Effect of bethanechol (urecholine) on gastric acid and nonparietal secretion in normal subjects and duodenal ulcer patients. Comparison with atropine, pentagastrin, and histamine.
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Adult↗
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[Manometry of the rectum end sigmoid in normal subjects. Basal motor activity and after stimulation with bethanechol chloride].
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Adolescent↗
Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol.
Gastroparesis is a relatively uncommon but clinically troublesome disorder that develops in some patients with diabetes mellitus or after gastric operations. Its pathogenesis remains obscure. We used a manometric technique to record pressure changes in fasting patients in the gastric fundus, distal stomach, and adjacent small bowel of patients with severe gastroparesis, asymptomatic diabetic patients, asymptomatic postsurgical patients, and healthy controls. Patients with gastroparesis had normal interdigestive motor cycles (phase III) in the intestine but not in the stomach. Sporadic motor activity in the stomach (phase II) also was markedly reduced. Metoclopramide and bethanecol significantly increased gastric motor activity in these patients, often triggering an intense burst of motor activity in the stomach, similar to phase III. These observations suggest that gastroparesis is a potentially reversible disorder and should encourage further attmpts for pharmacologic control of the syndrome.
Adult↗
The cholinergic and purinergic components of detrusor contractility in a whole rabbit bladder model.
Whole rabbit bladders were suspended in a bath chamber and stimulated with ATP, bethanechol, electrical field stimulation, and bethanechol + ATP. Detrusor pressure and fluid expelled by the bladder were recorded, synchronized, and digitized. Detrusor work and power were calculated with a computer program. Maximum work was 61.4 +/- 28.7, 83.3 +/- 17.0, 85.0 +/- 15.0, 90.8 +/- 13.1 cm. H2O, ml. for ATP, bethanechol, electrical and bethanechol + ATP, respectively. Maximum power generated by ATP was 4.8 +/- 3.0 cm. H2O, ml./sec and was approximately 66% of that generated by bethanechol, and 50% of that generated by electrical stimulation, and bethanechol + ATP. ATP cannot empty the bladder with moderate outlet resistance while bethanechol and electrical stimulation can. Our results suggest that ATP is able to generate detrusor power and achieve work in bladder emptying. However, ATP generated power and work is considerably less than that of electrical stimulation or bethanechol alone. ATP mediated contraction is not inhibited by atropine or tetrodotoxin but is inhibited by P2 purinoceptor desensitization, suggesting a functional role of purine receptors on detrusor smooth muscle. Since ATP generated pressure is more rapid than with bethanechol alone, we support the hypothesis that ATP may be important in the initiation of micturition.
Adenosine Triphosphate↗
Subtypes of muscarinic receptors in pancreatic exocrine secretion in anesthetized dog.
Characterization of muscarinic receptor subtypes on the dog pancreas in situ was examined by using specific muscarinic receptor antagonists to study pancreatic exocrine secretion. Bethanechol caused an increase in pancreatic exocrine secretion, with a high concentration of protein and little effect on bicarbonate concentration. Thus bethanechol may mainly affect the muscarinic receptors of the acinar cells. Bethanechol-stimulated secretion was inhibited by pirenzepine (a specific M1 muscarinic antagonist), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP, a specific M3 muscarinic antagonist), and atropine (a mixed muscarinic receptor antagonist). However, [11-[[2-(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11- dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepine-6-one (AF-DX 116, a specific cardioselective M2 antagonist) did not have any effects on bethanechol-stimulated secretion. Increased protein secretion in pancreatic juice stimulated by bethanechol was significantly inhibited by 4-DAMP and atropine and was suppressed by pirenzepine, but was not modified by AF-DX 116. Bicarbonate concentration was not modified by these antagonists. 4-DAMP, atropine, and pirenzepine caused a progressive parallel rightward shift in the dose-response curve of pancreatic secretion for bethanechol. Schild analysis of the data indicated a pA2 value of 8.7 for 4-DAMP, 7.9 for atropine, and 6.2 for pirenzepine, respectively. Thus 4-DAMP has 7.5 times and 440 times greater potency than atropine and pirenzepine to inhibit bethanechol-stimulated secretion. The slope of the Schild regression line was not different from 1. These results suggest that inhibitions of bethanechol-stimulated pancreatic secretion are competitive for 4-DAMP, atropine, and pirenzepine and that bethanechol-stimulated pancreatic secretion is mediated by M3 muscarinic receptors in dogs.
