[Effect of 13 cholinergic antagonists on M-cholinergic receptors in rat hearts].
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Animals↗
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Comparative behavioral and neurochemical activities of cholinergic antagonists in rats.
The comparative behavioral and neurochemical activities of the muscarinic cholinergic antagonists scopolamine, trihexyphenidyl and pirenzepine, and the nicotinic cholinergic antagonist mecamylamine were evaluated in rats. The three muscarinic antagonists, but not the nicotinic antagonist, impaired memory performance in a spatial alternation task. The minimal effective doses required to disrupt behavior were 0.03, 1.0 and 10 mg/kg for scopolamine, trihexyphenidyl and pirenzepine, respectively. Scopolamine and trihexyphenidyl inhibited ex vivo binding of [3H] pirenzepine to M1 receptors in cerebral cortex, indicating ready penetration into the brain. In contrast, pirenzepine penetrated into the brain at relatively high doses, suggesting poor penetration into the brain. Scopolamine and trihexyphenidyl, but not pirenzepine, inhibited [3H]quinuclidinyl benzilate binding to brain stem M2 receptors ex vivo after subcutaneous administration. In addition, scopolamine and trihexyphenidyl, but not pirenzepine, decreased acetylcholine (ACh) levels in striatum and hippocampus, presumably by increasing ACh release by blocking ACh feedback inhibition at M2 receptors. Scopolamine and trihexyphenidyl also produced modest decreases in levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in striatum, most likely due to blockade of M1 heteroreceptors on dopamine nerve terminals. The present results are consistent with the interpretation that muscarinic antagonists impair memory performance in rats, at least in part, by blocking M1 muscarinic receptors. The present results do not support a role for blockade of M2 receptors. Further research is needed to determine the extent to which blockade of other (M3, M4, M5) muscarinic receptor subtypes contributes to the memory-impairing effects of muscarinic cholinergic antagonists.
Acetylcholine↗
Morphine withdrawal syndrome responses to cholinergic antagonists and to a partial cholinergic agonist.
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Animals↗
Central muscarinic cholinergic antagonists block wet-dog shakes produced by the TRH analog MK-771 in the rat.
Thyrotropin-releasing hormone (TRH) is known to elicit wet-dog shakes in rats through a central mechanism of action. In the present study, the ability of muscarinic cholinergic antagonists to inhibit TRH-mediated wet-dog shakes was examined. The longer-acting TRH analog, MK-771, at doses of 1.0, 1.5 and 3.0 mg/kg elicited wet-dog shakes in a dose-dependent manner. The centrally-acting muscarinic cholinergic antagonists, atropine and scopolamine, at doses of 5 and 0.8 mg/kg, respectively, significantly reduced the ability of only the highest dose of MK-771 to elicit wet-dog shakes. When the peripherally-acting antagonists, methylscopolamine and methylatropine, were examined, they were not found to significantly reduce wet-dog shakes produced by MK-771 at doses of 5 and 0.8 mg/kg, respectively. The results of this study suggest that cholinergic antagonists inhibit MK-771-induced wet-dog shakes in a noncompetitive manner and support the view that TRH-mediated wet-dog shakes are modulated by central muscarinic cholinergic systems.
Animals↗
Inhibition of catecholamine secretion from adrenal medulla cells by neurotoxins and cholinergic antagonists.
