Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT02427 (Atropine)
 3,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to identify subtypes of muscarinic receptor on the rat pancreas, the effects of new muscarinic receptor antagonists, [11-[[2-(diethylamino)-methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) and 4-diphenylacetoxy-N-methylpiperadine-methiodide (4-DAMP), on amylase secretion stimulated by carbachol and binding of [3H]quinuclidinyl benzilate (QNB) were evaluated using isolated rat pancreatic acini. Atropine, pirenzepine, AF-DX 116 and 4-DAMP inhibited carbachol-stimulated amylase release in a dose-dependent manner. All these antagonists caused a concentration-dependent rightward shift of the dose-response curve for carbachol-stimulated amylase release without altering the maximal response. Schild plots revealed that pA2 values for atropine, pirenzepine, AF-DX 116 and 4-DAMP were 9.15, 6.78, 6.09 and 8.79, respectively. Every slope of Schild plots was not different from unity, suggesting that these antagonists act as competitive inhibitors. These antagonists also inhibited the binding of [3H]QNB in a dose-dependent manner. The inhibition constants were 1.21 x 10(-9) M (atropine), 1.26 x 10(-7) M (pirenzepine), 0.57 x 10(-6) M (AF-DX 116) and 2.75 x 10(-9) M (4-DAMP). Thus, the order of inhibitory potencies was atropine > or = 4-DAMP > pirenzepine > AF-DX 116. These findings suggest that 4-DAMP-sensitive M3 receptor may play an important role in the pancreatic exocrine functions.
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PMID:Characterization of muscarinic receptor subtypes on rat pancreatic acini: pharmacological identification by secretory responses and binding studies. 128 Nov 28

1. Airways derived from different levels of the lung exhibit a difference in the reactivity and sensitivity to agonists. We have evaluated the effect of acetylcholine and cholinergic selective (pirenzepine, gallamine and 4-dipherylacetoxymethyl piperidine [4-DAMP]) and non-selective (atropine) antagonists on bovine proximal and distal smooth muscle preparations. 2. The distal preparations are more sensitive to acetylcholine than proximal bronchi. The relaxant effect of three selective antagonists on the distal and proximal tissues was the same when the results for each drug were compared. 3. Atropine and 4-DAMP were more potent than pirenzepine and gallamine in relaxing both proximal and distal bovine smooth muscle preparations. 4. These data suggest that the muscarinic sites on the smooth muscle of bovine airways are of the M3 subtype.
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PMID:Responsiveness and sensitivity to cholinergic agonists and antagonists in bovine isolated bronchial muscle. 139 6

1. The nature of the muscarinic receptor subtype mediating endothelium-dependent vascular relaxation was investigated in the perfused mesenteric vascular bed preparation which is a model for resistance vessels. 2. After methoxamine-induced vasoconstriction the vessels were dilated with acetyl-beta-metacholine (MCh). 3. The potency of the M1-selective antagonist pirenzepine, the M2-selective antagonists AF-DX 116 and AQ-RA 741, the M3-selective antagonists 4-DAMP and p-FHHSiD to block the MCh-induced vasodilation was quantified by means of pA2-values. Atropine was used for comparison. 4. The rank order of potency for the various muscarinic receptor antagonists appears to be: atropine > 4-DAMP > p-FHHSiD > pirenzepine > AQ-RA 741 > AF-DX 116 which is similar to findings in conduit arteries. 5. The high potency of the M3-selective antagonists 4-DAMP and p-FHHSiD and the low potency of the M1- and M2-selective antagonists suggest a major role of M3-receptors in the cholinergic vasodilatation in the perfused mesenteric vascular bed.
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PMID:Characterization of the muscarinic receptor subtype mediating vasodilation in the rat perfused mesenteric vascular bed preparation. 147 6

Experiments were performed in bovine cerebral arteries preincubated with [3H]-choline or [3H]-noradrenaline to analyze the presynaptic muscarinic receptors involved in inhibition of acetylcholine and noradrenaline release induced by electrical stimulation (4 Hz, 200 mA, 0.3 ms, 1 min). For this purpose, the actions of several muscarinic receptor antagonists on the 3H overflow and on the carbachol-induced inhibition of this overflow were assessed. The evoked [3H]-acetylcholine release and [3H]-noradrenaline release were markedly reduced by the presence of tetrodotoxin, Ca(2+)-free medium, and the inhibitor of both choline transport and choline acetyltransferase, AF64A. Chemical sympathetic denervation with 6-hydroxydopamine (6-OHDA) decreased the uptake of [3H]-noradrenaline, and AF64A reduced mainly the uptake of [3H]-choline, but also of [3H]-noradrenaline. Carbachol reduced the evoked [3H]-noradrenaline and [3H]-acetylcholine release; the IC50 values were 0.37 and 0.43 mumol/l, respectively. Atropine and 4-DAMP, but not AF-DX 116, methoctramine or pirenzepine, increased the evoked [3H]-acetylcholine release. However, these muscarinic antagonists failed to modify the evoked [3H]-noradrenaline release. Carbachol inhibited the release of both acetylcholine and noradrenaline. The inhibition was blocked by the antagonists. The rank orders of potency (based on plC50 values) were, in the case of [3H]-acetylcholine release, atropine greater than 4-DAMP greater than AF-DX 116 greater than or equal to pirenzepine greater than or equal to methoctramine, and, in the case of [3H]-noradrenaline release, atropine greater than 4-DAMP greater than AF-DX 116 greater than or equal to methoctramine greater than or equal to pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presynaptic muscarinic receptor subtypes involved in the inhibition of acetylcholine and noradrenaline release in bovine cerebral arteries. 163 87

