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PubMedDate not supplied

Functional comparison between nuvenzepine and pirenzepine on different guinea pig isolated smooth muscle preparations.

The antimuscarinic agents nuvenzepine and pirenzepine were tested on four guinea pig isolated smooth muscle preparations in order to better investigate the existence of differences in the functional activities of such antagonists, as suggested by previous reports. The effects of both compounds were compared to those of atropine. Nuvenzepine showed a four-fold higher affinity than pirenzepine in competitively antagonizing acetylcholine-induced contractions on isolated ileal musculature (pA2 = 7.08 +/- 0.15) and on longitudinal ileum dispersed cells (pA2 = 7.11 +/- 0.19). By contrast, unlike pirenzepine which was ineffective, nuvenzepine inhibited histamine-induced ileal motor activity in a dualistic manner, behaving as an irreversible competitive H1 antagonist (pA2 = 5.02 +/- 0.11). Nuvenzepine was almost equipotent to pirenzepine in competitively preventing bethanechol-induced gall-bladder contractions (pA2 = 7.23 +/- 0.16) and it displayed a four-fold higher potency than pirenzepine in blocking vagal-stimulated tracheal constrictions (pIC50 = 6.77 +/- 0.06). Both compounds were definitely less potent than atropine. On the whole, these findings indicate that, on the selected preparations, nuvenzepine substantially shares the antimuscarinic properties of pirenzepine but it is also endowed with a (weak) H1-blocking action. Furthermore, based on some observations, the presence in gallbladder smooth muscle of muscarinic receptors distinguishable from those of ileum could be speculated.

Animals↗
PubMed1986

Action of pirenzepine on the human urinary bladder in vitro.

The novel compound pirenzepine was tested for its antimuscarinic effect on the human urinary bladder "in vitro." Its behavior towards the contractions induced by acetylcholine or bethanechol and towards electrically induced contractions was identical to that of atropine. However, its potency was 100 to 300 times lower than that of atropine. Results obtained with ganglion blocking agents, tetrodotoxin and cooled preparations of urinary bladder seem to indicate the virtually total absence of ganglionic cells. On the other hand they point out the fundamental role of post-synaptic muscarinic M2 receptors as the most important component of the cholinergic system in the bladder. Of course the existence of other transmitters released at the cholinergic nerve endings after electrical field stimulation cannot be excluded on the basis of our experiments.

Acetylcholine↗
PubMed1994

Calcium-dependent photodynamic action of di- and tetrasulphonated aluminium phthalocyanine on normal and tumour-derived rat pancreatic exocrine cells.

Important differences exist in the responses to photodynamic agents of normal and tumour-derived pancreatic acinar cells. In the present study amylase release has been used to assess the mechanisms by which the photodynamic drugs tetra- and disulphonated aluminium phthalocyanine (A1PcS4, A1PcS2) act on pancreatic cells via energy and calcium-dependent activation and transduction pathways. The photodynamic release of amylase was found to be energy dependent and inhibited by the chelation of free cytoplasmic calcium but not by the removal of extracellular calcium. In contrast to their effects on normal acinar cells, the photodynamic action of A1PcS4 and A1PcS2 was to inhibit amylase secretion from pancreatoma AR4-2J cells. Removal of extracellular calcium reversed this inhibitory effect on AR4-2J cells and produced a significant increase in amylase release, but chelation of free cytoplasmic calcium did not affect the inhibitory photodynamic action of the phthalocyanines on amylase release from the tumour cells. Overall, these results demonstrate further important distinctions between the photodynamic action of sulphonated aluminium phthalocyanines on normal versus tumour exocrine cells of the pancreas and indicate that calcium plays an important role in photodynamic drug action, since these agents affected intracellular calcium mobilisation at some distal point in the membrane signal transduction pathway for regulated secretion. Furthermore, the photodynamic inhibition of constitutive secretion in tumour cells may involve a calcium-dependent membrane target site or modulation of membrane calcium channels by activation of protein kinase C.

Amylases↗
PubMed1998

The effects of brucine and alcuronium on the inhibition of [3H]acetylcholine release from rat striatum by muscarinic receptor agonists.