The effects of several neurotoxins and cholinergic antagonists on the nicotine-induced secretion of catecholamines by adrenal medulla cells in culture were investigated. Aconitine, veratridine, and batrachotoxin, in the presence of 1 micrometer-tetrodotoxin inhibited the nicotine-stimulated secretion of catecholamines in a dose-dependent manner in Locke's solution. In Na+-free sucrose medium, tetrodotoxin was not required to inhibit the stimulatory effects of aconitine, veratridine, and batrachotoxin, and these agents by themselves inhibited the nicotine-stimulated secretion of catecholamines. Scorpion venom, which also increases the flux of Na+ through tetrodotoxin-sensitive channels, was not an effective inhibitor of nicotine-stimulated secretion. Histrionicotoxin, atropine, hexamethonium, and decamethonium--as well as the Na+-channel activators--noncompetitively inhibit nicotine-stimulated secretion. The effects of these agents on nicotine-stimulated secretion appears similar to their effects on the inhibition of depolarization at the neuromuscular junction. Reversibility studies suggest that the stimulatory and inhibitor sites of the neurotoxins are different, while studies in Na+-free media suggest that tetrodotoxin-insensitive sodium channels are not involved in the inhibitory effect of the neurotoxins. A possible site of action for the inhibitory effects of the neurotoxins. A possible site of action for the inhibitory effects of the neurotoxins is the nicotinic-receptor-associated ion channel.
Acetylcholine↗
Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue.
The nicotinic cholinergic antagonist, dihydro-beta-erythroidine, binds to two sites in rat cortical membranes with dissociation constants of 4 and 22 nM and respective apparent Bmax values of 52 and 164 fmol/mg of protein. Binding to the higher affinity site, defined by the use of 2 nM [3H]dihydro-beta-erythroidine, was saturable, reversible, and susceptible to protein denaturation. Binding was highest in the thalamus and lowest in the spinal cord and showed preferential enrichment in a synaptosomal subfraction of rat brain. Nicotine displaced [3H]dihydro-beta-erythroidine in a stereospecific manner, the (-)-isomer being approximately 6 times more potent than the (+)-isomer. The alkaloid nicotinic agonists, cytisine and lobeline, were potent inhibitors of binding, while acetylcholine in the presence of the cholinesterase inhibitor di-isopropylfluorophosphate was equipotent with (+)-nicotine. Binding was also inhibited by the muscarinic ligands, arecoline, atropine, and oxotremorine. The nicotinic antagonists mecamylamine, hexamethonium, and pempidine were essentially inactive in displacing [3H]dihydro-beta-erythroidine. These findings indicate that dihydro-beta-erythroidine binds to a nicotinic recognition site in rat brain which is neuromuscular, rather than ganglionic, in nature and that such binding is similar in several respects to that seen with nicotinic agonists. Whether such binding is to a nicotinic, as opposed to nicotinic cholinergic, recognition site or to a "common" nicotinic/muscarinic site is an issue that requires further study.
Alkaloids↗
The long latency component of retinotectal transmission: enhancement by stimulation of nucleus isthmi or tectobulbar tract and block by nicotinic cholinergic antagonists.
The optic tectum of teleosts contains high concentrations of nicotinic and muscarinic acetylcholine receptors and receives putative cholinergic innervation from both nucleus isthmi in the tegmentum and a population of intrinsic tectal cells. Using in vitro preparations of goldfish brain, we have examined the effects of cholinergic antagonists and stimulation of nucleus isthmi on the tectal response to optic nerve stimulation. Our results show that: (1) a long latency component of the retinotectal field potential is polysynaptic in origin and occurs in isolated tectum; (2) this component can spread across the tectum from a beam of stimulated fibers and can appear in areas where the monosynaptic response is small or absent; (3) both monosynaptic and long latency components of the field potential are enhanced by prior stimulation of nucleus isthmi or the tectobulbar tract (15-300 ms); (4) both the long latency component of the field potential and the effects of stimulation of nucleus isthmic or tectobulbar tract are blocked by low concentrations of nicotinic antagonists; and (5) in deeper tectum a second polysynaptic response uncovered by pharmacological block of inhibition is not blocked by nicotinic antagonists. These results indicate that the cholinergic neurons intrinsic to tectum have a role in the spread of retinotectal excitation by nicotinic actions, and that stimulation of nucleus isthmi or tectobulbar tract facilitates activity in this system. There is in addition a separate recurrent excitatory circuit in tectum.
Alcuronium↗
Cholinergic antagonists in a solitary wasp venom.