Animals↗
Signaling mechanisms for muscarinic receptor-mediated coronary vasoconstriction in isolated rat hearts.
Signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in potassium-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonist bethanechol was given by bolus injection or constant infusion. Perfusion pressure was monitored as an indicator of coronary vascular resistance. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, whereas infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Bethanechol-induced phasic vasoconstriction was eliminated by perfusion with a Ca(2+)-free buffer. The L-type voltage-operated Ca(2+) channel blocker nifedipine decreased the maximal constrictor response to bethanechol by 59 +/- 2% (n = 4, P <.001), whereas the putative receptor-operated Ca(2+) channel blocker SK&F 96365 converted this vasoconstriction into vasodilation that was not mediated by nitric oxide. The protein kinase C inhibitor chelerythrine reduced the maximal phasic vasoconstrictor response to bethanechol by 78 +/- 2% (n = 6, P <.001) Bethanechol-induced tonic vasoconstriction was rapidly converted to a sustained vasodilation during infusion of SK&F 96365 or nifedipine, whereas infusion of chelerythrine gradually attenuated the tonic response to bethanechol. Results from other experiments do not support a role for phospholipase A(2)-dependent mediators in generating coronary vasoconstrictor responses to bethanechol. It is concluded that voltage-independent receptor-operated Ca(2+) channels, voltage-operated Ca(2+) channels, and protein kinase C are major signaling components for muscarinic receptor-mediated contraction of rat coronary resistance arteries.
Animals↗
Activation of muscarinic receptors induces a long-lasting enhancement of Purkinje cell responses to glutamate.
The cerebellar cortex contains diffusely distributed cholinergic fibers and both muscarinic and nicotinic receptors. Behavioral studies suggest that an important function of this cholinergic innervation may be to modulate the effects of afferent input to the cerebellar cortex. The present study compared the effects of the muscarinic agonist bethanechol on basal firing rates and on glutamate-evoked firing of Purkinje cells in the vermis of the cerebellum of anesthetized rats. Microiontophoretic application of bethanechol produced a slowly developing, long-lasting enhancement of glutamate-evoked firing which was often disassociated from the bethanechol effect on the basal firing rate. Bethanechol increased the glutamate response of 22/33 Purkinje cells regardless of whether bethanechol increased, decreased or failed to alter the basal firing rate of the cell. The muscarinic antagonist scopolamine prevented the bethanechol-induced increase in the glutamate response. For 7/33 Purkinje cells, bethanechol decreased the glutamate-evoked response. However, this decrease did not appear to be mediated by muscarinic receptors because it was not blocked by scopolamine and it was mimicked by application of the vehicle alone. Acetylcholine application produced a long-lasting increase in the glutamate response of 4/5 Purkinje cells that was similar to the bethanechol effect. These data indicate that the cerebellar cholinergic system exerts a prominent modulatory influence on Purkinje cell excitability by acting through muscarinic receptors.
Acetylcholine↗
The source of calcium for CCK-induced contraction of the guinea-pig gall bladder.