1. Radioligand binding experiments indicate that the affinity of muscarinic receptors for their agonists may be enhanced by allosteric modulators. We have now investigated if brucine can enhance the inhibitory effects of muscarinic receptor agonists on the electrically evoked release of [3H]acetylcholine ([3H]ACh) from superfused slices of rat striatum. 2. The evoked release of [3H]ACh was inhibited by all agonists tested (i.e., furmethide, oxotremorine-M, bethanechol and oxotremorine). 3. Brucine enhanced the inhibitory effects of furmethide, oxotremorine-M and bethanechol on the evoked [3H]ACh release without altering the inhibitory effect of oxotremorine. 4. Alcuronium was applied for comparison and found to diminish the inhibitory effect of furmethide on the evoked [3H]ACh release. 5. The results demonstrate that it is possible both to enhance and diminish the functional effects of muscarinic receptor agonists by allosteric modulators. 6. The direction of the observed effects of brucine and alcuronium on [3H]ACh release fully agrees with the effects of these modulators on the affinities of human M4 receptors for furmethide, oxotremorine-M, bethanechol and oxotremorine, as described by Jakubik et al. (1997). This supports the view that the presynaptic muscarinic receptors responsible for the autoinhibition of ACh release in rat striatum belong to the M4 muscarinic receptor subtype.

Acetylcholine↗
PubMed2001

Secretion of the trefoil factor TFF3 from the isolated vascularly perfused rat colon.

The trefoil factor TFF3 is a peptide predominantly produced by mucus-secreting cells in the small and large intestines. It has been implicated in intestinal protection and repair. The mechanisms that govern TFF3 secretion are poorly understood. The aim of this study was, therefore, to evaluate the influence of neurotransmitters, hormonal peptides and mediators of inflammation on the release of TFF3. For this purpose, an isolated vascularly perfused rat colon preparation was used. After a bolus administration of 1 ml isotonic saline into the lumen, TFF3 secretion was induced by a 30-min intra-arterial infusion of the compounds to be tested. TFF3 was evaluated in the luminal effluent using a newly developed radioimmunoassay. TFF3 was barely detected in crude luminal samples. In contrast, dithiothreitol (DTT) treatment of the effluent revealed TFF3 immunoreactivity, which amounted to about 0.3 pmol min(-1) cm(-1) in the basal state. Gel chromatography of DTT-treated luminal samples revealed a single peak that co-eluted with the monomeric form of TFF3. TFF3 was not detected in the portal effluent. Bethanechol (10(-6)-10(-4) M), vasoactive intestinal peptide (VIP, 10(-8)-10(-7) M) or bombesin (10(-8)-10(-7) M) induced a dose-dependent release of TFF3. In contrast, substance P evoked a modest release of TFF3, whereas calcitonin gene-related peptide (CGRP), somatostatin, neurotensin or peptide YY (PYY) did not modify TFF3 secretion. The degranulator compound bromolasalocid, 16,16-dimethyl PGE2 (dmPGE2) or interleukin-1-beta (IL-1-beta) also evoked a marked release of TFF3. In conclusion, TFF3 in the colonic effluent is present in a complex. This association presumably involves a disulfide bond. Additionally, the present results suggest a role for enteric nervous system and resident immune cells in mediation of colonic TFF3 secretion.

16,16-Dimethylprostaglandin E2↗
PubMed1997

Cholinergic modulation of electrogenic ion transport in different regions of the rat small intestine.

Acetylcholine acting via muscarinic receptors located in the intestinal mucosa controls ion and fluid transport. This study examined the pathway(s) by which cholinergic receptors mediate secretion in rat isolated duodenum, jejunum and ileum using the short-circuit current (Isc) as an index of electrogenic CL- secretion. Carbachol and bethanechol induced electrogenic CL- transport which was insensitive to the neural blocker tetrodotoxin, indicating their direct action on the enterocytes. Functional characterization of electrogenic secretion activated via muscarinic receptors on jejunal and ileal enterocytes was achieved by use of selective muscarinic antagonists in the presence of tetrodotoxin. In both regions the rank order of potency of these compounds (atropine > 4-diphenylacetoxy-N-piperidine methiodide (4-DAMP) > hexahydro-sila-difenidol (HHSiD) > pirenzepine > methoctramine) indicated the M3 receptor subtype. Secretion activated by the muscarinic agonist 4-[[(3-chlorophenyl)amino]carbonyl]-N,N, N-trimethyl-2-butyn-1-ammonium chloride (McN-A-343) was sensitive to tetrodotoxin and pirenzepine but not to the ganglionic blocker, hexamethonium, indicating the M1 receptor subtype on post ganglionic neurons. Regional differences for bethanechol-activated secretion showed an increasing gradient in secretory capacity (Isc max) in a proximal-to-distal direction along the small intestine. Responses to McN-A-343 also showed regional differences but these were unlike those of bethanechol. These results show that cholinomimetic-induced electrogenic CL- secretion in rat isolated small intestine appears to be mediated by two dissimilar populations of muscarinic receptor: M3 muscarinic receptors positioned on enterocytes and M1 muscarinic receptors sited on submucosal neurons.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed2005

