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PubMed1986

Pirenzepine and propantheline effects on esophageal pressure responses to bethanechol.

Pirenzepine is an antisecretory anticholinergic type drug that has recently been shown to be relatively free of usual anticholinergic side effects on esophageal smooth muscle. It has also been suggested that this drug might release some of the inhibitory control of the esophagus and allow increased muscle contractions. To test this hypothesis, we compared the response of the lower esophageal sphincter (LES) and esophageal peristaltic contractions to bethanechol in 12 healthy controls after background oral doses of placebo, pirenzepine (50 mg), and propantheline (30 mg). After baseline placebo, bethanechol (40 micrograms/kg subcutaneously) produced the expected significant increases in LES pressure and amplitude of peristaltic contractions. Maximal increases were 51.9 +/- 14.9 and 29.5 +/- 7.0%, respectively. Also as expected, propantheline inhibited the cholinergic stimulation from bethanechol, allowing only a 10.1 +/- 13.6% increase in LES pressure and a decrease in peristaltic contraction amplitudes (-44.1 +/- 5.0%) after bethanechol. After background pirenzepine, the responses to bethanechol were intermediate between the other two drugs. A significant increase (44.2 +/- 16.4%) in LES pressure occurred after bethanechol while no significant changes (6.9 +/- 5.8%) were noted in peristaltic amplitudes with this drug. Typical side effects of dry mouth were noted in six of the 12 subjects with propantheline and in only three subjects after pirenzepine. These studies once again confirm the absence of usual anticholinergic side effects with oral pirenzepine compared to oral propantheline in the doses studied. We could find no evidence for a release of cholinergic inhibition after pirenzepine administration.

Adult↗
PubMed1986

Release of acetylcholine mediated by cholecystokinin receptor from the guinea pig sphincter of Oddi.

Mechanisms involved in the action of cholecystokinin octapeptide (CCK-8) on the isolated circular muscle of the guinea pig sphincter of Oddi were investigated. CCK-8 (10(-9) to 10(-6) M) caused a concentration-dependent contraction of the sphincter. Angiotensin II, bethanechol and serotonin also contracted this tissue. CCK-8 exerted the most potent effect. However, bradykinin, porcine motilin and norepinephrine failed to elicit any contraction. The CCK-8-induced contraction was inhibited by about 60% by atropine (3 X 10(-7) M) or tetrodotoxin (3 X 10(-7) M) but was not affected by hexamethonium (3 X 10(-5) to 10(-4) M) or phentolamine (3 X 10(-6) to 10(-5) M). Proglumide (3 X 10(-4) to 3 X 10(-3) M), a derivative of glutaramic acid, inhibited competitively the contraction by CCK-8. However, proglumide influenced neither the electrically elicited twitch contraction nor the bethanechol-induced contraction. CCK-8 evoked a concentration-related release of [3H]acetylcholine (ACh) from previously labeled stores. The CCK-8-evoked release of [3H]ACh was eliminated by tetrodotoxin and was inhibited, in a concentration-dependent manner, by proglumide. These results suggest that the contractile response to CCK-8 of the guinea pig sphincter of Oddi consists of a direct effect on the smooth muscle and an indirect effect mediated by ACh release from postganglionic parasympathetic neurons.

Acetylcholine↗
PubMed1987

AF-DX 116, a cardioselective muscarinic antagonist.

The M2 subtype of the muscarinic receptor was investigated using the antagonist AF-DX 116. In "in vitro" and "in vivo" experiments, AF-DX 116 behaved as a competitive antagonist and exhibited a selectivity for cardiac muscarinic-mediated functions. It antagonized negative chronotropic and inotropic effects exerted by muscarinic receptor activation in the guinea pig atria with an affinity (pA2) 10-fold greater than that estimated in intestinal and tracheal smooth muscle preparations. It also reversed the negative chronotropic effect induced by peripheral vagal stimulation, intrasinus node injection of bethanechol and central vagal activation by clonidine. In all these in vivo functions, AF-DX 116 was approximately 10 times less potent than atropine, while being several hundred-fold less potent in antagonizing acetylcholine-mediated bronchoconstriction and gastric emptying. These results are consistent with the hypothesis that the cardiac muscarinic receptors constitute a subclass of the M2 subtype.

Animals↗
PubMedDate not supplied

Proton magnetic resonance spectroscopic determination of bethanechol chloride in tablets.

