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Bethanechol chloride is a cholinergic agent used to treat acute postoperative and postpartum nonobstructive (functional) urinary retention and for neurogenic atony of the urinary bladder with retention. It is available in the United States as tablets for oral administration in four dosage strengths: 5 mg, 10 mg, 25 mg, and 50 mg. A review of the therapeutic uses of bethanechol chloride reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of bethanechol chloride currently exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded bethanechol chloride suspensions using two brands of commercially available tablets (Amneal and Upsher-Smith) in the PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two bethanechol chloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating ultra-high-performance liquid chromatographic assay for the determination of the chemical stability of bethanechol chloride in PCCA SuspendIt was validated. Suspensions of bethanechol chloride were prepared from the tablets in PCCA SuspendIt at 1-mg/mL and 5-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at room temperature (25°C). Samples were assayed initially, and on the following time points (days): 14, 30, 60, 90, and 180. Physical data such as pH and appearance were also noted. Microbiological stability was tested. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. Using this criterion, no significant degradation of the bethanechol chloride was observed over the 180-day test period for either concentration at room temperature. Drug concentrations were at, or above 93% of initial values for both brands of commercially available tablets. No microbial growth was observed. pH values remained fairly constant. This study demonstrates that bethanechol chloride tablets are physically, chemically, and microbiologically stable in PCCA SuspendIt for 180 days at room temperature at both concentrations studied, thus providing a viable, compounded alternative for bethanechol chloride in a liquid dosage form, with an extended BUD to meet patient needs., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Purpose: Few medical treatment options exist for detrusor underactivity or urinary retention in women. Bethanechol, a cholinergic agonist, may improve detrusor contractility in these conditions; however, its clinical efficacy is limited. We sought to examine the patterns of Bethanechol use by physicians in an ambulatory care setting using a national database to determine if it is still prescribed for patients with bladder dysfunction., Materials and Methods: The National Ambulatory Medical Care Survey (NAMCS) database was queried for a sample of patient visits to office-based physicians from 2003-2013. Visits were included for women aged 18 years or older with diagnosed lower urinary tract symptoms (LUTS), neurogenic bladder, or urinary retention based on ICD-9-CM codes. Visits in which Bethanechol was prescribed were analysed with descriptive statistics. Sampling weights were adjusted for nonresponders to yield an unbiased national estimate of ambulatory care visits., Results: Out of a weighted sample of 17 321 630 included patient visits, 132 281 (0.8%) visits included a prescription for Bethanechol. Patients prescribed Bethanechol had a mean age of 62.3 ± 2.1 and were predominantly Caucasian (67%) followed by African American (18%). The primary diagnosis associated with Bethanechol was atony of bladder (35%), urinary retention (20%), neurogenic bladder (18%), urinary incontinence (16%), and incomplete bladder emptying (10%). Visits were primarily for chronic conditions (63%). It was typically prescribed as a continued medication (79%) most often by urologists (92%) followed by internal medicine clinicians (8%)., Conclusions: Bethanechol continues to be prescribed in elderly women primarily for detrusor atony, urinary retention, or incomplete bladder emptying., (© 2018 John Wiley & Sons Ltd.)

Airway hyperreactivity is a hallmark feature of asthma and can be precipitated by airway insults, such as ozone exposure or viral infection. A proposed mechanism linking airway insults to airway hyperreactivity is augmented cholinergic transmission. In the current study, we tested the hypothesis that acute potentiation of cholinergic transmission is sufficient to induce airway hyperreactivity. We atomized the cholinergic agonist bethanechol to neonatal piglets and forty-eight hours later measured airway resistance. Bethanechol-treated piglets displayed increased airway resistance in response to intravenous methacholine compared to saline-treated controls. In the absence of an airway insult, we expected to find no evidence of airway inflammation; however, transcripts for several asthma-associated cytokines, including IL17A, IL1A, and IL8, were elevated in the tracheas of bethanechol-treated piglets. In the lungs, prior bethanechol treatment increased transcripts for IFNγ and its downstream target CXCL10. These findings suggest that augmented cholinergic transmission is sufficient to induce airway hyperreactivity, and raise the possibility that cholinergic-mediated regulation of pro-inflammatory pathways might contribute.

Unlabelled: Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans., Trial Registration: ClinicalTrials.gov NCT01434901.

Objective: To re-examine the function of the urinary bladder in vivoas well as to determine the functional and biochemical characteristics of bladder muscarinic receptors in long-term alloxan-induced diabetes rats., Methods: Two-month-old male Wistar rats were injected with alloxan and the animals showing blood glucose levels >300mg/dL together with age-paired untreated animals were kept for 11 months. Body weight, bladder weight, blood glucose, and urinary volume over a period of 24 hours were determined in both groups of animals. A voiding cystometry in conscious control and diabetic rats was performed to determine maximal micturition pressure, micturition contraction interval and duration as well as voided and post-voiding residual volume. In addition, concentration-response curves for bethanechol in isolated bladder strips, as well as [3H]-N methyl-scopolamine binding site characteristics in bladder homogenates were determined., Results: Mean bladder weight was 162.5±21.2mg versus 290±37.9mg in control and treated animals, respectively (p<0.05). Micturition contraction amplitude (34.6±4.7mmHg versus 49.6±2.5mmHg), duration (14.5±1.7 seconds versus 23.33±4.6 seconds) and interval (87.5±17.02 seconds versus 281.11±20.24 seconds) were significantly greater in alloxan diabetic rats. Voided urine volume per micturition contraction was also significantly higher in diabetic animals. However the post-voiding residual volume was not statistically different. Bethanechol potency (EC50 3µM versus 5µM) and maximal effect (31.2±5.9g/g versus 36.1±6.8g/g) in isolated bladder strips as well as number (169±4fmol/mg versus 176±3fmol/mg protein) and affinity (0.69±0.1nM versus 0.57±0.1nM) of bladder muscarinic receptors were also not statistically different., Conclusion: Bladder function in vivo is altered in chronic alloxan-induced diabetes rats without changes in functional and biochemical characteristics of bladder muscarinic receptors.