Effects of the selective acetylcholinesterase inhibitor TAK-802 on the voiding behavior and bladder mass increase in rats with partial bladder outlet obstruction.

PURPOSE: We examined the effects of the selective acetylcholinesterase (AChE) inhibitor TAK-802 on voiding behavior and residual urine volume in rats with partial bladder outlet obstruction (BOO) vs rats treated with the nonselective AChE inhibitor distigmine and the muscarinic agonist bethanechol. In addition, the effect of repeat doses of TAK-802 on the bladder mass increase associated with BOO was also examined. MATERIALS AND METHODS: Male rats with BOO were used. Six to 8 days after obstruction voiding behavior was observed in a metabolic cage. The animals were then treated orally with 1 drug, and voiding frequency and urine volume at each void were measured for 3 hours. Subsequently the volume of urine retained in the bladder (residual urine) was measured. In another experiment bladder weight in rats with BOO was measured after early repeat doses of TAK-802. RESULTS: BOO increased voiding frequency and decreased average voided volume. TAK-802 and distigmine increased average voided volume, while not causing any change in voiding frequency. On the other hand, bethanechol increased voiding frequency without affecting average voided volume. While all 3 drugs significantly decreased residual urine volume, TAK-802 was most efficacious. In addition, bladder weight in the control BOO group was greater (approximately 2.2-fold) than that in the sham operated group and early repeat administration of TAK-802 prevented the bladder mass increase. CONCLUSIONS: AChE inhibitors decreased residual urine volume by restoring voiding function in rats with BOO, although only the effect of TAK-802 was dose dependent. Bethanechol also decreased residual urine volume in a dose dependent manner but by increasing voiding frequency. The prevention of a bladder mass increase by TAK-802 treatment may be attributable to its effect on restoring voiding.

Administration, Oral↗
PubMed2000

Release of guanylin immunoreactivity from the isolated vascularly perfused rat colon.

The intestinal peptide guanylin regulates the electrolyte/water transport in the intestinal epithelium. The aim of the present study was to investigate the mechanisms that modulate its secretion in the isolated vascularly perfused rat colon by using a specific guanylin RIA. Intraarterial infusion of bethanechol (10(-4) M) or bombesin (10(-7) M) elicited a significant 6-fold increase in the release of guanylin immunoreactivity (G-IR) in the lumen. Bombesin-stimulated G-IR secretion was strongly reduced by tetrodotoxin, whereas atropine had no effect. VIP (10(-7) M) induced a moderate release of G-IR, whereas substance P, calcitonin gene-related peptide, peptide YY, somatostatin, and neurotensin were without effect. Dimethyl-PGE2 (1.4 x 10(-5) M) or interleukin-1beta (2.5 x 10(-10) M) induced a 3-fold increase in G-IR in the lumen, whereas the degranulator compound bromolasalocid did not stimulate guanylin secretion. Forskolin (10(-5) M) or sodium nitroprusside (10(-4)-10(-3) M) induced a significant release of G-IR. In contrast, PMA (10(-7) M) or ionophore A23187 (10(-6) M) did not modify basal secretion of G-IR. Upon stimulation of guanylin release with bombesin or bethanechol, an increase in G-IR in the portal effluent was also detected. The release of G-IR in the portal effluent was 40-fold lower than that of G-IR into the luminal perfusate. Additionally, analysis with gel chromatography revealed that the immunoreactive material released in the lumen or in the portal effluent coeluted with the 15-amino acid peptide originally isolated from rat intestine. In conclusion, the present data suggest that the enteric nervous system and immune cells may modulate guanylin release from the rat colon. The release of guanylin in the lumen and portal effluent suggests that this peptide may exert both luminal/paracrine and hormonal effects.