The sources of calcium for cholecystokinin octapeptide (CCK-OP)-induced gallbladder smooth muscle contraction are considered both extracellular and intracellular, but the relative need for intracellular calcium especially at low, physiological concentrations is not clear. To better define the calcium sources responsible for guinea-pig gallbladder contractions in vitro, we inhibited calcium influx using the calcium channel blocker, methoxyverapamil, and a calcium-free Krebs' solution. Availability and release of intracellular calcium stores were depleted by strontium substitution and ryanodine. CCK-OP was compared to bethanechol and potassium chloride (KCl). Preventing calcium influx with 10(-5) M methoxyverapamil depressed the responses to CCK-OP, bethanechol and KCl. Methoxyverapamil, however, had little effect on the time-dependent generation of tension to CCK-OP, but significantly reduced the response to bethanechol and KCl, each at ED50. The duration of the contractile response in the calcium-free Krebs' solution to CCK-OP was longer than that for bethanechol. Strontium (2.5 mM) significantly attenuated the response to CCK-OP and bethanechol, but not to KCl. Ryanodine significantly reduced contractions induced by CCK-OP but not for bethanechol, both at low dose ED25. These results indicate that contraction of the guinea-pig gallbladder induced by CCK-OP, bethanechol and KCl requires extracellular calcium influx. Further, the initiation and maintenance of contraction by CCK-OP and bethanechol necessitates calcium mobilisation from intracellular stores. CCK-OP may have a greater penchant for these calcium stores, particularly at physiological doses.
Animals↗
Effect of prostaglandin E2 on rabbit colonic smooth muscle cell contraction.
Isolated circular smooth muscle cells from the rabbit distal colon were used to study the effect of prostaglandin E2 (PGE2) on bethanechol-stimulated smooth muscle cell contraction. Contraction was expressed as the percentage decrease in mean cell length compared with unstimulated cells. Incubation with different concentrations of PGE2 (10(-10)-10(-6) M) did not cause contraction or relaxation of unstimulated smooth muscle cells. Bethanechol stimulated a dose-dependent contraction that was maximal at 30 s. The threshold for bethanechol-stimulated contraction was 10(-11) M; the ED50 was 10(-10) M; and the maximum contraction (23.0 +/- 1.8%) occurred at 10(-8) M. Preincubation with PGE2 reduced both the efficacy and potency of bethanechol-stimulated contraction. Preincubation with 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or dibutyryl-cAMP reduced the efficacy of bethanechol-stimulated contraction without affecting potency. Increasing concentrations of PGE2 stimulated a dose-dependent increase in the production of intracellular cAMP (P less than 0.05). These studies show that PGE2 inhibits bethanechol-stimulated contraction of isolated colonic circular myocytes and is associated with increased production of intracellular cAMP. There is also a cAMP-independent effect of PGE2 on the potency of bethanechol stimulation.
Animals↗
Muscarinic stimulation and antagonism and glucoregulation in nondiabetic and obese hyperglycemic mice.
Plasma glucose and insulin responses to a muscarinic agonist (bethanechol chloride) and a muscarinic antagonist (atropine) were evaluated in obese C57BL/6J ob/ob mice and in lean C57BL/6J + /? mice. In lean +/? mice, plasma glucose decreased in response to 1 and 2 micrograms/g bethanechol chloride, whereas insulin increased significantly. In ob/ob mice, insulin increased remarkably in response to bethanechol administration (saline, 632 +/- 80 microU/ml; 2 micrograms/g bethanechol chloride, 1794 +/- 97 microU/ml; n = 10), but surprisingly, plasma glucose also rose significantly (saline, 230 +/- 14 mg/dl; 2 micrograms/g bethanechol chloride, 363 +/- 18 mg/dl, n = 10). This exaggerated hyperglycemia in ob/ob mice was not associated with significant changes in plasma glucagon. Furthermore, administration of propranolol hydrochloride did not diminish bethanechol chloride-induced hyperglycemia in ob/ob mice. Administration of atropine (2.5, 5, and 10 mg/kg body wt) induced a significant decrease in plasma insulin without changes in plasma glucose in ob/ob mice, whereas neither plasma insulin nor plasma glucose changed in lean mice. Finally, conversion of [14C]alanine to glucose was increased in ob/ob mice after bethanechol chloride administration, indicating that muscarinic stimulation increases gluconeogenesis in an animal model of type II (non-insulin-dependent) diabetes.