Objectives: We studied a case series to evaluate the effect of topical bethanechol chloride on esophageal function in individuals with ineffective esophageal motility., Methods: Five subjects with ineffective esophageal motility underwent high resolution esophageal manometry. Ten 5 mL liquid swallows were performed to establish a baseline. Five milligrams of topical bethanechol was then administered. After 10 minutes, the subjects completed 10 additional liquid swallows. This procedure was repeated with 10 mg of bethanechol in 4 subjects., Results: After administration of 5 mg of topical bethanechol, the mean (+/- SD) distal contractile integral, an index of esophageal contractility, increased from 178.3 +/- 83.1 mm Hg x s x cm to 272.3 +/- 216.9 mm Hg x s x cm (p = 0.69). The percentage of failed swallows decreased from 52.8% +/- 33.2% to 29.4% +/- 18.3% (p = 0.14). The percentage of peristaltic swallows increased from 28.0% +/- 26.8% to 67.2% +/- 15.3% (p = 0.04). The contractile front velocity was essentially unchanged. After administration of 10 mg of bethanechol,the distal contractile integral decreased from 349.3 +/- 371.0 mm Hg x s x cm to 261.8 +/- 293.5 mm Hg x s x cm (p = 0.72). The percentage of failed swallows increased from 57.5% +/- 37.7% to 66.8% +/- 24.9% (p = 0.46). The percentage of peristaltic swallows increased from 17.5% +/- 23.6% to 28.3% +/- 19.1% (p = 0.29). The contractile front velocity decreased from 11.6 +/- 5.2 cm/s to 4.9 +/- 3.0 cm/s (p = 0.32). No adverse side effects occurred., Conclusions: The results of this pilot study support the need for further investigation with larger sample sizes and dose escalation.

Aim: Our aim was to determine mechanisms of action of the gasotransmitter hydrogen sulfide (H(2)S) on contractile activity in circular muscle of rat jejunum., Methods: Jejunal circular muscle strips were prepared to measure isometric contractions. Effects of sodium hydrosulfide (NaHS), a H(2)S donor, were evaluated on spontaneous contractile activity and after pre-contraction with bethanechol. L-cysteine was evaluated as an endogenous H(2)S donor. We evaluated extrinsic nerves, enteric nervous system, visceral afferent nerves, nitric oxide, K(ATP)+ and K(Ca)+ channels, and myosin light chain phosphatase on action of H(2)S using non-adrenergic/non-cholinergic conditions, tetrodotoxin, capsaicin, L-N(G)-nitro arginine (L-NNA), glibenclamide, apamin, and calyculin A, respectively, and electrical field stimulation (EFS)., Results: NaHS dose-dependently and reversibly inhibited spontaneous and bethanechol-stimulated contractile activity (p < 0.05). L-cysteine had a dose-dependent inhibitory effect. Non-adrenergic/non-cholinergic conditions, tetrodotoxin, capsaicin, L-NNA, or apamin had no effect on contractile inhibition by NaHS; in contrast, low-dose glibenclamide and calyculin A prevented NaHS-induced inhibition. We could not demonstrate H(2)S release by EFS., Conclusions: H(2)S inhibits contractile activity of jejunal circular muscle dose-dependently, in part by K(ATP)+ channels and via myosin light chain phosphatase, but not via pathways mediated by the extrinsic or enteric nervous system, visceral afferent nerves, nitric oxide, or K(Ca)+ channels.

Acute pandysautonomia is a rare disease defined as acute widespread and severe sympathetic and parasympathetic failure and sparing of somatic nerve fibers. The causes of this syndrome are often an autoimmune disease leading to autonomic ganglionopathy. The majority of cases have a poor prognosis with a chronic debilitating course. We present a previously healthy 24-year-old female patient, who developed a loss of accommodation, pupillotonia, lacrimation, swallowing disturbances, gastrointestinal symptoms and an atonic bladder with 750 ml residual volume. The Ewing battery showed signs of parasympathetic and sympathetic dysfunction leading to the diagnosis of acute pandysautonomia. Further tests failed to find a cause of acute neuropathy especially where there was no evidence for paraneoplastic or infectious etiology. The patient was treated with high dose intravenous prednisolone and completely recovered.