The venom of the solitary wasp Philanthus triangulum contains a cholinergic antagonist of the nicotinic receptor of the rectus abdominis muscle of the frog, Xenopus laevis. The venom of African P. triangulum contains two different cholinergic factors, a competitive and a non-competitive antagonist. The venom of the European P. triangulum may not contain a competitive antagonist of the nicotinic receptor of X. laevis, but only a very strong non-competitive antagonist. The possible non-synonymity of both groups of P. triangulum is discussed.
Acetylcholinesterase↗
Effects of a selective and a nonselective muscarinic cholinergic antagonist on heart rate and intestinal motility in dogs.
The effects of methoctramine, a cardioselective muscarinic cholinergic antagonist, on heart rate and small intestinal motor activity were compared to those of the nonselective competitive muscarinic antagonist, atropine. Methoctramine or atropine, 6, 10, 30, 60 micrograms/kg, or sterile isotonic saline, was administered intravenously to six conscious dogs in cross-over studies. Methoctramine administration caused dose-dependent tachycardia without affecting intestinal motility, while atropine administration caused dose-dependent tachycardia accompanied by significant reductions in small intestinal motility. Additionally, methoctramine did not inhibit intestinal smooth muscle contractile activity initiated by the muscarinic agonist bethanechol, while atropine inhibited bethanechol-induced contractile activity in a dose-dependent manner. Calculated, dosages of methoctramine and atropine required to produce a 50% increase in heart rate over baseline were 35.1 +/- 5.3 and 39.5 +/- 6.2 micrograms/kg, respectively. This dosage of atropine caused a 93 +/- 13.9% reduction in intestinal motility. These findings suggest that selective muscarinic antagonists may be useful drugs for those veterinary patients in which nonselective muscarinic antagonists have the potential to produce untoward effects on intestinal motility.
Animals↗
Effect of cholinergic antagonists on basal and osmotically stimulated vasopressin release in compartmentalized hypothalamo-neurohypophysial explants.
The effects of cholinergic antagonists on vasopressin (VP) release were studied in an organ-cultured, compartmentalized, rat hypothalamo-neurohypophysial system which allows selective application of stimuli to either hypothalamus or pituitary without disrupting axonal connections. Release of vasopressin from the neurohypophysis was measured by radioimmunoassay. Hexamethonium (10(-5) M) and atropine (5 X 10(-5) M) were tested both alone and in combination with hypothalamic osmotic stimulation (+ 15 mosm/kg H2O). In hypothalamus, neither hexamethonium nor atropine had any effect on basal VP release from pituitary. Hexamethonium, but not atropine, prevented the increase in VP release produced by increased osmolality of the hypothalamus side culture medium. In contrast, hexamethonium had no effect when applied to pituitary side, whereas atropine suppressed both basal and osmotically stimulated VP release. Atropine had no effect on basal or KCl-induced VP release in detached neural lobes. Acetylcholine (Ach) (10(-5) M) to pituitary plus simultaneous, hypothalamic stimulation (osmotic or 10(-5) M Ach) did not increase VP release above the hypothalamic stimulus alone. The results support a role for a hypothalamic excitatory nicotinic mechanism in osmoregulation. The presence of a muscarinic mechanism affecting VP release in pituitary was reconfirmed, but the data did not support the hypothesis that Ach stimulates VP release in pituitary by a presynaptic facilitatory mechanism.
Acetylcholine↗
Methoctramine, a cardioselective muscarinic cholinergic antagonist, prevents fentanyl-induced bradycardia in the dog.
A controlled study examining the effects of the cardioselective muscarinic cholinergic antagonist methoctramine on fentanyl-induced bradycardia was performed in six dogs. Five doses of methoctramine (6, 10, 20, 30 and 60 micrograms/kg) followed by fentanyl (20 micrograms/kg) were administered randomly on separate days. Fentanyl caused a significant reduction in heart rate from baseline values. Moreover, fentanyl produced a variety of arrhythmogenic actions indicative of vagal hyperactivity, including sinus bradycardia, second-degree atrioventricular block and ventricular and supraventricular escape beats. Administration of methoctramine 5 min before fentanyl injection prevented the bradycardic effects of fentanyl in a dose-dependent manner, with high doses of methoctramine causing sinus tachycardia. Using regression analysis, the dose of methoctramine necessary to prevent fentanyl-induced bradyarrhythmias without causing tachycardia was calculated as 14.4 micrograms/kg. The study confirmed that fentanyl administration in the conscious dog causes profound bradycardia with bradyarrhythmias. The cardioselective muscarinic antagonist agent methoctramine prevented the bradycardic effects of fentanyl.