Animals↗
Selective muscarinic sensitivity in perfused pancreata of obese Zucker rats.
Insulin secretion was evaluated in response to the muscarinic agonist, bethanechol, and to the antagonist, atropine, in three-month-old female homozygous lean (Fa/Fa) and obese (fa/fa) Zucker rats, using an in vitro pancreas perfusion. Three doses of bethanechol were used (0.5, 5 or 50 microM). Bethanechol at 50 microM concentration had a significant potentiating effect on glucose-induced insulin secretion in pancreata from both lean and obese rats. There was no effect of atropine (25 microM) on insulin secretion in pancreata from either lean or obese rats. In another study, the perfusate used contained glucose at 75, 125 or 200 mg/dl for the entire 60 min period. Perfusate, with or without bethanechol (50 microM), was infused from 21-40 min, using a side-arm syringe. In general, bethanechol significantly increased insulin secretory rates in both lean and obese rats. Since the pancreas of obese rats secretes more insulin to the same glucose concentration than the pancreas of lean rats, we compared changes in insulin release due to bethanechol in obese and lean rats having comparable basal insulin secretory rates during the 11-20 min period. To produce comparable insulin secretion, glucose levels in the perfusate were kept lower in the obese group (75 mg/dl). In the comparably secreting lean group, a glucose level of 200 mg/dl was required. We also compared changes in insulin secretory rate due to bethanechol stimulation between groups with comparable insulin secretory rates during the 21-40 min period in the control groups, i.e. 75 mg/dl glucose in the obese group vs. 125 mg/dl glucose in the lean group.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
The adverse effect of chocolate on lower esophageal sphincter pressure.
Decreased lower esophageal sphincter (LES) pressure after ingestion of chocolate has been previously noted. We have further evaluated the effect of chocolate on the known ability of gastric alkalinization or bethanechol to increase LES tone. 9 normal subjects were studied using an infused open-tip recording system. Pressure was monitored for a 15-min basal period, and for 60 min after ingestion of 120 ml of chocolate syrup either alone or with the concurrent administration of commercial antacid, oral bethanechol, or subcutaneous bethanechol. After chocolate ingestion, mean basal LES pressure of 14.6 +/- 1.1 (+/-SEM) mm Hg decreased significantly (P less than 0.01) to 7.9 +/- 1.3 mm Hg. An identical LES response occurred when antacid was given with the chocolate dose. Oral bethanechol (25 mg) and chocolate together resulted in lesser decreases in LES pressure. Subcutaneous bethanechol (5 mg) and chocolate produced significant increases (P less than 0.05) in sphincter pressure, although of lesser magnitude than reported with bethanechol alone. These results indicate that the adverse effect of chocolate on the LES is not reversed by gastric alkalinization and suggest that bethanechol in sufficient dose may overcome chocolate-induced decreases in LES pressure.
Adult↗
The use of anxiolytic and parasympathomimetic agents in the treatment of postoperative urinary retention following anorectal surgery. A prospective, randomized, double-blind study.