The biochemical events which are coupled to the subtypes of muscarinic cholinergic receptors in rat salivary glands were studied. The subtype property of this receptor system was characterized by the use of 3H-QNB binding to glandular membrane homogenates. The Kd and Bmax values of this binding were found to be 0.2 nM and 210 fmole/mg protein respectively. In the drug-displacement study on the 3H-QNB binding the following potency order was obtained (based on the IC50 values calculated from each individual dose-response curve): Atropine greater than 4-DAMP greater than HHSiD greater than Pirenzepine greater than AF-DX 116. This order is a typical M3 muscarinic subtype, according to the recent consensus. Carbachol (0.1 mM) caused a 4.4-fold increased in IP3 production over the basal level, when tissue fragments were prelabeled with 3H-inositol. The above mentioned cholinergic antagonists could block this event in a similar potency order. Carbachol (0.1 mM) did not have a significant effect on the basal level of cAMP formation of these tissue homogenates. On the other hand, it had a 33% reduction of isoproterenol (10 microM)-enhancing cAMP formation. The reduction effect of carbachol on cAMP formation could also be blocked by the above mentioned cholinergic antagonists in a similar order. Our results indicated that rat salivary glands have M3 muscarinic receptors and the activation of these receptors causes changes in both phosphatidylinositol turnover and cAMP formation.
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PMID:Evidence for the coupling of muscarinic M3 receptor to cyclic AMP formation and poly-phosphatidylinositol turnover in rat salivary glands. 166 96

The antagonism of carbachol-induced contractions of guinea-pig common bile duct smooth muscle strips by various antagonists has been investigated in order to find out the muscarinic receptor subtype(s) of common bile duct smooth muscle. Atropine, pirenzepine, 4-DAMP and AF-DX 116 were used as nonselective, M1-selective, M1- and M3-selective and M2-selective muscarinic antagonists, respectively. All muscarinic antagonists examined displaced the concentration-response curves to the right, parallelly and in a concentration-dependent manner, without affecting maximum response. Schild analysis of data was consistent with competitive antagonism. pA2 values of the antagonists were as follows: atropine, 9.59; pirenzepine, 7.32; 4-DAMP, 8.99; AF-DX 116, 6.85. When these pA2 values are compared with those obtained in the ileum, it may be concluded that the muscarinic receptors of the guinea-pig common bile duct mediating cholinomimetic-induced contractions, are of the M3 subtype, but not of the M1 and M2 subtypes.
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PMID:Muscarinic receptor subtypes of guinea-pig common bile duct. 177 34

The regulation of acetylcholine (ACh) release by the different subtypes of muscarinic (M) receptors in the hippocampus of freely-moving Fischer and Sprague-Dawley rats, was investigated. Atropine (10 mumol/kg i.p.) induced a pronounced increase of ACh release (+400% over basal values) in the hippocampus of young rats (3 months) while the effect was drastically reduced (+100% over basal values) in old rats (24 months). The preferential M2 antagonist AF-DX 116 (50 mumol/kg i.p.) showed similar effects in young and old rats being, furthermore, 10 times less potent than atropine. The preferential M1 antagonist pirenzepine (50 mumol/kg i.p.) was even less potent than AF-DX 116 in enhancing ACh release in young rats, while the effect was more pronounced in the old ones. Therefore, the effect of the preferential M3 antagonist 4-DAMP was studied. 4-DAMP 10(-6) M, dissolved in the Ringer solution perfusing the hippocampus, induced an enhancement of ACh release (+200% and +70% over basal values, in young and old rats, respectively) which was comparable to that obtained after atropine at the same concentration. AF-DX 116 and pirenzepine, on the other hand, were by far less potent. Six months' pretreatment with acetyl-l-carnitine (ALCAR) reduced the significant differences between young and old rats in the release response after M1 and M3 receptor antagonists. Taken all together, these findings indicate that the regulation of ACh release, at least in the hippocampus, is mainly through the M3 receptors subtype of muscarinic receptors and that this subtype is the most involved in the aging process. Moreover, the ability of ALCAR to preserve the receptor-mediated functional ACh release response with respect to old animals suggests that ALCAR could be utilized in the amelioration of receptor functionality in the aging brain.
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PMID:In vivo probing of the brain cholinergic system in the aged rat. Effects of long-term treatment with acetyl-L-carnitine. 185 4