Analysis of Variance↗
Acute toxicity of several organophosphorous insecticides and protection by cholinergic antagonists and 2-PAM on Artemia salina larvae.
The acute toxicity of chlorpyrifos, methylchlorpyrifos, parathion and methylparathion to three age classes of Artemia salina was determined. In general, A. salina 24-h old was less sensitive to these organophosphorous insecticides (OPI) than A. salina 48-h old and A. salina 48-h old was significantly more tolerant than A. salina 72-h old, in contrast, chlorpyrifos was equally toxic to A. salina 48- and 72-h old. There were some differences among the three age classes of A. salina in the relative order of toxicity of OPI tested. The rank order of toxicity to A. salina 48-h old was methylparathion < parathion < methyl-chlorpyrifos < chlorpyrifos, while to A. salina 24- and 72-h old it was methylparathion = parathion < methyl-chlorpyrifos < chlorpyrifos. The protective effect of the cholinergic antagonists atropine, hexamethonium, pirenzepine and 11-(2-((diethyl-amino)methyl)-1-piperidinylacetyl)-5, 11-dihydro-6H-pyrido(2,3-b)-(1,4)-benzodiazepine-6-one (AF-DX 116) and a cholinesterase-reactivating oxime 2-pyridine aldoxime methochloride (2-PAM) on the mortality due to four selected OPI in Artemia salina 24-h old was investigated. The lethal action of OPI tested was completely prevented by pretreatment of Artemia salina 24-h old with 2-PAM (10(-5) M) and atropine (10(-4 )M). However no concentration of hexamethonium, pirenzepine or AF-DX 116 protected 100% of the animals poisoned by LC84 of the OPI selected, maximum protection obtained was 71 to 88%. In contrast, the maximum inhibition of mortality obtained with AF-DX 116 pretreatment was about 55% because this compound was used at concentrations which were non toxic to control Artemia salina. Atropine, hexamethonium, pirenzepine, AF-DX 116 and 2-PAM afforded 50 % protection (IC50) of Artemia salina against mortality by LC84 of the OPI selected at concentrations in the range of 6.62x10(-7)-1.6x10(-6) M, 2. 38x10(-4)-2.05x10(-3)M, 8.91x10(-7)-1.24x10(-6) M, 9.66x10(-8)-1. 34x10(-7 )M, and 1.95x10(-8)-2.73x10(-8 )M, respectively. Pretreatment of atropine plus 2-PAM to determine whether this combination afforded greater inhibition of the lethality induced by four OPI tested than pretreatment with either atropine or 2-PAM alone was investigated. Atropine (10(-5) M) in combination with 2-PAM (10(-7 )M) inhibited completely the acute toxicity of all OPI tested, while the pretreatment with atropine (10(-6) M) plus 2-PAM at the same concentration gave a inhibition of mortality (about 62%) significantly greater than each antagonist alone (about 14 and 46%, respectively).
Animals↗
Neither adrenergic nor cholinergic antagonists in the central nervous system affect 2-deoxy-D-glucose(2-DG)-induced hyperglycemia.