A simple and reliable proton magnetic resonance spectroscopic method was developed for the assay of bethanechol chloride in tablets. The proposed method entails a minimum of procedural steps and reagents. The recovery of bethanechol chloride from synthetic formulations was 99.9 +/- 0.4% (n = 15), CV = 0.4%. Mean assay values for 25 and 10 mg commercial tablets were 100.5% (n = 8) and 99.7% (n = 7) of declared, respectively. A detailed interpretation of the proton magnetic resonance spectrum is also presented.

Bethanechol↗
PubMed1987

(R)-nipecotic acid ethyl ester: a direct-acting cholinergic agonist that displays greater efficacy at M2 than at M1 muscarinic receptors.

Previous reports have suggested that the ethyl ester of (R)-nipecotic acid ethyl ester [(R)-NAEE] displays cholinomimetic properties in vivo. The present study was undertaken to characterize more fully this action by examining the effects of (R)-NAEE in a number of pharmacological and biochemical tests of cholinergic action. (R)-NAEE was found to produce negative inotropic and chronotropic effects on the guinea pig atria (pD2 = 5.91 and 5.62, respectively), and was capable of stimulating contractions in the guinea pig ileum (pD2 = 5.95) and rat jejunum (pD2 = 5.40) at concentrations similar to bethanechol. Both the cardiac and intestinal effects of (R)-NAEE were reversed by atropine. Moreover, (R)-NAEE competed with N-[3H]methylscopolamine and [3H]pirenzepine for muscarinic binding sites in a variety of tissues. Like carbachol, (R)-NAEE inhibited GTP-stimulated adenylate cyclase in rat striatal membranes (EC50 = 52 microM), whereas, unlike carbachol, (R)-NAEE was unable to stimulate inositol phosphate accumulation in rat cerebral cortical slices, behaving as an antagonist in this latter system (pA2 = 5.0). The results indicate that (R)-NAEE interacts directly with cholinergic muscarinic receptors, being an agonist for the M2 subtype and an antagonist at M1 sites.

Adenylyl Cyclase Inhibitors↗
PubMed1987

Myocardial opiate receptor activity is stereospecific, independent of muscarinic receptor antagonism, and may play a role in depressing cardiac function.

Earlier work has shown that morphine sulfate can produce a dose-related decrease in heart rate (HR) and cardiac output (CO) in isolated working rat hearts. This response is preventable with the use of the opiate receptor antagonist, naloxone hydrochloride. In this study, the stereospecificity of the opiate response was tested with the use of levorphanol tartrate and its d-isomer, dextrorphan, in our Langendorff rat heart model. The interaction of muscarinic receptor activity with the opiate response was tested by first adding bethanechol chloride to the perfusate in the presence and absence of atropine (5 X 10(-9) mmol/L). Our earlier studies with morphine sulfate were then repeated in the presence of the same concentration of atropine. At a concentration of 5 X 10(-6) mmol/L, levorphanol tartrate produced a significant decrease in CO (p less than 0.05), while a similar concentration of dextrorphan produced little change in either HR or CO. Bethanechol chloride, in a concentration of 3 X 10(-6) mmol/L, produced a significant decrease in HR and CO (p less than 0.05), which was prevented by atropine. When morphine sulfate was added to the standard perfusate (3 X 10(-4) mmol/L), HR and CO were significantly decreased (p less than 0.05). This change was not prevented by the addition of atropine. The opiate effect on myocardial function is mediated by a stereospecific opiate receptor, which acts independently of muscarinic receptor antagonism.

Animals↗
PubMed1987

Intracerebroventricular cholinergic drug administration in Alzheimer's disease: preliminary results of a double-blind study.

In June 1983, we began evaluating intracerebroventricular (ICV) cholinergic drug infusion in patients with biopsy-documented Alzheimer's disease (AD). An initial trial in four patients showed this treatment approach to be feasible, but objective improvement in cognitive or social function was not documented (Harbaugh et al., 1984; Harbaugh, 1986). A double-blind, placebo-controlled crossover study involving a larger number of patients has since been done. The results of this study, presented here, document a statistically significant improvement in some cognitive test results during periods of drug infusion. However, the clinical applicability of this treatment approach is still questionable. A collaborative, double-blind study evaluating activities of daily living and cognitive test results during drug and placebo infusion is presently underway and should better define the safety and efficacy of this treatment approach for patients with AD.