Background: Bethanechol chloride is considered as a treatment in patients with high postvoid residual urine (PVR). It enhances detrusor muscle contraction, resulting in higher maximum flow rate, higher detrusor pressure at maximum flow, and lower PVR. The efficacy of this agent in patients after radical hysterectomy is unclear. We aim to evaluate the efficacy of bethanechol chloride compared with placebo for the prevention of bladder dysfunction after type III radical hysterectomy., Methods: Gynecologic cancer patients who underwent type III radical hysterectomy were randomized by computer-generated schedule to assign patients in a 1:1 ratio into 2 groups. The treatment group received bethanechol chloride (Ucholine 20 mg 3 times a day on the third to seventh postoperative day), and the control group received placebo. Patients and physicians were masked to treatment allocation. The primary end point was the rate of urethral catheter removal at 1 week postoperatively. If PVR was more than 30% of voided volume, the urethral catheter was reinserted, and medication would be continued but not for more than 1 month. This study was registered as ISRCTN92687416., Findings: There were 31 patients in each group without significant difference in baseline characteristics. Twenty-one patients (67.7%) in the treatment group and 12 patients (38.7%) in the control group had the urethral catheter removed at 1 week postoperatively (P = 0.04). Median duration of urethral catheterization was shorter in the treatment group (7 and 14 days, P = 0.03). However, the PVR and the incidence of urinary tract infection at 1 month postoperatively were not significantly different. Nine patients (29%) in the treatment group had adverse events such as nausea, abdominal distension, and abdominal cramping, which was higher than the control group (1 patient, 3.2%; P = 0.01). However, no patients required any medical treatments., Conclusions: Bethanechol chloride decreases the duration of urethral catheterization in patients who underwent type III radical hysterectomy with manageable adverse events.

1. Cholinergic agonists and acetylcholinesterase inhibitors, such as neostigmine, produce a muscarinic receptor-mediated antinociception in several animal species that depends on activation of spinal cholinergic neurons. However, neostigmine causes antinociception in sheep only in the early, and not late, postoperative period. 2. In the present study, a model of postoperative pain was used to determine the antinociceptive effects of bethanechol (a muscarinic agonist) and neostigmine administered intrathecally 2, 24 or 48 h after a plantar incision in a rat hind paw. Changes in the threshold to punctate mechanical stimuli were evaluated using an automated electronic von Frey apparatus. 3. Mechanical hyperalgesia was obtained following plantar incision, the effect being stronger during the immediate (2 h) than the late post-surgical period. Bethanechol (15-90 microg/5 microL) or neostigmine (1-3 microg/5 microL) reduced incision-induced mechanical hyperalgesia, the effects of both drugs being more intense during the immediate (2 h) than the late post-surgical period. 4. The ED(50) for bethanechol injected at 2, 24 and 48 h was 5.6, 51.9 and 82.5 microg/5 microL, respectively. The corresponding ED(50) for neostigmine was 1.62, 3.02 and 3.8 microg/5 microL, respectively. 5. The decline in the antinociceptive potency of neostigmine with postoperative time is interpreted as resulting from a reduction in pain-induced activation of acetylcholine-releasing descending pathways. However, the similar behaviour of bethanechol in the same model points to an additional mechanism involving intrinsic changes in spinal muscarinic receptors.

Background: Previous studies in humans, dogs, and rats have shown that intraprostatic injection of botulinum neurotoxin type A (BoNTA) reduces gland size., Objective: To investigate the role of eventual impairment of sympathetic, parasympathetic, and sensory nerves to gland atrophy after intraprostatic BoNTA administration., Design, Setting, and Participants: Adult male Wistar rats weighing 300-350 g were used., Intervention: Animals were injected in the prostate ventral lobes with 0.2 ml of saline (n=6) or the same volume containing 10 U BoNTA (BOTOX) (n=18). Six rats treated with BoNTA further received the adrenergic agent phenylephrine (PHE, 0.05 mg/kg per day), six received the cholinergic drug bethanechol (2 mg/kg per day), and six received subcutaneous saline. Animals were sacrificed 1 wk later., Measurements: Prostates were weighed, fixed, and stained for sympathetic (tyrosine hydroxylase [TH]), parasympathetic (vesicular acetylcholine [ACh] transporter [VAChT]), and sensory nerve (calcitonin gene-related peptide [CGRP]) visualisation. Terminal deoxynucleotidyl transferase biotin-dUTP nick-end labelling (TUNEL) reaction was performed to investigate apoptosis., Results and Limitations: Prostate weight in controls was 1.82+/-0.24 mg/100 g of rat weight. In BoNTA-treated rats, weight decreased to 1.28+/-0.18 mg /100 g of rat weight (p=0.002). In BoNTA plus PHE-treated rats, prostate weight was similar to controls: 1.78+/-0.27 (p=0.87). In rats treated with BoNTA plus bethanechol, weight was less than controls: 1.41+/-0.17 (p=0.01). The number of TH-positive fibres was markedly reduced after BoNTA (p<0.001). VAChT- and CGRP-positive fibres were scarce in controls, preventing further evaluation. Rats treated with BoNTA had more TUNEL-positive cells than controls (p<0.001) and rats treated with BoNTA plus PHE (p<0.001). There were no differences between the BoNTA and BoNTA plus bethanechol groups (p=0.81). Although showing atrophy after BoNTA injection, rat prostates do not develop benign prostatic hyperplasia (BPH). Thus, present findings should be used cautiously to explain prostate atrophy seen in men with BPH treated with BoNTA., Conclusions: Prostate atrophy induced by BoNTA in the rat may be the result of sympathetic nerve impairment and decreased adrenergic stimulation of the gland. Data indirectly suggest that sympathetic drive plays a role in prostate-size regulation.

