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PubMed1977

The quantitative histologic distribution of pyridoxal phosphate in the rat stomach, effects of drugs influencing secretion.

The quantitative histologic distribution of pyridoxal phosphate (PLP), the coenzyme of histidine decarboxylase in the biosynthesis of histamine as well as the coenzyme of other enzyme systems, was established in the rat glandular stomach in different secretory states. This was accomplished by analyzing PLP with an improved fluorometric microprocedure in histologically identified fresh-frozen microtome tissue sections cut serially through the stomach wall of fed and 24-hr fasted rats, and of the latter injected with drugs that stimulate (histamine, theophylline and urecholine) or inhibit (atropine) secretion. In fasted compared with fed rats, and in fasted rats injected with histamine (low dose) or theophylline, compared with saline injected controls, the PLP level was reduced not only in the chief cell region where PLP is utilized in histamine production, but also in the parietal and mucous neck cell region, indicating PLP function in other enzyme systems in these sites. No change in PLP level occurred when histamine was injected at a high dose known to suppress histidine decarboxylase activity. Administration of urecholine or atropine had negligible effect on the PLP levels, indicating a lack of vagal stimulatory or inhibitory influence.

Animals↗
PubMed1985

Effect of metoclopramide and bethanechol on gastric emptying in infants.

In a double-blind, placebo controlled study of 10 infants with upper gastrointestinal motor disorders, metoclopramide (1 mg/kg, intravenous) but not bethanechol (0.075 mg/kg, subcutaneous), significantly increased the fractional rate of gastric emptying following a 5% glucose meal. Infants were tested on 3 consecutive days with a phenol red dye-dilution technique which, if combined with acid titration of gastric samples, permits simultaneous measurements of gastric volume, fractional emptying rate, fluid output, and acid output. Metoclopramide increased the fractional emptying rate in eight of 10 infants (mean +/- SE increasing from 4.6 +/- 0.6 to 7.3 +/- 1.0%/min, p less than 0.02). Neither drug altered gastric acid secretion, but metoclopramide significantly increased gastric fluid output (mean +/- SE increased from 3.5 +/- 0.6 to 6.5 +/- 1.4 ml/min, p less than 0.02). No undesirable side effects or complications occurred during testing. We conclude that trials are warranted to assess the clinical efficacy of metoclopramide in infants with nonobstructive causes of delayed gastric emptying.

Bethanechol Compounds↗
PubMed1986

The effect of tracheal smooth muscle tone on neonatal airway collapsibility.

The effect of smooth muscle tone on the functional characteristics of neonatal airways was studied in six newborn lambs. Tracheal mechanics, resistance, and collapsibility were determined in tracheal segments of uniform length which were surgically isolated just caudal to the cricoid cartilage. Resistance to airflow through uncompressed (zero transmural pressure) and compressed (increased transmural pressure) trachea was evaluated over a range of physiological flows both before and after induced contraction of airway smooth muscle. Results demonstrate that neonatal tracheal smooth muscle does respond to cholinergic stimulation and that there was a significant decrease in airway compliance. Furthermore, the consequent increase in airway rigidity may play a role in resisting collapse or compression of the intrathoracic airway during expiration.

Airway Resistance↗
PubMed1986

The role of tracheal smooth muscle contraction on neonatal tracheal mechanics.

The ability of tracheal smooth muscle tone to modulate the mechanical properties of neonatal airways was evaluated in six newborn lambs. Tracheal pressure-volume relationships, isovolumic compliance, hysteresis, and the relaxation time constant of the smooth muscle were evaluated as a function of incremental cholinergic stimulation. Tracheal active tensions were also determined at the graded levels of cholinergic stimulation. Data show that a maximal cholinergic stimulation resulted in a mean developed active tension value of 14.3 +/- 2.13 SEM X 10(3) dynes/cm. The resultant 55% decrease in tracheal compliance was linearly correlated to the increase in active tension (r = 0.90, p less than 0.01). Cholinergic stimulation also resulted in a 18.4% decrease (p less than 0.02) in the relaxation time constant of the smooth muscle, and in a 82% increase (p less than 0.01) in tracheal hysteresis. This study demonstrates that both elastic and viscoelastic properties of the neonatal lamb trachea are effected by tracheal smooth muscle contraction. Since neonatal airways are more compliant than adult airways, cholinergic stimulation could conceivably enhance airway rigidity and may provide a protective mechanism against pressure-induced deformation.