Aged↗
PubMed1987

Somatostatin effects on gastric electrolytes and pepsin in dogs with various secretory stimuli.

To determine possible sites and mechanisms of action of somatostatin (SS) in gastric secretory mucosa, secretion of pepsin, H+, Cl-, Na+ and K+ was stimulated in conscious fistula dogs by i.v. infusion of bethanechol, pentagastrin and histamine in the absence and presence of SS-14. At low dose (0.5 micrograms or 300 pmol/kg/h), SS-14 potently inhibited H+ and pepsin stimulated by bethanechol (80 micrograms/kg/h) to less than 5% of control; it required 2 micrograms or 1200 pmol/kg/h of SS-14 to achieve similar inhibition of pentagastrin (1.5 micrograms/kg/h)-stimulated secretion. In both cases, gastric [K+] was depressed by SS-14 infusion and recovered before H+ and pepsin. Similar sensitivity to SS suggests a Ca++-dependent mechanism or pathway of stimulation by gastrin similar to that by cholinergic agonists. By contrast, histamine, which acts via cyclic AMP pathways, was not inhibited by a large dose of SS-14 (20 micrograms/kg/h). SS inhibition is thus agonist (or pathway)- rather than organ- or cell-specific.

Adenylyl Cyclase Inhibitors↗
PubMed1987

Exocrine pancreatic response to secretin and bethanechol in rabbits under hypothermia.

The effect of the administration of secretin and bethanechol on exocrine pancreatic secretion was studied in rabbits subjected to temperature changes; these involved a drop from 38 degrees C +/- 1 to 28 degrees C +/- 1 (hypothermia) and a subsequent return to 38 degrees C +/- 1 (normothermia). It was observed that hypothermia does not depress the action of secretin on the secretion of fluid, HCO3- and Cl-. Neither was the action of bethanechol on the enzyme secretion affected by changes in body temperature.

Animals↗
PubMed1988

Increment of calmodulin in proportion to enhancement of non-nicotinic responses after preganglionic stimulation of the dog cardiac sympathetic ganglia.

The possible involvement of calmodulin in ganglionic function was investigated. Drugs were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.), unless otherwise stated. Positive chronotropic responses to angiotensin II (0.1 and 0.2 micrograms) were enhanced after repetitive high frequency preganglionic stimulation to the right stellate ganglion. After the stimulation, positive chronotropic responses to bethanechol (2.5, 5 and 10 micrograms), but not those to dimethylphenylpiperazinium (2.5, 5 and 10 micrograms), also were enhanced. The enhancement of response to angiotensin II was not affected by i.v. pretreatment with hexamethonium (40 mg/kg) plus atropine (1 mg/kg) or nifedipine (1 mg/kg). Responses to angiotensin II were not enhanced by A23187 (0.3 mg). The enhanced response to angiotensin II after the stimulation was reduced by the calmodulin antagonists, trifluoperazine (0.1, 0.2 and 0.4 mg) and by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (0.5, 1 and 2 mg), but not by promethazine (1 mg) and N-(6-aminohexyl)-1-naphthalenesulfonamide (0.5, 1 and 2 mg). The enhanced response to bethanechol after the stimulation also was inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. Pretreatment with N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide before the stimulation prevented development of the enhancement in responses to the peptide. The inhibition of endogenous protein synthesis by cycloheximide, 2.5 or 5 mg/kg i.v. 6 hr before surgical procedures, strongly inhibited development of the enhancement in responses to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1988

Antihistaminic and antimuscarinic effects of amitriptyline on guinea pig ileal electrolyte transport and muscle contractility in vitro.

