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)

Muscarinic receptor agonist and antagonist effects on acetylcholine release evoked by electrical or dimethylphenylpiperazinium stimulation from guinea pig ileum were evaluated by measuring acetylcholine with a high performance liquid chromatography-electrochemical detector system. AF102B (cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine), a muscarinic M1 receptor agonist, increased markedly the evoked release of acetylcholine. In contrast, pirenzepine decreased the evoked acetylcholine release. 4-DAMP (4-diphenyl-acetoxy-N-methylpiperidine methiodide) and p-F-HHSiD (p-fluoro-hexahydrosiladifenidol), muscarinic M3 antagonists, increased the release of acetylcholine. Atropine enhanced acetylcholine release to a similar extent while bethanechol reduced the electrically evoked acetylcholine release. This reduction was virtually unaffected by methoctramine, but was antagonized by 4-DAMP or p-F-HHSiD. The results from direct determination of acetylcholine suggest that, in contrast to autoinhibition by stimulation of muscarinic M3 receptors, stimulation of presynaptic muscarinic M1 receptors is predominantly involved in enhancement of the acetylcholine release from guinea pig ileal nerves, and that AF102B functions as a muscarinic M1 agonist in this peripheral neuron.
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PMID:Opposite modulation by muscarinic M1 and M3 receptors of acetylcholine release from guinea pig ileum as measured directly. 790 45

1. Experiments were designed to characterize the subtype(s) of endothelial muscarinic receptor that mediate(s) endothelium-dependent relaxation and contraction in the aorta of spontaneously hypertensive rats (SHR). 2. Rings of SHR aorta with endothelium were suspended in organ baths for the measurement of isometric force. Ecothiopate (an inhibitor of acetylcholinesterase) was present throughout the experiments. Endothelium-dependent contraction to acetylcholine was studied in quiescent aortic rings in the presence of NG-nitro-L-arginine (to prevent the formation of nitric oxide). Endothelium-dependent relaxation to acetylcholine was obtained during contraction to phenylephrine and in the presence of indomethacin (to inhibit cyclo-oxygenase activity). Responses to acetylcholine were assessed against the non-preferential muscarinic receptor antagonist, atropine, and the preferential antagonists pirenzepine (M1), methoctramine (M2) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M3). 3. The potency of acetylcholine in inducing endothelium-dependent contraction was 6.54 +/- 0.07 (EC50). Atropine, pirenzepine, methoctramine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent contraction to acetylcholine. The pA2 values for these muscarinic receptor antagonists were estimated from Arunlakshana-Schild plots to be (-log M) 9.48 +/- 0.07, 6.74 +/- 0.22, 6.30 +/- 0.20 and 9.39 +/- 0.22 respectively. The potency of acetylcholine in inducing endothelium-dependent relaxation was 7.82 +/- 0.09 (IC50). Atropine, pirenzepine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent relaxation to acetylcholine but methoctramine had no effect. The pA2 values for atropine and 4-DAMP for the relaxation to acetylcholine were estimated from Arunlakshana-Schild plots to be (-log M) 9.15 +/- 0.23 and 9.63 +/- 0.28, respectively. These results suggest that the muscarinic M3 receptor subtype mediates both endothelium-dependent relaxation and contraction to acetylcholine in SHR aorta.
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PMID:Mediation by M3-muscarinic receptors of both endothelium-dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat. 807 71

1. Atropine (EC50 = 87 microM), pirenzepine (447 microM), and AF-DX 116 (95.5 microM), but not 4-DAMP (at concentrations of up to 110 microM), produced neuromuscular facilitation and antagonized the oxotremorine-induced neuromuscular blockade in the rat isolated diaphragm. 2. Atropine, pirenzepine, and AF-DX 116 did not change the responses of curarized diaphragms to direct stimulation, or the twitch tension produced by retrograde injection of acetylcholine. 3. These results indicate that neuromuscular facilitation induced by muscarinic antagonists may depend on drug interaction with the M2 subtype of muscarinic autoreceptors to increase acetylcholine output in the neuromuscular junction.
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PMID:Neuromuscular facilitation induced by muscarinic antagonists in the rat isolated diaphragm. 811 27