Background: There is limited information on medications with promotility effects on the esophagus. Studies in healthy volunteers have shown the potential role of the direct cholinergic agonist bethanechol and the serotonin receptor agonist buspirone in improving esophageal motility. It has been also shown that an acetylcholinesterase inhibitor, the short-acting drug edrophonium administered intravenously caused a greater increase in the esophageal contraction amplitude and duration than bethanechol. Edrophonium cannot be used as a promotility therapy owing to short duration of action and lack of oral administration. The use of another acetylcholinesterase inhibitor pyridostygmine with longer duration of action has not been studied. The aim of the study was to evaluate the effect of oral pyridostygmine (60 mg), buspirone (20 mg), and bethanechol (25 mg) on esophageal function assessed by combined multichannel intraluminal impedance-esophageal manometry., Materials and Methods: Ten healthy volunteers were enrolled in a double blind randomized 3-period crossover study. Multichannel intraluminal impedance-esophageal manometry recorded esophageal pressures and bolus transit data during 6 liquid and 6 viscous swallows at baseline and 20, 40, and 60 minutes after the randomized oral administration of each drug., Results: Blinded analysis found significant increases in mean distal esophageal amplitude for liquid swallows from baseline to 60 minutes postdosing after pyridostygmine (87.6 vs. 118.0 mm Hg, P<0.001), buspirone (85.1 vs. 101.9 mm Hg, P<0.05), and bethanechol (87.6 vs. 118.8 mm Hg, P<0.01). Only pyridostygmine showed a significant decrease in mean distal onset velocity for liquid swallows at 60 minutes postdosing (3.4 vs. 2.3 cm/s, P<0.01) and increase in total bolus transit time at 60 minutes postdosing (7.9 vs. 9.3 s, P<0.05). All 3 agents significantly increased mean lower esophageal sphincter residual pressure for liquid swallows at 20, 40, and 60 minutes postdosing. Increased lower esophageal sphincter resting pressure was not significant. Similar results were found with viscous swallows., Conclusions: Oral pyridostygmine, buspirone, and bethanechol enhance esophageal motility with pyridostygmine appearing to have the greatest effect. A potential effect on improving esophageal function and symptoms in patients requires further study.

Our primary purpose was to characterize vagal pathways controlling gastric motility by microinjecting l-glutamate into the dorsal motor nucleus of the vagus (DMV) in the rat. An intragastric balloon was used to monitor motility. In 39 out of 43 experiments, microinjection of l-glutamate into different areas of the DMV rostral to calamus scriptorius (CS) resulted in vagally mediated excitatory effects on motility. We observed little evidence for inhibitory effects, even with intravenous atropine or with activation of gastric muscle muscarinic receptors by intravenous bethanechol. Inhibition of nitric oxide synthase with N(omega)-nitro-l-arginine methyl ester (l-NAME) HCl did not augment DMV-evoked excitatory effects on gastric motility. Microinjection of l-glutamate into the DMV caudal to CS produced vagally mediated gastric inhibition that was resistant to l-NAME. l-Glutamate microinjected into the medial subnucleus of the tractus solitarius (mNTS) also produced vagally mediated inhibition of gastric motility. Motility responses evoked from the DMV were always blocked by ipsilateral vagotomy, while responses evoked from the mNTS required bilateral vagotomy to be blocked. Microinjection of oxytocin into the DMV inhibited gastric motility, but the effect was never blocked by ipsilateral vagotomy, suggesting that the effect may have been due to diffusion of oxytocin to the mNTS. Microinjection of substance P and N-methyl-d-aspartate into the DMV also produced inhibitory effects attributable to excitation of nearby mNTS neurons. Our results do not support previous studies indicating parallel vagal excitatory and inhibitory pathways originating in the DMV rostral to CS. Our results do support previous findings of vagal inhibitory pathways originating in the DMV caudal to CS.

This study was conducted to assess the clinical efficacy and adverse effects of pilocarpine, bethanechol and cevimeline in patients with xerostomia. In this open-label crossover assessment in 20 patients with xerostomia, a one- to two-week course of each medication with a one-week washout period was prescribed. Side effects, symptoms, whole stimulated and unstimulated saliva were measured. Each sialogogue was found to increase saliva and decrease symptoms. A mixed-effects analysis showed a greater increase in stimulated saliva on bethanechol compared to pilocarpine (0.106, p = 0.0272). Increased sweating was the most common side effect, experienced more frequently with pilocarpine as compared to bethanechol (p = 0.0588) or cevimeline (p = 0.0143). A carryover effect beyond the washout period was seen. Effects on saliva and side effects vary between sialogogues, suggesting a benefit of trials with different sialogogues to determine individual patient preference. The observed carryover effect suggests that intermittent treatment may be an alternative to continuous treatment with sialogogues.