Approximately 30 percent of patients undergoing anorectal surgery will develop acute urinary retention. The cause of this complication is poorly understood. Anxiety, anal distention, bladder distention as a result of vigorous hydration during surgery, and reflex inhibition of the urinary bladder detrusor muscle secondary to pain have been postulated as contributing factors. A four-armed prospective, double-blind, randomized trial was carried out to determine whether an anxiolytic agent (midazolam, 5 mg intramuscularly) and/or a parasympathomimetic agent (bethanechol, 10 mg subcutaneously) reduce the incidence of postoperative urinary retention following anorectal surgery. One hundred thirty-two patients (ages, 18 to 50 years), in acute urinary retention 6 to 12 hours following anorectal surgery, were enrolled. Sixty-nine percent of patients responded to bethanechol. Side effects were minimal. Midazolam alone had no effect on retention. Bethanechol and midazolam in combination resulted in less retention than midazolam and a placebo (P less than 0.05). Bethanechol alone was better than a placebo (P less than 0.002). Mean intraoperative intravenous fluid volume for the entire study group was 900 cc. Initial postoperative urinary volumes of patients who failed the treatment protocol were significantly higher than in those responding to bethanechol (mean of 527 cc vs. 241 cc, P less than 0.001). The use of an anxiolytic agent was not effective in the treatment of postoperative urinary retention. Bladder distention may increase the incidence of urinary retention. Bethanechol, in a dose of 10 mg subcutaneously, significantly lowered the incidence of postoperative urinary catheterization and should be considered as initial treatment of postoperative urinary retention following anorectal surgery.
Acute Disease↗
Effects of ionophore A23187 and lanthanum on pepsinogen secretion from frog esophageal mucosa in vitro.
The role of Ca2+ in the mediation of pepsinogen secretion from frog esophagus was investigated by means of ionophore A23187 and LaCl3. The esophageal mucosa from Asian bullfrog Rana tigerina was mounted in a double-chamber system to preserve its polarity and was incubated in a medium containing 1.5 mM CaCl2. Pepsinogen secreted was measured and expressed as % of total. The basal secretion averaged 3.5%/h. Bethanechol (25 microM), dibutyryl-cAMP (10 mM), ionophore A23187 (30 microM) and 3-isobutyl-1-methylxanthine (0.1 mM) increased the secretion to 8.7, 7.4, 7.1 and 6.8%, respectively. The stimulatory effect of bethanechol and of dibutyryl-cAMP were not affected by removing the exogenous Ca2+ with EGTA. The basal secretion was, however, reduced by 50% when Ca2+ in the incubation medium was lowered to 20 microM. At this low Ca2+ concentration, ionophore A23187 not only lost its stimulatory effect but also diminished the stimulation caused by bethanechol and dibutyryl-cAMP. While LaCl3 at 1 mM had no effect on basal and bethanechol-stimulated secretion, at 10 mM it abolished the stimulation evoked by bethanechol or dibutyryl-cAMP. The conclusions are: (1) both Ca2+ and cAMP are involved in the mediation of pepsinogen secretion from frog esophagus, (2) basal secretion is dependent on extracellular Ca2+, whereas bethanechol-stimulated secretion is not, (3) in the plasma membranes of peptic cells may exist a distinct Ca2+ pool (La3+-and ionophore A23187-sensitive) which is involved in the stimulated pepsinogen secretion.
1-Methyl-3-isobutylxanthine↗
In vitro intravesical instillation of anticholinergic, antispasmodic and calcium blocking agents (rabbit whole bladder model).
The systemic side effects accompanying oral pharmacotherapy of neurogenic bladder dysfunction present significant drawbacks to this type of therapy. In these studies we investigated the effect of intravesical administration of anticholinergic, antispasmodic and calcium blocking agents on pressure response mediated by field stimulation and bethanechol. We used the rabbit in vitro whole bladder model for these experiments. The bladder from a mature male NZW rabbit was mounted in an organ bath as a whole bladder preparation. After control field stimulation and bethanechol stimulation, 20 ml. of saline containing the specific drug being evaluated was instilled into the bladder. At 30 minute intervals, the responses to field stimulation and bethanechol were determined. Two hours after instillation of 100 microM of each specific drug, the inhibition of the contractile response to bethanechol and field stimulation (as % inhibition) was as follows: oxybutynin (95%/64%), verapamil (85%/81%), atropine (68%/31%), diltiazem (47%/39%), and imipramine (44%/47%). Atropine and oxybutynin suppressed the contractile response of the bladder to bethanechol to a much greater extent than that to field stimulation, while verapamil, diltiazem and imipramine suppressed the contractile response to bethanechol and field stimulation to approximately the same extent. Two hours after drug instillation, the intravesical solution was washed out and replaced with saline, but the recovery of the bladder contraction was slow and incomplete. The results of this study suggest that the use of self-intravesical instillation to suppress bladder contractility should be a good therapeutic approach for patients with neurogenic bladder, especially those who are already managed by intermittent catheterization.