Animals↗
PubMed1989

Developmental differences in neurohumoral modulation of the cat lower esophageal sphincter.

It is possible that age-related differences in gastroesophageal function during infancy may predispose the infant to abnormalities. We have therefore evaluated developmental differences in neurohumoral modulation of lower esophageal sphincter function in the cat. These studies were performed in an in vitro setting. In the adult cat, lower esophageal sphincter smooth muscle and postganglionic inhibitory neurons are more sensitive to muscarinic agonists than in the kitten. The circular smooth muscle of the adult lower esophageal sphincter is also more responsive to neurally mediated relaxation, brought about by electrical stimulation. However, there is no difference in response to exogenous vasoactive intestinal peptide between the two age groups. These data suggest that developmental differences in neurohumoral modulation of the lower esophageal sphincter occur in the cat.

Animals↗
PubMed1989

Developmental changes in agonist-mediated gastric smooth muscle contraction in the rabbit.

We studied smooth muscle strips from rabbit proximal stomach to explore the age-related changes in agonist-mediated contraction. Strips from neonatal (1 d) and weanling (11 wk) rabbits were oriented to measure isometric tension in circular muscle. Bethanechol stimulated maximal tension in both age groups. Although the potencies for bethanechol were similar (ED50 approximately 5 microM), the maximal response was nearly 4-fold greater in weanling (1140 +/- 73 mN/cm2) versus neonate (305 +/- 54 mN/cm2), p less than 0.001. Maximum stress increased with age for bethanechol, high extracellular K+, and substance P, but not for serotonin, cholecystokinin octapeptide, neurotensin, or bombesin. Only bombesin stimulated larger contraction in neonates (152 +/- 37 mN/cm2) versus weanlings (86 +/- 20 mN/cm2), p less than 0.05. Potencies did not change with age, except for substance P and serotonin. Substance P and serotonin induced early phasic and prolonged tonic contractions, which were unaffected by tetrodotoxin or atropine. ED50 for the phasic and tonic components of substance P-stimulated contraction in neonates were 1.8 and 7.7 nM. Substance P was 60-70 times more potent in neonates versus weanlings (p less than 0.001). ED50 for serotonin-stimulated contraction in neonates (33 and 22 nM, respectively) were 20-30 times more potent than in weanlings (p less than 0.05). Motilin, morphine, epidermal growth factor, and gastrin did not stimulate contraction at either age. We conclude that age-dependent changes in agonist potency and efficacy may be one factor to explain in part the changes that occur in gastric motility during postnatal development.

Animals↗
PubMed1991

Developmental changes in agonist-mediated colonic smooth muscle contraction in the rabbit.

We studied smooth muscle strips from rabbit distal colon to determine age-related changes in length-tension properties and agonist-mediated contraction. Strips from newborn (1-d-old) and weanling (11-wk-old) rabbits were oriented to measure isometric tension in longitudinal muscle. Active tension comprised 47 +/- 4 and 75 +/- 5% of the total tension in the newborn and weanling, respectively. Total and active tensions in the weanling were greater than in the newborn (p less than 0.001). Although the potencies for bethanechol were similar, the maximal response was nearly 9-fold greater in weanlings (6900 +/- 292 mN/cm2) versus newborns (753 +/- 112 mN/cm2), p less than 0.001. Maximal stress increased with age for bethanechol, high extracellular potassium, substance P, neurokinin A, cholecystokinin octapeptide, bombesin, and serotonin. ED50 for bethanechol, substance P, neurokinin A, and bombesin did not change with age. Serotonin was 12 times more potent in newborns versus weanlings (p less than 0.05). In contrast, cholecystokinin octapeptide was five times less potent in newborns (18.6 nM versus 3.4 nM, respectively, p less than 0.05). Substance P-induced contractions were inhibited partially by atropine. We conclude that length-tension properties of longitudinal colonic smooth muscle differ, and responses to agonists increase with age.