The goal of this study was to investigate the effect of bethanechol (BeCh) on contractility patterns of smooth muscle preparations of equine duodenum descendens, jejunum, caecum and pelvic flexure in vitro. Concentration-response relationships were developed for BeCh using in vitro assays with and without preincubation of muscarinic (M) receptor antagonists for M2 and M3 receptors. BeCh induced a significant, concentration-dependent increase in contractile response in equine intestine in specimens with circular orientation. The maximal effect was largest for jejunal specimens with no difference in EC50 within the different locations investigated. The M2 antagonist, AF-DX 116, caused a rightward shift of the concentration-response curve and the M3 antagonist, 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), almost completely inhibited the effect of BeCh over the entire concentration-response curve. These data provide evidence that, although the effect of BeCh is predominantly mediated by M3 receptors, M2 muscarinic receptors also play a role in BeCh-induced contraction in specimens of equine intestine. The involvement of other muscarinic receptor subtypes cannot be excluded. Further studies are necessary to understand the effect of BeCh in vivo including diseased animals.

The mechanism by which muscarinic or nicotinic agonists produce antinociception has been the subject of several studies. In the present investigation, we used intrathecal administration of drugs to rats to show that muscarinic or nicotinic agonists such as bethanechol (BCh) and dimethylphenylpiperazinium (DM), respectively, dose-dependently increased the tail flick latency and reduced the pain produced by a surgical incision performed on the plantar aspect of a hind paw. The effects of BCh in both tests were inhibited by the previous intrathecal administration of atropine, but not mecamylamine (muscarinic and nicotinic antagonists, respectively). Mecamylamine significantly reduced the effects of DM in both tests. Atropine significantly reduced the effect of DM in the tail flick test and inhibited the effect of DM against the incisional pain. Intrathecal hemicholinium-3 (HC-3), a reversible inhibitor of choline transporter, did not change the effect of BCh in the tail flick test but produced a non-significant reduction of the effect of BCh against incisional pain. In contrast, HC-3 produced a non-significant reduction of the effect of DM in the tail flick test but fully inhibited the effect of DM against incisional pain. Therefore, the BCh-induced antinociception depends on a direct activation of muscarinic receptors, whereas DM-induced antinociception results in drug interaction with nicotinic receptors to activate the further release of acetylcholine from intrinsic spinal cholinergic terminals. The acetylcholine released by DM in turn induces antinociception via activation of muscarinic receptors.

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.

Purpose: Esophageal histology in the opossum reveals numerous submucosal mucous glands closely resembling those commonly found in humans. The aim of the study was to examine the secretion of these glands using the commonest secretagogues., Material and Methods: The esophageal lumen in 5 male opossums was continuously perfused with saline during sixteen consecutive 5 min perfusion periods. After four initial equilibrating periods, each animal was injected (s.c.) with pentagastrin (6 microg/kg), bethanechol chloride (100 microg/kg) or histamine dihydrochloride (0.5 mg/kg). All sixteen (5 min) perfusates were assayed for protein by Lowry, mucin by PAS and viscosity using a cone/plate digital viscometer. Results were expressed as mean +/- SE. Statistical analysis was performed using paired Student's t-test., Results: Administration of bethanechol resulted in a significant increase in esophageal mucin release from 2.4 +/- 0.4 to 8.0 +/- 1.2 microg/cm2/min (p < 0.01); enhancement of protein output from 8.9 +/- 2.0 to 20.4 +/- 2.9 microg/cm2/min (p < 0.01) and potentiation of specific viscosity from 7.5 +/- 0.6 to 14.4 +/- 0.8 (p < 0.01). Pentagastrin-induced release of mucin reached the maximal value of 5.5 +/- 0.7 microg/cm2/min (p < 0.01), protein output increased to 20.0 +/- 2.7 (p < 0.01) and viscosity expanded to 11.7 +/- 0.9 (p < 0.05). Histamine evoked an increase in mucin release to 3.9 +/- 0.4 microg/cm2/min (p < 0.01), protein output to 24.1 +/- 3.3 microg/cm2/min (p < 0.01) and viscosity to 12.8 +/- 1.1 (p < 0.05)., Conclusions: The significant influence of cholinergic, histaminergic and peptidergic stimulation on physical and chemical properties of the esophageal secretion provides evidence for the role of these pathways in the pathophysiology of the esophageal mucosa.

The objective of this study was to investigate the effects of cisapride (CIS), metoclopramide (MET) and bethanechol (BET) on contractility parameters from smooth muscle preparations of the abomasal antrum and proximal duodenum of cows. Smooth muscle preparations were harvested shortly post-mortem from 42 healthy dairy cows, and concentration-response curves were performed by cumulative application of the drugs. Cisapride and MET did not have any significant effect on the contractility parameters studied, while BET induced a significant, concentration-dependent increase in basal tone (BT), mean amplitude (Amean), and area under the curve (AUC) in smooth muscle preparations from the abomasal antrum, but not from the duodenum. The effect of BET on BT was more pronounced in specimens with longitudinal orientation while the maximal obtainable effect (Vm) in Amean was more pronounced in circular-oriented preparations. Atropine (1 x 10-5 m) significantly inhibited the effect of BET, whereas pre-incubation with hexamethonium or tetrodotoxin (TTX) had no effect, suggesting that the effect was mediated by cholinergic receptors on the smooth muscle. The results may be relevant to diseases or disorders associated with gastric emptying and gastric hypomotility. Further investigations are warranted to investigate the potential ability of BET to enhance abomasal emptying of adult dairy cows.