Animals↗
PubMed1998

Regulation of the choline transport system in superfused microcarrier cultures of BeWo cells.

BeWo choriocarcinoma cells were cultured onto solid microcarrier beads, packed into syringe barrels and superfused. The unidirectional choline uptake across the microvillous membrane of the cells was measured by a rapid single-circulation paired-tracer dilution procedure using methyl[3H]choline with D-[14C]mannitol as the extracellular reference molecule. Choline influx was saturable with a K(t) of 214+/-15 microM and a V(max) of 45.29+/-0.94 nmol/min/mg of cell protein. Uptake of labelled choline was partially inhibited by nicotine, strongly inhibited by hemicolinium-3, and was reduced by about 50 per cent in sodium-free perfusates. A range of agents was added to the stirrer flasks 24 h prior to the experiments to determine if intracellular or extracellular levels of choline or its metabolic product, acetylcholine, regulated choline uptake. Pre-incubation with 2 mM choline reduced the choline maximal uptake by half, while pre-incubation with 100 microM alpha-NETA [2-(alpha-naphthoyl)ethyltrimethyl-ammonium] reduced the influx by 77 per cent. Choline influx was also reduced to about half in the presence of 100 microM vesamicol, bethanecol or neostigmine. It is concluded that BeWo cells possess a choline transporter similar to that described in isolated cytotrophoblasts and syncytiotrophoblast microvillous membrane preparations, and that uptake appeared to be regulated by both intracellular and extracellular concentrations of choline and acetylcholine. Therefore, these cells provide a novel model for studying the role of acetylcholine in human placenta.

Bethanechol↗
PubMed1997

Colonic mucin discharge by a cholinergic agonist, prostaglandins, and peptide YY in the isolated vascularly perfused rat colon.

UNLABELLED: The model of the isolated, vascularly perfused rat colon was assessed in the present study to investigate the nervous, hormonal, and local/paracrine pathways involved in colonic mucin secretion. A colonic loop was perfused via the superior mesenteric artery with a Krebs-Henseleit buffer containing 25% washed bovine erythrocytes at a rate of 2.5 ml/min. After a 10-min control period, each compound to be tested was infused intra-arterially for 30 min. Tissue samples from the proximal and midsegments of the perfused rat colon were then fixed and stained for mucus cell count. Intra-arterial administration of bethanechol evoked a concentration-dependent decrease in the number of stained mucus cells per crypt section over the range 2 x 10(-6) to 2 x 10(-4) M: 16.6 +/- 1.4 stained mucus cells per crypt in the midportion of the perfused rat colon (n = 5) with bethanechol 2 x 10(-4) M versus 28.8 +/- 1.5 for controls (n = 6). After infusion of 1.25 and 2.5 microM 16,16-dimethyl prostaglandin E2 (dmPGE2), the number of stained mucus cells per crypt section was significantly reduced: 21.6 +/- 0.6 (n = 6) and 20.6 +/- 1.4 (n = 7), respectively. An increase in the number of cavitated mucus cells was also observed (22.1 +/- 6.7 and 38.5 +/- 4.1% of cavitated mucus cells in the midsegment of the perfused rat colon with 1.25 and 2.5 microM dmPGE2, respectively, vs. 12.3 +/- 4.1% for controls). In contrast, prostaglandin F2alpha did not significantly affect mucus discharge from colonic cells. Peptide YY (10(-10), 10(-9) and 10(-8) M) induced a dose-dependent increase in the percentage of cavitated mucus cells (16.7 +/- 2.8, 23.1 +/- 4.2, and 31.2 +/- 3.4% of cavitated mucus cells in the midsegment, respectively). The proximal and midsegments of the perfused rat colon were equally sensitive to each secretagogue. CONCLUSION: In the isolated, vascularly perfused rat colon, mucus cells strongly respond to the well-known mucin secretagogues, bethanechol and dmPGE2. This approach has already led to the identification of a novel stimulant of mucin secretion: peptide YY. Our ex vivo model, in which goblet cells are submitted to well-defined luminal and blood-borne stimuli is, therefore, reliable to investigate the nervous, hormonal, and local/paracrine pathways involved in the colonic mucin secretion.