The potency of centrally administered non-selective (atropine and N-methyl scopolamine) and putatively selective muscarinic antagonists (pirenzepine, AF-DX 116 and 4-DAMP) in inhibition of oxotremorine-induced hypothermia, tremor and salivation in male mice has been compared with their potency in vitro in three functional systems, where muscarinic effects are mediated preferentially by M1 (i.e. superior cervical ganglion), M2 (i.e. atrium), and M3 (i.e. ileum) receptors. Atropine, N-methyl scopolamine and 4-DAMP potently abolished the effects of oxotremorine. Pirenzepine abolished tremor and salivation, whereas hypothermia was antagonized partially only. AF-DX 116 had but weak antagonistic effects. Atropine and N-methyl scopolamine were potent antagonists in all three in vitro test systems. High potency was also seen with 4-DAMP, in particular in the ileum preparation. Pirenzepine showed its highest potency in the ganglion preparation. AF-DX 116 was a weak and non-selective antagonist in all three in vitro preparations. Our studies indicate that the muscarinic induction of tremor and salivation may be preferentially mediated by M3 receptors whereas both M2 and M3 receptors may be involved in the mediation of hypothermia. However, the overall conclusion is that compounds with higher receptor subtype selectivity are needed.
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PMID:The involvement of muscarinic receptor subtypes in the mediation of hypothermia, tremor, and salivation in male mice. 815 35

1. The regulation of cytosolic Ca2+ concentrations ([Ca2+]i) during exposure to carbachol was measured directly in canine cultured tracheal smooth muscle cells (TSMCs) loaded with fura-2. Stimulation of muscarinic cholinoceptors (muscarinic AChRs) by carbachol produced a dose-dependent rise in [Ca2+]i which was followed by a stable plateau phase. The EC50 values of carbachol for the peak and sustained plateau responses were 0.34 and 0.33 microM, respectively. 2. Atropine (10 microM) prevented all the responses to carbachol, and when added during a response to carbachol, significantly, but not completely decreased [Ca2+]i within 5 s. Therefore, the changes in [Ca2+]i by carbachol were mediated through the muscarinic AChRs. 3. AF-DX 116 (a selective M2 antagonist) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a selective M3 antagonist) inhibited the carbachol-stimulated increase in [Ca2+]i with pKB values of 6.4 and 9.4, respectively, corresponding to low affinity for AF-DX 119 and high affinity for 4-DAMP in antagonizing this response. 4. The plateau elevation of [Ca2+]i was dependent on the presence of external Ca2+. Removal of Ca2+ by the addition of 2 mM EGTA caused the [Ca2+]i to decline rapidly to the resting level. In the absence of external Ca2+, only an initial transient peak of [Ca2+]i was seen which then declined to the resting level; the sustained elevation of [Ca2+]i could then be evoked by the addition of Ca2+ (1.8 mM) in the continued presence of carbachol. 5.Ca2+ influx was required for the changes of [Ca2+]i, since the Ca2+-channel blockers, diltiazem(10 microM), nifedipine (10 microM), verapamil (10 microM) and Ni2+ (5 mM), decreased both the initial and sustained elevation of [Ca2+], in response to carbachol. These Ca2+-channel blockers also decreased the sustained elevation of [Ca2+], when applied during the plateau phase.6. In conclusion, we have demonstrated that the initial detectable increase in carbachol-stimulated[Ca2+]J is due to the release of Ca2+ from internal stores, followed by the flux of external Ca2+ into the cells. This influx of extracellular Ca2+ partially involves an L-type Ca2+-channel. M3 muscarinic receptors appear to mediate the Ca2+ mobilization in canine TSMCs.
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PMID:Intracellular calcium in canine cultured tracheal smooth muscle cells is regulated by M3 muscarinic receptors. 829 22