Amitriptyline, a tricyclic antidepressant, was tested for antimuscarinic and antihistamine effects against bethanechol and histamine-stimulated contractility and secretion in the guinea pig ileum in vitro. Comparisons were made with muscarinic-receptor antagonists, as well as with H1 and H2 histamine-receptor antagonists. Amitriptyline (0.01-5.0 microM) produced a parallel rightward shift in the concentration-response curves to histamine in muscle (Ki 0.4 nM) and mucosa (Ki 450 nM). The H1-receptor antagonists pyrilamine and diphenhydramine were less potent against histamine in the muscle and more potent against histamine in the mucosa than was amitriptyline. The H2-receptor antagonist cimetidine was ineffective in the muscle and mucosa. Amitriptyline (0.1-2 microM) also produced a parallel rightward shift in the concentration-response curve to bethanechol in muscle (Ki 133 nM) and mucosa (Ki 143 nM). Against bethanechol, in both tissues, atropine and 4-diphenylacetoxy-N-methyl piperidine methiodide were more potent competitive antagonists than was amitriptyline. Pirenzepine produced a competitive blockade of bethanechol in the muscle and a noncompetitive blockade in the mucosa. The data indicate that amitriptyline exerts more potent antihistaminic effects on guinea pig ileal muscle than the mucosa but that the tricyclic drug is equipotent as an antimuscarinic in both tissues.

Amitriptyline↗
PubMed1988

Effect of chlorpromazine (CPZ) on cholecystokinin-induced gallbladder contraction: the role of calcium.

Smooth muscle contraction is initiated by a rise in intracellular calcium, which binds to calmodulin resulting in myosin phosphorylation. CPZ impairs smooth muscle contraction by either interfering with calcium influx at low concentrations (less than 1.25 x 10(-5) M) or inactivating calcium-calmodulin at higher levels. This chlorpromazine effect was used to determine if gallbladder agonists act through different intracellular mechanisms. Guinea pig gallbladders were mounted in an organ bath and auxotonic contractions induced by bethanechol, KCl and the octapeptide of cholecystokinin (CCK). Bethanechol and KCl-induced contractions were profoundly inhibited by 1.25 x 10(-5) M CPZ throughout the dose-response curve. In contrast, CPZ did not affect CCK-mediated contractions at CCK concentrations less than 5.7 x 10(-8) M. At maximal CCK doses (3 x 10(-7) M), CPZ had only a modest inhibitory effect of 20%, compared with tension losses of 62 and 80% for bethanechol and KCl, respectively. This inhibition with high-dose CCK was offset by increasing extracellular calcium in the organ bath. The resistance of CCK to CPZ inhibition at low doses within the physiologic range implies that CCK acts independently of extracellular Ca2+ unlike the other agonists. Higher CPZ concentrations, greater than or equal to 1.25 x 10(-4) M, markedly suppressed CCK throughout the dose-response curve. Cholecystokinin may act via myosin phosphorylation, but unlike other agonists any rise in cytoplasmic calcium likely originates from an intracellular site.

Animals↗
PubMed1988

Muscarinic cholinergic receptor subtype on frog esophageal peptic cells: binding and secretion studies.

The muscarinic receptors coupled to pepsinogen secretion on isolated frog esophageal peptic cells have been characterized using functional and radioligand binding techniques. N-[3H]methylscopolamine [( 3H]NMS) binding to intact cells was complex and indicative of a high affinity, low capacity site and a high capacity uptake site. Binding to the high capacity site was inhibited by atropine with high affinity (IC50, 3 nM) and by imipramine and propranolol with IC50 values of 70 and 270 nM, respectively. After inhibition of uptake by 30 microM propranolol, [3H]NMS bound to a single population of high affinity sites (KD, 125 +/- 16 pM), which exhibited binding site maximum of 2.1 fmol/10(6) cells, equivalent to 1260 sites/cell. Binding to these sites was reversible, stereoselective and inhibited by muscarinic receptor agonists with an order of potency: oxotremorine greater than acetylcholine greater than carbachol greater than bethanechol and by antagonists with an order of potency:atropine greater than 4-diphenylacetoxy-N-methylpiperidine methobromide greater than pirenzepine greater than AF-DX 116 (11-2[2-[[diethylamino) methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one). Pepsinogen secretion was stimulated by the agonists with an order of potency: acetylcholine greater than or equal to carbachol greater than oxotremorine greater than bethanechol. Atropine, pirenzepine and AF-DX 116 competitively inhibited carbachol-stimulated pepsinogen secretion with pA2 values of 9.58, 7.37 and 6.68, respectively, which correlated with their log (inhibition constants) for receptor binding. By contrast, agonists with significant efficacy exhibited EC50 values which were 20 to 90 times lower than their inhibition constants for binding which suggests the possibility of "spare" muscarinic receptors. Our findings indicate that functional muscarinic receptors on peptic cells exhibit similar characteristics to the high affinity sites labeled by [3H]NMS.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