Administration, Intravesical↗
The effects of K+ channel blockers on ovine parotid secretion depend on the mode of stimulation.
The vascularly isolated parotid glands of sheep were submaximally stimulated for 4 min by nerve stimulation, or by infusion of acetylcholine (ACh) or bethanechol directly into the artery supplying the gland. The three modes of stimulation caused almost equal increases in the rate of salivary flow, initial losses of K+ and phosphate from the gland and total glandular deficits of K+ and phosphate. Concurrent arterial infusion of the K+ channel blocker tetraethylammonium (TEA), at 1.5-3.3 mM in blood, almost abolished these responses to bethanechol but did not alter the responses to nerve stimulation or ACh. The responses to bethanechol were restored by increasing the concentration fourfold. Concurrent arterial infusion of 4-aminopyridine (4-AP), at 0.1-2.3 mM in blood, partially inhibited the increase in salivary flow due to bethanechol but not the response to nerve stimulation or ACh. The specificity and competitive nature of the action of TEA and 4-AP on responses to direct muscarinic stimulation by bethanechol are consistent with blockade of K+ channels in secretory end-piece cells. The failure of TEA and 4-AP to inhibit responses to nerve stimulation and ACh may be due to the blocking agents potentiating the release of neurotransmitter ACh. It is also possible that nerve stimulation and ACh may cause the release of a co-transmitter which bethanechol does not.
4-Aminopyridine↗
Mechanism of cholinergic regulation of electrolyte transport in rat colon in vitro.
Cholinergic agonists inhibit sodium and chloride absorption in the intestine and often produce secretion. To determine the mechanism of cholinergic regulation of intestinal electrolyte transport, the effects of bethanechol on ion transport were studied in the rat colon in vitro. The addition of 1 mM bethanechol produced an initially large but short-lived increase in short-circuit current (Isc) (171 +/- 19 microA/cm2). Bethanechol decreased net sodium and net chloride absorption (2.5 +/- 0.5 and 2.9 +/- 0.9 mueq . h-1 . cm-2, respectively) and increased Isc (0.8 +/- 0.3 mueq . h-1 . cm-2) during the steady-state period. All these effects were inhibited by 1 microM atropine, which alone had no effect on ion transport. The removal of either sodium or chloride also inhibited the effect of bethanechol. cAMP content did not increase in isolated enterocytes incubated with bethanechol; however, calcium removal from the serosal bathing solution inhibited the bethanechol-induced changes in ion transport. These results indicate that cholinergic muscarinic agonists alter sodium and chloride transport in the colon by inhibiting coupled NaCl absorption by a calcium-dependent, non-cAMP-mediated process.
Animals↗
Pirenzepine inhibits acid and pepsinogen secretion by the isolated perfused mouse stomach.
Acid and pepsinogen secretion were studied in the isolated luminally perfused mouse stomach. Stimulation was obtained with bethanechol 10(-5)M. Pirenzepine blocked the effect of bethanechol in a dose dependent manner. The minimal blocking dose was 10(-5)M. Atropine 10(-6)M blocked secretion to a similar extent as pirenzepine 10(-5)M. Addition of tetrodotoxin did not change the response to bethanechol or to bethanechol together with pirenzepine. It is concluded that acid and pepsinogen secretion stimulated by bethanechol are inhibited by atropine and pirenzepine. There is at present no evidence that bethanechol stimulation or antimuscarinic inhibition act via intramural nerves.
Animals↗