Animals↗
PubMed1985

Nicotinic cholinergic agonists inhibit androgen biosynthesis by cultured rat testicular cells.

The actions of cholinomimetics on androgen biosynthesis were investigated using a primary culture of testicular cells derived from adult hypophysectomized rats. Testicular cells were maintained in serum-free medium and treated with hCG and/or drugs on day 8 of culture. Media were collected 2 days later for measurement of steroids and cAMP. Treatment with hCG increased testosterone production 50-fold over control values, whereas treatment with cholinomimetics alone failed to increase androgen production. Concomitant treatment of testicular cells with nicotinic cholinergic agonists (lobeline, nicotine, and dimethylphenylpiperazinium iodide) inhibited hCG-stimulated androgen biosynthesis in a dose-dependent fashion, with IC50 values of 3 X 10(-5), 1.7 X 10(-4), and greater than 10(-3) M, respectively. In contrast, two muscarinic cholinergic agonists, muscarine and bethanechol, failed to inhibit androgen production at concentrations up to 10(-3) M. A ganglionic nicotinic antagonist (hexamethonium), but not a skeletal muscle nicotinic antagonist (decamethonium), partially blocked the actions of lobeline. Lobeline (10-4) M) decreased hCG-stimulated testosterone production (50-75%) throughout the 2-day culture period; however, this inhibition was reversible upon removal of the drug. Lobeline also inhibited hCG-stimulated cAMP accumulation as well as testosterone production induced by cholera toxin (65% inhibition), forskolin (50% inhibition), or (Bu)2cAMP (70% inhibition). Lobeline inhibition of hCG-stimulated testosterone production was accompanied by decreases in medium accumulation of 17 alpha-hydroxypregnenolone (75%), 17 alpha-hydroxyprogesterone (85%), dehydroepiandrosterone (50%), and androstenedione (61%); however, the medium content of pregnenolone and progesterone were unchanged. Additional experiments demonstrated that lobeline suppressed the conversion of exogenous progesterone to testosterone, but did not affect the conversion of exogenous 17 alpha-hydroxyprogesterone to testosterone. These results indicate that nicotinic, but not muscarinic, cholinergic agonists inhibit androgen biosynthesis through selective inhibition of 17 alpha-hydroxylase activity. Thus, endogenous acetylcholine may be involved in the negative regulation of testicular steroidogenesis.

Androgens↗
PubMed1989

Evidence for cholinergic modulation of aldosterone secretion in man.

Acetylcholine stimulates aldosterone secretion in bovine glomerulosa cells in vitro via specific cholinergic receptors. In this study we examined the effect of peripheral muscarinic blockade with atropine on metoclopramide-, angiotensin-II-, and ACTH-stimulated aldosterone secretion in man. Atropine (0.6 mg, iv) administered 10 min before MCP delayed the onset of the plasma aldosterone response and attenuated the mean peak response from 502 +/- 103 (+/- SE) to 322 +/- 72 pmol/L (P less than 0.05) without affecting zero time mean plasma aldosterone levels (144 +/- 28 vs. 136 +/- 36 pmol/L for control and atropine, respectively). This inhibitory effect was not mediated by changes in PRA or plasma potassium or ACTH (as reflected by cortisol) concentrations. Atropine also attenuated the plasma aldosterone response to a low dose angiotensin II infusion (2 ng/kg.min; control, 449 +/- 99 pmol/L; atropine, 297 +/- 78 pmol/L; P less than 0.05). In contrast, atropine had no effect on the plasma aldosterone response to a bolus dose (250 micrograms) of ACTH. Neither atropine (0.6 mg, iv) nor the cholinergic muscarinic agonist bethanechol (5 mg, sc) alone elicited a change in plasma aldosterone. Collectively, these data provide evidence for cholinergic modulation of aldosterone secretion in man. We conclude that cholinergic mechanisms may facilitate the aldosterone responses to angiotensin-II and metoclopramide, but not to ACTH.

