorly absorbable drug via passive diffusion.

To investigate the regulation of drug absorption from the small intestine by the enteric nervous system (ENS), the vascular-luminal perfusion study and the in-vitro transport study were performed by employing phenol red as a poorly absorbable model compound. The effect of ENS on the intestinal absorption of phenol red was examined by adding epinephrine, an adrenergic agonist, or bethanechol, a cholinergic agonist into the vascular perfusate in the vascular-luminal perfused rat small-intestine preparation. The viability of the perfused intestine was checked by the recovery of the vascular perfusate, net water flux and absorbability of antipyrine, a well absorbable drug, and it was confirmed that the function of the perfused small-intestine preparation was maintained for at least 1 hr. The effect of epinephrine or bethanechol on the function of the small intestine was recognized as the increase in net water absorption, or the promotion of the water secretion, respectively. These phenomena are ones that are typically observed when adrenergic or cholinergic neuron is stimulated. Then, we investigated the small-intestinal absorption of phenol red in the vascular-luminal perfused preparation. Absorption clearance (CL(abs)) of phenol red was gradually increasing during the perfusion for 1 hr, but the 20-min vascular perfusion with the perfusate containing epinephrine made CL(abs) of phenol red constant and significantly lower than those for control study. Furthermore, after the perfusate was changed with the one without any agonist, again, CL(abs) of phenol red started to increase. These results clearly indicate that the stimulation of adrenergic neuron by epinephrine leads to the decrease in the small-intestinal absorption of phenol red. On the other hand, the vascular perfusion of bethanechol resulted in the increase in CL(abs) of phenol red comparing to the control study. Removing bethanechol from the vascular perfusate decreased CL(abs) of phenol red, again. The in-vitro transport study using the isolated jejunum sheet also showed that epinephrine in the serosal solution significantly decreased the transport of phenol red, which can be ascribed to the paracellular pathway tightened by the action of epinephrine because of the increase in transmucosal electrical resistance (TER). On the other hand, although the effect of bethanechol on both the transport of phenol red and TER was not statistically significant, the transport of phenol red tended to increase and the values of TER are smaller than those of control study.

Animals↗