1. In vitro experiments in a microvascular myograph were designed to characterize postjunctional muscarinic receptors producing contraction both in the presence and absence of the endothelium in coronary resistance arteries (normalized diameter of 150-450 microns), isolated from the left ventricle of hearts from 3-6 month old lambs. Preferential muscarinic receptor antagonists were used to determine the receptor subtype: pirenzepine (M1 receptor), AFDX 116 (M2 receptor), 4-DAMP and pFHHSiD (M3 receptor). 2. The rank order of potency for muscarinic agonist-induced increases in tension in endothelium-intact preparations was oxotremorine-M = methacholine = acetylcholine (ACh) > carbachol. Removal of the endothelium increased the potency of ACh, but this procedure did not change either the sensitivity or maximal response to carbachol. 3. The contractile response to ACh was reproducible. Incubation with 3 x 10(-7)-3 x 10(-6) M pirenzepine induced non-parallel rightward shifts and depressed the maximum of the concentration-response curve to ACh in endothelium-intact arteries. The slope by Schild analysis was 2.9 +/- 0.8 (P < 0.05, n = 7). Atropine, AFDX 116, 4-DAMP and pFHHSiD produced parallel rightward shifts of the curves to ACh and the slopes of the Schild plots were not significantly different from unity. The pKB values for the antagonists from plots constrained to unity in endothelium-intact segments were: atropine (9.4), 4-DAMP (9.0), pFHHSiD (7.9) and AFDX 116 (6.2). 4. In endothelium-denuded arteries, pirenzepine, AFDX 116 and pFHHSiD caused concentration-dependent, parallel rightward displacements of the concentration-response curves to ACh and the slopes of the Schild plots were not significantly different from unity. The plots constrained to a slope of unity gave the following pKB values: pFHHSiD (8.7), pirenzepine (7.5) and AFDX 116 (6.2). 5. In the presence of the endothelium, low concentrations of pirenzepine (10(-9)-10(-7) M) produced leftward shifts of the ACh concentration-response curves. This potentiating effect of pirenzepine was reversed by endothelial cell removal. In preparations precontracted with the thromboxane-mimetic, U46619, the putative M1-selective agonist, McN-A-343, induced a biphasic relaxation with log IC50 of 8.53 +/- 0.14 and 5.02 +/- 0.08 for the first and second phase of the relaxation, respectively, and maximal relaxations of 22.8 +/- 4.3% and 41.1 +/- 5.4% (n = 16). McN-A-343 relaxed the vessels in the presence of 10(-7) M pFHHSiD and 3 x 10(-7) M AFDX 116, but not after incubation with 10(-9) M pirenzepine. 6. It is concluded from the pKB values for the antagonists used, that contraction induced by ACh in lamb coronary resistance arteries, in either the presence or the absence of the endothelium, is mediated via the M3 subtype of muscarinic receptors, while muscarinic receptors of another subtype at the endothelium seem to modulate the contractile response to ACh.
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PMID:Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries. 840 54

1. The characterization of muscarinic receptors on single cells of the guinea-pig ileum longitudinal smooth muscle, devoid of neuronal elements, was functionally studied by estimating the affinities of muscarinic antagonists on acetylcholine-induced contractions. 2. Atropine (5 x 10(-11) to 5 x 10(-6) M), 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, 5 x 10(-8) to 5 x 10(-6) M), cyclohexyl(4-fluoro-phenyl) (3-piperidinopropyl) silanol (pFHHSiD, 5 x 10(-7) to 5 x 10(-5) M) as well as pirenzepine (5 x 10(-7) to 5 x 10(-5) M) competitively antagonized the acetylcholine-dependent contractions with different affinities (atropine > 4-DAMP > pFHHSiD > pirenzepine). 3. Methoctramine (5 x 10(-7) to 5 x 10(-5) M), and AF-DX 116 (5 x 10(-6) and 5 x 10(-5) M) also showed antagonist properties but these deviated from simple competition. These compounds, which discriminate between M2 and M3 receptors, showed a potency lower than that of pirenzepine, the rank order of potencies being pirenzepine > methoctramine > AF-DX 116. When concentrations of AF-DX 116, methoctramine and pirenzepine were increased an unspecific contractile effect occurred. 4. McN-A-343, a partial agonist on intact guinea-pig longitudinal smooth muscle strips, on this preparation induced a weak contraction (about 7% in comparison to control) that was not reversed by antimuscarinic agents. 5. These data indicate that M3 rather than M2 receptor sites are present on this tissue.
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PMID:Interaction of selective compounds with muscarinic receptors at dispersed intestinal smooth muscle cells. 844 89