Adrenocorticotropic Hormone↗
PubMed1980

Management of bladder dysfunction in multiple sclerosis.

Sixty-seven consecutive patients participated in a prospective urodynamic study of the diagnosis and treatment of urinary bladder symptoms in multiple sclerosis. The etiology of symptoms was classified as either failure to store urine (30%), failure to empty the bladder (18%), or a combination of the two (50%). Treatment was individualized on the basis of the underlying pathophysiology and consisted of intermittent self-catheterization (21%), none (20%), surgical (12%), drugs (9%), voiding maneuvers (6%), and external condom drainage (6%). In 18 patients (27%), lesser forms of treatment were unsuccessful, and indwelling vesical catheters were required. Symptoms correlated poorly with urodynamic findings, and treatment based on symptoms alone would have been ineffective in over half the patients.

Adult↗
PubMed1980

Shy-Drager syndrome: diagnosis and treatment of cholinergic dysfunction.

Two patients with Shy-Drager syndrome demonstrated unusually widespread and unequivocal cholinergic dysfunction as well as the usual evidence of adrenergic insufficiency. Progressive constipation preceded impotence, nocturia, hesitancy in micturition, anhidrosis, orthostatic hypotension, and xerostomia. Nonautonomic neurologic signs appeared several years later. Cholinergic dysfunction involved eyes, lacrimal glands, salivary glands, heart, gastrointestinal tract, urinary bladder, and sweat glands. Subcutaneous administration of bethanechol chloride--a muscarinic receptor agonist--improved tearing, salivation, sweating, and gastrointestinal and bladder functions. Daily administration of this drug resulted in symptomatic improvement of the autonomic functions, and relapse followed discontinuation of treatment.

Aged↗
PubMed1988

Intraventricular bethanechol infusion for Alzheimer's disease: results of double-blind and escalating-dose trials.

Ten patients with biopsy-proven Alzheimer's disease (AD) received low-dose (0.35 mg/d) intraventricular bethanechol, a muscarinic agonist, and saline placebo in a 24-week double-blind crossover design. Eight of these ten patients later participated in an open escalating-dose (to 1.75 mg/d) trial of bethanechol. Patients' drug responses were assessed by neuropsychological examination and informant measures of activities of daily living, mood disturbance, and abnormal behavior. Bethanechol appears to have a narrow therapeutic window for positive effects; low doses did not reliably alter patient functioning, moderately increased doses appeared to have a palliative effect on patient mood and behavior, and the highest dose was detrimental to patient functioning. Bethanechol does not appear to ameliorate the dementia of AD, but may exert a mildly positive effect on patient behavior and mood.

Aged↗
PubMed1984

Preliminary report: intracranial cholinergic drug infusion in patients with Alzheimer's disease.

After toxicity studies in dogs, a preliminary feasibility trial of the continuous intracranial infusion of a muscarinic agonist was begun in four patients with biopsy-documented Alzheimer's disease. During the last 8 months, a totally implantable infusion system has been used to deliver bethanechol chloride into the cerebrospinal fluid of these patients at doses of 0.05 to 0.7 mg/day. Complications have been few and resolved spontaneously or were easily reversible. The subjective response to this treatment has been encouraging, with reports of improved cognitive and social function during drug infusion and a return to base line function with single-blind saline placebo infusions. Obviously, further evaluation will be necessary to demonstrate the efficacy of this treatment, and a double-blind placebo-controlled crossover trial is now being done. However, we think the preliminary results are encouraging and warrant the consideration of this approach as a potential treatment in patients with Alzheimer's disease.

Aged↗