Animals↗
PubMed1985

Cimetropium: characterization of antimuscarinic and spasmolytic properties.

Cimetropium displaced 3H-NMS binding from membranes derived from gastrointestinal smooth muscle. The affinity of cimetropium for intestinal muscarinic receptors was in the range 70-100 nM. The competitive antagonism of cimetropium was demonstrated in guinea-pig ileum and taenia coli stimulated by bethanechol. Comparing pA2 values, cimetropium (8.19 and 7.91, resp.) was 0.3 times as potent as atropine (8.52 and 8.41, resp.). Cimetropium displayed strong inhibitory effects towards BaCl2 and 5-hydroxytryptamine induced contractions of the guinea-pig ileum. The compound was devoid of antihistaminic or Ca++ channel blocking activity. A binding study performed in vivo confirmed the ability of i.v. cimetropium to displace 3H-N-methylscopolamine binding from muscarinic receptors in peripheral organs. In addition, when injected into ileal loops, cimetropium displaced 3H-NMS binding solely from the surrounding tissue of the loop, indicating a topical effect of the compound.

Animals↗
PubMed1995

Selective blockade of M2 and M3 muscarinic receptors by hexahydrobenzyl-fourdapine and a comparison with zamifenacin.

1. 4-Diphenylacetoxy-N-cyclohexylmethyl-piperidine HCl (hexahydro-benz-4DAP) is more active as an antagonist of carbachol at receptors in guinea-pig isolated ileum, log K (pA2) = 6.64 +/- 0.14 (s.e. 7 results), than at receptors in guinea-pig isolated atria, log K = 5.43 +/- 0.14 (7). In the presence of neostigmine bromide (0.2 microM) the value for atria was 5.62 +/- 0.19 (4), so the lower activity on atria cannot be attributed to hydrolysis of the compound by cholinesterases present in this tissue. 2. The limit of solubility of the free base in Krebs solution (pH 7.6) is about 50 microM for both hexahydrobenz-4DAP and benzyl-fourdapine (benz-4DAP). 3. In experiments on guinea-pig isolated ileum with hexahydro-benz-4DAP given together with 4-DAMP methobromide, the combined dose-ratio was consistent with competition: similar results were obtained with benz-4DAP. 4. In rats anaesthetized with pentobarbitone, hexahydro-benz-4DAP antagonized the effects of bethanechol on blood-pressure in doses that had little effect on heart rate or airflow. There was a limit to the effect which could be obtained, however, and the slopes of the Schild plots were less than one. The effects on rat blood-pressure had a half-life of at least 30 min. 5. In similar experiments with zamifenacin the slopes of the Schild plots were close to 1 and the compound was 10 to 20 times as active on blood-pressure at it was on heart-rate. 6. The limited solubility of the base probably accounts for the flat Schild plots obtained with hexahydro-benz-4DAP, which had about 10 fold selectivity for effects on blood-pressure and was more active than expected from tests on isolated ileum.

Animals↗
PubMed1991

The pharmacology of cholinoceptors on the somatic muscle cells of the parasitic nematode Ascaris suum.

1. Acetylcholine (ACh) elicited depolarization and an increase in input conductance of the somatic muscle cells of the parasitic nematode Ascaris suum. 2. The relative potency of nicotinic and muscarinic agents was studied in this preparation. The order of potency of these compounds was metahydroxy-phenylpropyltrimethylammonium (HPPT) greater than 1.1 dimethyl-4-phenylpiperazinium (DMPP) greater than ACh greater than carbachol greater than nicotine greater than tetramethylammonium (TMA+) greater than muscarone greater than furtrethonium greater than arecoline. Decamethonium was also a weak agonist. McN-A-343 elicited a very weak depolarization at concentrations above 1 mmol l-1. Bethanechol and methacholine were without effect up to 1 mmol l-1. Pilocarpine and muscarine elicited a slight hyperpolarization of up to 3 mV with a threshold for the response of around 500 mumol l-1. Oxotremorine (1 mmol l-1) was without effect. 3. The nitromethylene insecticide 2(nitromethylene)tetrahydro 1,3-thiazine (NMTHT), an agonist at insect nicotinic receptors, was without effect on Ascaris muscle cells up to 1 mmol l-1. 4. Mecamylamine and benzoquinonium were the most potent antagonists of the acetylcholine response. The order of potency of the other antagonists was tetraphenylphosphonium (TPP) greater than quinacrine greater than pancuronium, curare greater than trimethaphan greater than atropine greater than chlorisondamine, decamethonium greater than hexamethonium greater than dihydro-beta-erythroidine. 5. The agonist profile of the Ascaris muscle cell ACh receptor clearly indicates that it is nicotinic. The potency of ganglionic and neuromuscular nicotinic receptor antagonists in Ascaris does not enable a further subclassification of this nicotinic receptor. The Ascaris nicotinic receptor seems to possess some of the pharmacological properties of each type of vertebrate nicotinic receptor. The pharmacology of the Ascaris nicotinic receptor is discussed in relation to that of nicotinic receptors in other invertebrate preparations and in vertebrate preparations.