Rationale: The brain regions and receptor subtypes involved in water intake following central cholinergic stimulation have been incompletely characterized., Objectives: To examine whether drinking and brain Fos-immunoreactivity (ir) induced in rats by central administration of bethanecol is reversed by either the preferential M1 antagonist pirenzepine, the M3 antagonist 4-DAMP, or their combination., Methods: Male Sprague-Dawley rats were surgically implanted with cerebroventricular cannulae. The muscarinic agonist, bethanecol was used as the dipsogenic agent. Either nonselective (atropine) or selective muscarinic receptor antagonists were injected together with bethanecol to determine blockade of drinking. In parallel studies, Fos-ir was assessed in discrete brain regions., Results: Bethanecol-induced drinking was completely blocked by atropine or by a combination of pirenzepine and 4-DAMP; these latter antagonists alone produced sub-total inhibition of drinking. In contrast, water intake induced by angiotensin II was unaffected by combination of pirenzepine and 4-DAMP. Fos-ir was induced by bethanecol in many brain regions previously implicated in body fluid regulation, including subfornical organ and the magnocellular supraoptic and paraventricular hypothalamic nuclei. Induced Fos-ir was substantially but not completely prevented by co-injection of either pirenzepine or 4-DAMP, but their combination did not seem markedly more effective than either alone., Conclusions: Drinking induced by brain muscarinic receptor stimulation seems to proceed by a combination of M1 and M3 receptor subtypes. Drinking induced by angiotensin II occurs independently of this mechanism. Fos-ir induced in fluid-related brain regions by bethanecol either uses additional receptor type(s) or is less easily blocked than drinking behavior.

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.

Purpose: It is often difficult to determine the functional status of the detrusor muscle in patients with detrusor areflexia. We performed a clinical study to establish a test defining residual detrusor capacity in such patients., Materials and Methods: In phase 1, 5 controls with detrusor areflexia were tested with an intravesical instillation of 20 mg. bethanechol in 150 cc of sodium chloride 0.3% with and without 20 mA. of pulsed current applied via an electrode catheter through the saline. Cystometry simultaneously recorded intravesical pressure changes. In phase 2, 45 patients with detrusor areflexia were tested with electromotive administration of intravesical bethanechol. In phase 3, 25 mg. bethanechol given orally once daily were prescribed for 15 patients and voiding control was assessed after 6 weeks of therapy., Results: Neither bethanechol without current nor current through saline only led to increased intravesical pressure. However, we noted a mean pressure increase of 34 cm. water during the electromotive administration of bethanechol in 24 of 26 patients with areflexia and neurological disease compared to only 3 cm. water in 3 of 11 with a history of chronic bladder dilatation. Oral bethanechol restored spontaneous voiding in 9 of 11 patients who had had a positive response to the electromotive administration of bethanechol, whereas all 4 without a pressure increase during the electromotive administration of bethanechol did not void spontaneously., Conclusions: Electromotive administration of intravesical bethanechol identifies patients with an atonic bladder and adequate residual detrusor muscle function who are candidates for restorative measures, such as oral bethanechol and intravesical electrostimulation. Those who do not respond to the electromotive administration of bethanechol do not benefit from oral bethanechol and are candidates for catheterization.

Purpose: Topical glyceryl trinitrate heals anal fissures, but a majority of patients experience headache. Topical gels of the calcium channel blocker diltiazem and the cholinomimetic bethanechol significantly lower anal sphincter pressure in volunteers. This study investigated the use of these two new pharmacologic agents in the treatment of patients with chronic anal fissure., Methods: Two studies were conducted, each involving 15 patients with chronic anal fissure. In each study patients underwent anal manometry and laser doppler flowmetry before treatment. They were treated with either 2 percent diltiazem gel or 0.1 percent bethanechol gel three times daily for eight weeks. Assessment every two weeks was by clinical examination, repeat anal manometry, and laser doppler flowmetry. Daily pain was assessed by linear analog charts., Results: Fissures healed in 10 of 15 (67 percent) patients treated with 2 percent diltiazem gel and in 9 (60 percent) patients treated with 0.1 percent bethanechol gel. There was no significant difference in the pretreatment maximum resting sphincter pressure (MRP) between responders and nonresponders in either group. There was significant reduction in the pain score after treatment with diltiazem (P = 0.002) and bethanechol (P = 0.005) compared with that before treatment. MRP was significantly lower after diltiazem (P = 0.0001) and bethanechol (P = 0.02) compared with pretreatment MRP. No headaches or side effects were reported., Conclusions: Both topical diltiazem and bethanechol substantially reduce anal sphincter pressure and achieve fissure healing to a similar degree reported with topical nitrates, but without side effects.

Background: Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects., Aims: To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure., Methods: Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure., Results: A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours., Conclusions: Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.