To investigate whether the brain adrenergic and cholinergic neurotransmitter systems are involved in the regulation of 2-deoxy-D-glucose (2-DG)-induced hyperglycemia, we studied the effects of adrenergic and cholinergic antagonists on 2-DG-induced secretion of epinephrine and glucagon, and hyperglycemia, in anesthetized fed rats. When 2-DG (10 mg/10 microliters) was injected into the third cerebral ventricle, hepatic venous plasma glucose, glucagon, and epinephrine concentrations were significantly increased. Co-administration of phentolamine, propranolol, atropine and hexamethonium (1 X 10(-7) mol) with 2-DG did not modify the hyperglycemia and hormonal responses normally observed after the administration of 2-DG alone. From this evidence we concluded that neither brain adrenoceptive nor cholinoceptive neurons are involved in the regulation of 2-DG-induced hyperglycemia.
Adrenergic Fibers↗
[Hypersensitivity in the pupil dilation response to a cholinergic antagonist in patients with Alzheimer's disease and Down's syndrome].
In 1994, Scinto et al. reported hypersensitivity in the pupil-dilation response to topical application of a cholinergic antagonist, tropicamide, in patients with Alzheimer-type dementia. Similar tests on Japanese subjects showed significant differences in pupil response between subjects with Alzheimer-type dementia (under age 70 years) and age-matched controls. The present study included 24 patients with early-onset Alzheimer-type dementia, 29 patients with late-onset Alzheimer-type dementia, 15 healthy controls (all spouse of patients with Alzheimer-type dementia), 9 patients with vascular dementia and 5 patients with Down's syndrome. After adapting to semi-darkness (10 lux), a solution of tropicamide (Midrin-P, Santen Co, Ltd) was instilled into the right eye. Pupil diameters were measured every 5 to 10 min, and the maximum pupil diameter for each eye was used in the data analysis. The solution was diluted until the tropicamide concentration reached 0.01%. Pupil diameters were measured, and differences between baseline and maximum pupil diameter were computed. Among 18 patients with early-onset Alzheimer-type dementia (mean age 63.9 years) the pupils dilated by 1.12 +/- 0.52 mm (mean +/- SD) as compared with 0.20 +/- 0.75 mm in 7 age-matched controls (mean age 57.8 years); this difference was significant (T-test, p < 0.05). Correlations between the degrees of pupillary dilation and the scores on the revised version of Hasegawa's Dementia Scale were not significant. These data suggest that in subjects under 70 years of age, the diagnostic methods described by Scinto et al. can be used to distinguish those with Alzheimer-type dementia from those without dementia, but those methods may not be effective in subjects over 70 years of age.
Adult↗
Effect of cholinergic antagonists on sympathetic ganglionic transmission of vasomotor reflexes from the carotid baroreceptors and chemoreceptors of the dog.
1. In anaesthetized dogs the reflex vascular resistance changes in a perfused hind limb were studied following carotid baroreceptor or chemoreceptor stimulation. 2. The observed rises in resistance were sympathetically mediated and thus provided a means of studying the action of the cholinergic antagonists on the sympathetic ganglion transmission. 3. The reflex response to carotid baroreceptor stimulation produced by lowering the pressure in the carotid sinuses was abolished by hexamethonium bromide but not reduced by hyoscine methyl bromide. 4. The reflex response to carotid body chemoreceptor stimulation, by hypoxia, was not altered by hexamethonium bromide but was greatly reduced by the hyoscine methyl bromide. No reflex response was seen when both antagonists were present. 5. These results indicate that sympathetic ganglion synaptic transmission during the baroreceptor reflex is mediated by nicotinic receptor activation. The transmission evoked by chemoreceptor stimulation involves muscarinic receptors with a subsidiary nicotinic pathway. High doses of an antagonist were necessary to block the muscarinic component of transmission and this is discussed in relation to previous work. 6. No non-cholinergic transmission of the reflex responses was observed.
Animals↗
Effects of serotonergic and cholinergic antagonists on suckling behavior of neonatal, infant, and weanling rat pups.