Acetylcholine↗
PubMed1995

Whole-cell and perforated patch recordings of four distinct K+ currents in acutely dispersed coeliac-superior mesenteric ganglia neurons of adult rats.

Properties and modulation of outward membrane currents in sympathetic neurons acutely dispersed from coeliac-superior mesenteric ganglia (C-SMG) of adult rats were examined using both the whole-cell variant of the patch-clamp technique and the perforated patch approach. Under voltage-clamp, four distinct outward currents were observed: a transient outward current (IA), a voltage-dependent sustained outward current consisting of a Ca(2+)-dependent component (IKCa) and a Ca(2+)-insensitive component (IKV), and a muscarinic agonist-sensitive outward current (IM). IA was isolated by digital subtraction, and characterized by very rapid activation at potentials more positive than -60 mV and by fast and complete voltage-dependent inactivation. Half inactivation potential (Vh) and slope factor (K) were -76 mV and 8.3 mV, respectively. IA was not affected by removal of external Ca2+, 1 mM tetraethylammonium ions, muscarinic agonists, or 8-bromo-cyclic AMP, but was suppressed by 4-aminopyridine (1 mM). Depolarizing pulses from of a holding potential of -50 or -60 mV to potentials more positive than -25 mV concomitantly activated two, independent sustained outward currents which decayed slowly; one exhibited voltage-dependent activation similar to the delayed rectifier current (IKV) and the other being triggered by Ca2+ influx into the cell (IKCa). The addition of tetraethylammonium ions (1 mM) strongly reduced the amplitude of the sustained outward currents. IM was characterized as a noninactivating time- and voltage-dependent outward current which activated at membrane potentials more positive than -60 mV and slowly turned off when the membrane was hyperpolarized back to -60 mV, and was suppressed by muscarinic agonists. The rank order of potency of the agonists tested was: oxotremorine > muscarine > bethanechol.

4-Aminopyridine↗
PubMed2004

Combination of a cholinergic drug and an alpha-blocker is more effective than monotherapy for the treatment of voiding difficulty in patients with underactive detrusor.

AIM: The aim of the present study was to compare the effectiveness of a cholinergic drug, an alpha-blocker and combinations of the two for the treatment of underactive detrusor. METHODS: One hundred and nineteen patients with underactive bladder were assigned to three groups: the cholinergic group, consisting of 40 patients taking bethanechol chloride (60 mg/day) or distigmine bromide (15 mg/day); the alpha-blocker group, consisting of 38 patients taking urapidil (60 mg/day); and the combination group, consisting of 41 patients taking both a cholinergic drug and an alpha-blocker. The effectiveness of each therapy was assessed 4 weeks after initialization of the therapy. RESULTS: Total urinary symptom scores (International Prostate Symptom Score, IPSS) remained unchanged after the cholinergic therapy, but were significantly lower after the alpha-blocker treatment (P = 0.0001) and the combination therapy (P = 0.0001). With regard to the total IPSS, there were significant differences between the cholinergic and the alpha-blocker groups (P = 0.0008), and also between the cholinergic and combination groups (P = 0.0033), in favor of the latter. The average and maximum flow rates did not increase significantly after monotherapy with either the cholinergic drug or the alpha-blocker, but they significantly increased after combination therapy compared to baseline values (P = 0.0033 and P= 0.0004, respectively). Postvoid residual volume did not decrease significantly after the cholinergic drug therapy, but decreased significantly after the alpha-blocker (P = 0.0043) and the combination therapies (P = 0.0008). The percentage of residual urine decreased significantly after therapy in all groups (P = 0.0005, P= 0.0176 and P= 0.0001, respectively). CONCLUSION: Combination therapy with a cholinergic drug and an alpha-blocker appears to be more useful than monotherapy for the treatment of underactive detrusor.