We investigated the M3/M2 antagonist selectivity of [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCI (DAC 5945) in vivo. ED50 values for reversal of methacholine-induced bronchoconstriction and bradycardia by muscarinic antagonists were determined in anesthetized and ventilated guinea pigs. Atropine, ipratopium, pirenzepine and diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) were non-selective, whereas methoctramine was cardioselective. In contrast, DAC 5945 was a more potent muscarinic antagonist in the airways than in the heart, demonstrating M3/M2 selectivity in vivo.
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PMID:Airway smooth muscle selectivity of the muscarinic antagonist DAC 5945 in vivo. 189 17

Acetylcholine is present in a majority of submucosal neurons which project to the intestinal epithelium. In this study, we examined the role of acetylcholine and the actions of cholinomimetic drugs, such as carbachol (CCH), on ion transport across muscle-stripped sheets of mucosa-submucosa from the proximal jejunum of weaned piglets. Serosal administration of CCH (10 nM-100 microM) produced rapid increases in short-circuit current (Isc) which were attributed to net Cl secretion. Acetylcholine, bethanechol and (4-hydroxy-2-butynyl)-1-trimethylammonium m-chlorocarbanilate chloride were partially effective in increasing Isc. Atropine and selective muscarinic cholinergic antagonists produced dextral shifts in the CCH concentration-effect relationship with an order of relative potency of 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP) greater than atropine much greater than pirenzepine greater than 11-[[[2-(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one(AF-DX116). The muscarinic receptor blocker [3H]quinuclidinyl benzilate (QNB) bound specifically and saturably to two sites in the mucosa-submucosa having equilibrium dissociation constants of approximately 10 +/- 3 and 890 +/- 120 pM and Bmax = 7 +/- 3 and 47 +/- 9 fmol/mg protein, respectively. Selective cholinergic antagonists competed for [3H]QNB binding with a rank order of affinity of 4-DAMP greater than hexahydrosiladifenidol much greater than AF-DX 116 greater than or equal to pirenzepine. Specific [3H]QNB binding sites were autoradiographically localized in the jejunal wall to the epithelium, submucosa, and muscularis propria. Electrical transmural stimulation (10-300 pulses/10 sec, 0.5 msec duration, 60 V stimulus strength) delivered to mucosal sheets produced tetrodotoxin-sensitive Isc elevations which were proportional to the number of impulses delivered. Mucosal Isc responses to electrical stimulation were attenuated by 10 microM hexamethonium, 1 microM atropine or autotachyphylaxis to CCH. Tetrodotoxin, at 0.1 microM, produced a 20-fold increase in the secretory potency of CCH. These results suggest that acetylcholine released from intramural neurons in porcine proximal jejunum produces transepithelial Cl secretion. Its effects may be mediated through interactions with two populations of muscarinic cholinergic receptors, located on neuronal and non-neuronal cells within the intestinal mucosa and submucosa, which serve to inhibit and promote Cl secretion respectively.
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PMID:Muscarinic cholinergic regulation of electrogenic chloride secretion in porcine proximal jejunum. 203 27

The antagonism of acetylcholine-induced contractions of guinea-pig gallbladder and ileum smooth muscle strips via various antagonists has been investigated in order to find out the muscarinic receptor subtype(s) of gallbladder smooth muscle. Atropine, pirenzepine, 4-DAMP and AF-DX 116 were used as nonselective, M1-selective, M1- and smooth muscle M3-selective and cardiac M2-selective muscarinic antagonists, respectively. All the muscarinic antagonists examined displaced the concentration-response curves to the right parallelly in a concentration-dependent manner without affecting the maximum response in both tissues. Schild analysis of data was consistent with competitive antagonism. pA2 values of the antagonists were as follows: a) gallbladder: atropine: 8.43; pirenzepine: 7.81; 4-DAMP: 8.10; AF-DX 116: 6.71; b) ileum: atropine: 9.62; pirenzepine: 6.94; 4-DAMP: 9.41; AF-DX 116: 6.55. It may be concluded that the muscarinic receptors of the guinea-pig gallbladder, which mediate acetylcholine-induced contractions, are not of the cardiac M2-subtype and may be distinguished from ileal smooth muscle M3-receptors because 4-DAMP has a 20.4 times greater affinity for ileal smooth muscle muscarinic receptors.
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PMID:Muscarinic receptor subtypes of guinea-pig gallbladder smooth muscle. 209 36


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