In Experiment 1, Sprague-Dawley rat pups at postnatal days 3-4, 7-8, 10-11, 15-16, and 23-24 were tested for suckling behavior on their anesthesized multiparous dams following administration of metergoline or scopolamine. The serotonergic antagonist, metergoline, inhibited suckling in 3- to 4- and 7- to 8-day-old rat pups, but was not found to influence suckling in older pups. Scopolamine, a cholinergic antagonist, reduced suckling primarily in 3- to 4-day-old pups. In Experiment 2, parity of the maternal female was manipulated to assess whether this variable would influence suckling behavior and the effects of metergoline on suckling of weanlings. Baseline levels of suckling were reduced in 23- to 24-day-old pups of primiparous dams when compared with multiparous-derived offspring. Administration of metergoline increased the amount of time that these primiparous-derived pups spent attached to nipples, but did not influence suckling of offspring of multiparous dams, perhaps as a result of a ceiling effect on suckling behavior in these animals.
Acetylcholine↗
Effects of selective cholinergic antagonists and alpha,beta-methylene ATP on guinea-pig urinary bladder contractions in vivo following pelvic nerve stimulation.
1. An in vivo preparation measuring functional detrusor muscle strength in terms of intravesical bladder pressure (Pves) following in situ pelvic nerve stimulation has been developed in urethane-anaesthetized guinea pigs. 2. The increase in bladder pressure following pelvic nerve stimulation was abolished by topical lidocaine or tetrodotoxin, suggesting a neurogenic origin for the in vivo contractile response. 3. Cholinergic antagonists (i.v.) decreased the amplitude of the peak pressure response by about 50% at both high (30 Hz) and low (5 Hz) stimulation rates, with a rank order of potency of atropine greater than propantheline greater than oxybutynin greater than hexahydrosiladifenidol greater than pirenzepine greater than methoctramine. 4. The P2 purine receptor antagonist, alpha,beta-methylene ATP (i.v.), antagonized pelvic nerve-stimulated bladder contractions differentially at 5 and 30 Hz. At low frequencies, alpha, beta-methylene ATP was both more potent (2.5-fold) and more efficacious (-77 compared to -55% delta) than at 30 Hz. Atropine and alpha,beta-methylene ATP together completely inhibited the contractile response. 5. Together, the findings indicate that in guinea pigs, urinary bladder contractions induced by pelvic nerve stimulation in vivo may be mediated by both muscarinic and purinergic receptors and that these bladder contractions may be mediated by the M2 beta subtype rather than by M1 or M2 alpha muscarinic receptors.
Adenosine Triphosphate↗
A cholinergic antagonist, mecamylamine, blocks light-induced fos immunoreactivity in specific regions of the hamster suprachiasmatic nucleus.
Recent studies have shown that light-induced phase shifts of the circadian rhythm of locomotor activity are associated with c-fos expression in the suprachiasmatic nucleus (SCN) of rodents. In order to explore further the importance of c-fos expression for the phase-shifting effects of light, we examined the effects of mecamylamine on light-induced Fos-like immunoreactivity (Fos-lir) in the SCN. Mecamylamine was chosen because it is a cholinergic antagonist that blocks the phase-shifting effects of light on the circadian activity rhythm in the golden hamster. Golden hamsters were entrained for at least 14 days to a 14 h light: 10 h dark photoperiod. Animals were then placed in constant darkness (DD) and during exposure to DD were subjected to one or more of the following treatments: (1) vehicle alone; (2) mecamylamine alone (450 micrograms, i.c.v.) at circadian time (CT) 19; (3) vehicle plus a light pulse at CT 19; (4) mecamylamine 10 min prior to the light pulse at CT 19. Mecamylamine blocked the phase-shifting effects of light on the circadian rhythm of locomotor activity when compared to vehicle-treated animals (P < 0.001). A light pulse at CT 19 induced Fos-lir in the SCN within 1 h, whereas treatment with vehicle or mecamylamine had no noticeable effect on Fos-lir in the SCN. Mecamylamine pretreatment dramatically reduced light-induced Fos-lir in the SCN by 75%. The most striking observation was the clear inhibition of Fos-lir by mecamylamine in the dorsomedial region of the SCN while there was little inhibition of Fos-lir in the most ventral portions of the SCN.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