Objectives: To quantify the progression of senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, and microglial activation in the cortex and white matter of patients with Alzheimer disease evaluated at both biopsy and subsequent autopsy and correlate these changes with the progression of neurologic impairment., Setting: Academic referral center for patient with Alzheimer disease., Patients: Four patients meeting the clinical criteria for Alzheimer disease, enrolled in a pilot study for the evaluation of response to intracerebroventricular administration of bethanechol chloride. The patients were followed up until death occurred and autopsy was performed., Results: All 4 patients had progressive deterioration from the time of biopsy to autopsy (9-11 years). Pathological investigations showed a striking increase in the density of senile plaques and neurofibrillary tangles in 2 of 4 patients from biopsy to autopsy, and a significant increase in microglial activation in 1 of 4 cases. Severity of cerebral amyloid angiopathy varied significantly among patients, 1 of whom displayed striking amyloid deposition with associated subcortical white matter atrophy., Conclusions: These unique data demonstrate that the progressive neurologic impairment in Alzheimer disease is accompanied by a significant increase in senile plaque and neurofibrillary tangle counts in the frontal cortex and, possibly in some patients, by increased microglial cell activation. Cerebral amyloid angiopathy was associated with significant white matter disease.

Tyrosine hydroxylase (TH) gene expression in the adrenal medulla is regulated by numerous stimuli via transsynaptic mechanisms. The adrenal chromaffin cell receptors that mediate this transsynaptic response remain unidentified. In this report we demonstrate that the muscarinic acetylcholine receptor agonist bethanechol stimulates the TH gene transcription rate in both innervated and denervated adrenal glands. Hence, this muscarinic response is not dependent on transsynaptic influences, suggesting that agonist occupation of adrenal chromaffin cell muscarinic receptors is sufficient to activate intracellular signaling pathways that stimulate the TH gene. When bethanechol is administered repeatedly over a 3-h interval (four injections spaced 1 h apart), TH mRNA levels are increased two- to threefold at 6 and 12 h after the initial injection of drug. It is surprising that this induction of TH mRNA does not lead to increases in TH activity or TH protein level. These results are consistent with the hypothesis that both transcriptional and posttranscriptional mechanisms must be regulated to induce TH protein and that muscarinic agonists activate only a subset of these mechanisms.

The stability of five drugs commonly prescribed for use in oral liquids but not commercially available as such was studied. Bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, quinidine sulfate 10 mg/mL, rifampin 25 mg/mL, and tetracycline hydrochloride 25 mg/mL were each prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and cherry syrup and placed in 120-mL amber clear polyethylene terephthalate bottles. Three bottles of each liquid were stored at 5 degrees C and three at 25 degrees C, all in the dark. Samples were taken initially and at various times up to 60 days for analysis by high-performance liquid chromatography and assessment of appearance and odor; pH was measured. A mean of at least 90% of the initial drug concentration was retained for 60 days in the liquids containing bethanechol chloride, pyrazinamide, or quinidine sulfate and for 28 days in the rifampin-containing liquids and the mixture of tetracycline hydrochloride and Ora-Sweet-Ora-Plus at both 5 and 25 degrees C. Tetracycline hydrochloride concentrations of 90% or more of the initial concentration were retained in the liquids prepared with Ora-Sweet SF-Ora-Plus for 10 days at 5 degrees C and 7 days at 25 degrees C and in those prepared with cherry syrup for 7 days at 5 degrees C and 2 days at 25 degrees C. No substantial changes in the appearance, odor, or pH of any liquid were observed. At 5 and 25 degrees C, bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, and quinidine sulfate 10 mg/mL were stable in three extemporaneously compounded oral liquids for 60 days and rifampin 25 mg/mL was stable for 28 days. The stability of tetracycline hydrochloride 25 mg/mL varied with the vehicle.

Objective: To assess the stability of a bethanechol chloride oral solution prepared from tablets., Method: The initial concentrations were determined. These solutions were stored at 4 degrees C for 90 days. During this period, the concentrations of the bethanechol chloride solutions were determined by spectrophotometry. The clinical efficacy of the oral solution was tested in five infants with gastroesophageal reflux disease by comparison of gastric pH before and after treatment., Results: Significant decomposition of bethanechol chloride occurred in the two formulations. Bethanechol oral solution in sterile water for irrigation was well tolerated by five pediatric patients, and the clinical efficacy was equivalent to that of the tablet formulation., Conclusions: The bethanechol chloride oral solution 1 mg/mL in sterile water for irrigation was stable at least 30 days when stored at 4 degrees C and at an initial pH of 6.5. This formulation appears to be clinically acceptable and provides a convenient dosage form for use in pediatric patients.

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.