Administration, Oral↗
PubMed1993

Mediation of anaphylaxis-induced jejunal circular smooth muscle contraction in rats.

Altered intestinal motility and diarrhea are features of food protein-induced intestinal anaphylaxis in the conscious rat. These experiments were performed to determine the mediator(s) responsible for jejunal circular smooth muscle contraction during this response. Hooded-Lister rats were sensitized by intraperitoneal injection of 10-micrograms egg albumin, and controls were sham-sensitized with saline. Fourteen days later the contractility of the circular muscle in jejunal segments (mucosa intact) was examined in standard tissue baths in response to antigen (Ag) or other agents. While control and sensitized tissues contracted in similar fashion in response to stretch, bethanechol, histamine, or 5-hydroxytryptamine (5HT), Ag contracted only the segments of sensitized animals. The contractile response was: (1) specific to the sensitizing Ag, as bovine serum albumin did not induce contraction and (2) could be passively transferred with serum containing specific immunoglobulin E antibody (IgE-Ab). Concanavalin A, which degranulates both mucosal and connective tissue-type mast cells, and compound 48/80, which degranulates only connective tissue-type mast cells produced contractile responses. Ag-induced contraction was significantly inhibited by the mucosal and connective tissue-type mast cell stabilizer doxantrazole, but not the connective tissue mast cell stabilizer disodium cromoglycate. Diphenhydramine and cimetidine together significantly inhibited histamine-induced contraction, but failed to effect the Ag-induced contraction in sensitized tissues. While the contractile response to 5HT was reduced in the presence of methysergide (5HT1-receptor antagonist), cinanserin (5HT2-receptor antagonist), and ICS 205-930 (5HT3-receptor antagonist), only cinanserin significantly inhibited the contractile response to Ag. Indomethacin significantly inhibited Ag-induced contraction. Ag-induced contraction was resistant to atropine and tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis↗
PubMed1976

Effects of cholinergic stimulation on human esophageal peristalsis.

The effects of cholinergic stimulation on esophageal peristalsis were studied in normal subjects. An intraesophageal transducer assembly was used to measure the dynamics of esophageal peristalsis before and after edrophonium chloride, 80 mug/kg intravenously. Following endrophonium, there was a marked increase in amplitude of esophageal persistalsis associated with a significant reduction in velocity of esophageal peristalsis and a significant increase in width and time of appearance of the contraction wave following a swallow. Graded doses of endrophonium all resulted in significant increases in peristaltic amplitude with the maximal response occurring at doses of 80 and 160 mug/kg. Similar results were obtained with a more direct-acting cholinergic agent, bethanechol, 80 mug/kg subcutaneously. The relevance of these results as an indication of the importance of cholinergic innervation in regulating esophageal motility are discussed.

Adult↗
PubMed1975

The lower esophageal sphincter. Physiologic and clinical aspects.

Current concepts in physiology and pathophysiology of lower esophageal sphincteric mechanism are reviewed. With recent advances in manometric method for more accurate in-vivo human studies combined with in-vivo and in-vitro studies in animal models, there is much information regarding function of this sphincter. Three components of sphincter control have been identified: specialized circular smooth muscle at esophagogastric junction, autonomic nervous system, and probable physiology effects of gastrointestinal hormones, particularly gastrin. Clinical syndromes of sphincteric dysfunction have been identified relative to these three controlling elements. Foods and drugs that adversely effect sphincter pressure have been identified and indicate that anticholinergic agents, fatty foods, chocolate, alcohol, and cigarette smoking may have a harmful effect on a patient with heartburn. Drugs that increase the antireflux sphincter barrier have been studied. Clinical effectiveness of antacids and bethanechol in therapy of heartburn is supported by controlled treatment trials. Research continues on other medications producing increases in sphincter pressure.

Anemia, Pernicious↗