Background: Peptide YY (PYY) is promptly released from endocrine cells of the distal part of the gut after food intake. To test the possibility that hormones produced by the proximal small intestine or transmitters of the enteric nervous system may take part in the early phase of meal-induced PYY release, various regulatory peptides and neurotransmitters of the gut were administered intra-arterially in the isolated, vascularly perfused rat colon., Methods: A colonic loop was perfused with a Krebs-Henseleit buffer containing 20% washed bovine erythrocytes via the superior mesenteric artery. The release of PYY in portal effluent was measured by radioimmunoassay., Results: Cholecystokinin and secretin produced a small release of PYY. In contrast, infusion of gastric inhibitory polypeptide (GIP) over the concentration range 0.25-1 nM for 30 min produced a dose-dependent secretion of PYY with a maximal response at 800% above basal. Tetrodotoxin (TTX) did not modify the GIP-induced PYY release. Bethanechol (10(-5) M, 10(-4) M) produced a PYY release that was maximal at the end of the 30-min infusion period. The beta-adrenergic agonist isoproterenol (10(-7) M, 10(-6) M) caused a prompt release of PYY, followed by a sustained release at a lower value. Calcitonin gene-related peptide (CGRP) (5.10(-9) M and 5.10(-8) M) induced a PYY release with kinetics similar to that found for isoproterenol. Finally, bombesin (10(-9)-10(-7) M) provoked a dose-dependent release of PYY, consisting of an early peak followed by a sustained response. TTX did not modify the bethanechol-, isoproterenol-, CGRP-, and bombesin-induced PYY secretion., Conclusion: The hormonal peptide GIP and several transmitters of the nervous enteric system may mediate the release of PYY through the occupation of receptors possibly located at the surface of the colonic L-cells.

The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 micrograms kg-1 h-1) with and without a background of atropine (5 micrograms kg-1 h-1) or loxiglumide (10 mg kg-1 h-1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion (P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened (P < 0.05). Only high doses of bethanechol enhanced gastrin (P < 0.05), cholecystokinin (P < 0.05), and pancreatic polypeptide (P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co-infusion of bethanechol and loxiglumide, PP release dropped by 63% (P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively (P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co-infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells.

1. The characteristics of muscarinic receptors mediating relaxation and/or contraction in the rat iris dilator muscle were examined. 2. Relaxation was induced in a dilator muscle by application of acetylcholine (ACh) at low doses (3 microM or less) and contraction was induced by high doses. Methacholine and carbachol also showed biphasic effects similar to those of ACh; in contrast, bethanechol, arecoline, pilocarpine and McN-A-343 induced mainly relaxation but no substantial contraction. 3. After parasympathetic denervation by ciliary ganglionectomy, the relaxant response to muscarinic agonists disappeared upon nerve stimulation. Application of McN-A-343 and pilocarpine induced only small contractions in denervated dilator muscles, indicating that these are partial agonists for contraction. 4. pA2 values of pirenzepine, methoctramine, AF-DX 116, himbacine, and 4-DAMP for antagonism to pilocarpine-induced relaxation in normal dilator muscles and those for antagonism to ACh-induced contraction in denervated dilator muscles were determined. The pA2 values for antagonism to relaxation of all these antagonists were most similar to those for M3-type muscarinic receptors. 5. Although pA2 values for contraction of these antagonists, except for methoctramine, were very close to those for relaxation, contraction was not significantly antagonized by methoctramine. Contraction might be mediated by M3-like receptors which have a very low affinity for methoctramine. 6. In conclusion, ACh-induced biphasic responses in rat iris dilator muscles were clearly distinguished from each other by specific muscarinic agonists and parasympathetic denervation, whereas muscarinic receptors could not be subclassified according to the pA2 values of 5 specific antagonists only.

Reabsorption of peritoneal dialysis fluid during the prolonged dwell time of continuous ambulatory peritoneal dialysis (CAPD) reduces the efficiency of ultrafiltration and sacrifices effective dialysis adequacy. Studies by Nolph indicate a predominant role of lymphatics in this fluid loss. Khanna has reported that lymphatic flow may be influenced by acetylcholine. This study was designed to determine if bethanechol chloride (BC) would increase the availability of drained volume during CAPD. Nine patients were studied, including 7 patients who exhibited inadequate ultrafiltration. During a 5-day control period, total dialysate drained volume was collected and a standard peritoneal equilibration test (PET) performed. This was followed by a corresponding 5-day test period in which BC (mean dose 0.27 +/- 0.13 mg/kg/day) was administered orally. Drained volume during the control standard 4-hr PET was 1996.68 +/- 279.87 mL. The result for the test period was 2363.33 +/- 321.13 mL (p < 0.05), indicating an 18.4% increase using BC. The PET indicated no change in transport of urea, creatinine, and glucose. In conclusion, the total drained volume can be effectively increased with a subsequent increase in metabolite clearance using BC. Patients exhibiting inadequate ultrafiltration were able to be maintained on CAPD using this cholinergic drug.

The effects of reversible enhancement or suppression of locus coeruleus (LC) neuronal discharge activity on forebrain electroencephalographic (EEG) activity have been previously examined in two series of experiments in halothane-anesthetized rats. Unilateral enhancement of LC activity increased EEG measures of arousal in frontal cortex and hippocampus. The EEG effects of LC activation were blocked by intracerebroventricular pretreatment with the noradrenergic beta-antagonist, propranolol. Bilateral, but not unilateral, suppression of LC activity substantially increased EEG measures of sedation/anesthesia in cortex and hippocampus. In all experiments: a) EEG responses were only observed following changes in LC activity levels; b) onset of EEG responses closely followed changes in LC neuronal activity; c) recovery of EEG responses closely followed the recovery of LC neuronal activity. The present report integrates these previous results and considers their implications for the hypothesis that the LC may be an important modulator of behavioral state and/or state-dependent processes. Together, the two series of experiments yield complementary observations that have implications for LC function that are not apparent when considering each series in isolation.