In the electrically field-stimulated rabbit vas deferens, muscarinic receptor agonists increase twitch-height by actions at postjunctional M2 receptors and decrease twitch-height by actions at prejunctional M1 receptors. In the present studies, in contrast to previous reports, muscarinic receptor agonists primarily decreased twitch-height, produced minimal increases in twitch-height, and, produced identical responses in both epididymal and prostatic tissue segments, thus permitting a more detailed investigation of the M1 receptor component of action of muscarinic receptor agonists in the rabbit vas deferens. The nonselective muscarinic receptor agonist carbachol produced biphasic effects on twitch-height in the vas deferens: lower concentrations increased twitch-height to only approximately 25-30% over control, whereas higher concentrations inhibited the twitch. The selective M1 receptor antagonist pirenzepine blocked the inhibitory effects of carbachol, and unmasked carbachol-induced increases in twitch-height. Atropine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) and AF-DX 116 (11-2[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) blocked both the inhibitory and stimulatory effects of carbachol, but atropine and 4-DAMP were more potent in blocking the inhibitory than the stimulatory effects of carbachol, whereas the reverse was true for AF-DX 116. McN-A-343 (4-hydroxy-2-butynyl)trimethylammonium chloride, m-chlorocarbanilate) and 12 other muscarinic receptor agonists from a variety of chemical classes also produced concentration-dependent decreases in twitch-height. The log IC50s of the muscarinic receptor agonists for decreasing twitch-height were highly correlated with their log Kis for inhibiting [3H]pirenzepine (r = 0.96) and [3H]oxotremorine-M (r = 0.85) binding in rat hippocampal membranes. The present results demonstrate that the muscarinic M1 receptor mediating inhibition of twitch-height in the rabbit vas deferens has pharmacologic properties similar to the muscarinic M1 receptor in rat hippocampus.
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PMID:Muscarinic M1 receptor agonist actions of muscarinic receptor agonists in rabbit vas deferens. 845 95

1. The effects of muscarinic receptor antagonists considered to be selective for M1 receptors (pirenzepine; PZ), M2 receptors (AFDX-116), and for M3 receptors (4-diphenyl acetoxy N-methyl-piperidine (4-DAMP)) were used to investigate the existence of muscarinic receptors subtypes in murine airways. Atropine was used as a nonselective antagonist. The effects of these antagonists were studied upon tracheal contractions induced either by EFS (electric field stimulation) or by application of an exogenous cholinoceptor agonist (arecoline). 2. The muscarinic receptor antagonists tested inhibited arecoline-induced tracheal contractions with the following rank order of potency: 4-DAMP = atropine > pirenzepine = AFDX-116. The rank order of potency of the muscarinic antagonists used in inhibiting EFS-induced tracheal contractions was: 4-DAMP = atropine > PZ > AFDX-116. The pA2 values for these antagonists were similar when compared to the pA2 values determined in guinea-pig and bovine airway smooth muscle. 3. In addition to in vitro studies, the effects of inhalation of the different muscarinic antagonists on lung function parameters in vivo were investigated. Inhalation of 4-DAMP induced a decrease in airway resistance and an increase in lung compliance. In contrast, inhalation of AFDX-116 induced an increase in airway resistance and almost no change in lung compliance. Apart from some minor effects of atropine on airway resistance, atropine, PZ, and pilocarpine failed to induce changes in lung mechanics as determined by in vivo lung function measurements. 4. The results provide evidence for the existence of M3 receptors on murine tracheae that are involved in the contraction of tracheal smooth muscle. This is in agreement with other animal species such as the guinea-pig and bovine. In vivo experiments also demonstrated that in the mouse, M3 receptors play an important role in bronchial smooth muscle contraction and thus in bronchoconstriction. Interestingly we have also demonstrated that M2 receptors can play a role in bronchodilatation. Inhalation of an M2 receptor antagonist induced an increase in airway resistance whereas inhalation of an M3 receptor antagonist induced a decrease in airway resistance. It is therefore likely that an M3/M2 receptor balance plays an important role in the regulation of airway function.
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PMID:Functional characterization of muscarinic receptors in murine airways. 849 46

1. The effects of seven muscarinic receptor antagonists were used to characterize the receptors which mediate carbachol-evoked contractions of intertaenial circular and taenial longitudinal muscle in human isolated colon. The effects of these antagonists were studied upon colon contractions induced by cumulatively added carbachol which had mean EC50 values of 11.7 +/- 2.3 microM (n = 8) and 12.6 +/- 2.3 microM (n = 8) respectively upon circular and longitudinal smooth muscle. 2. All antagonists displaced concentration-response curves to carbachol to the right in a parallel manner. The maximum concentration of each antagonist added (30 nM-10 microM) did not significantly suppress the maximum response. 3. In circular muscle, the M3 muscarinic receptor antagonists, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), hexahydrosiladiphenidol (HHSiD) and para-fluoro-hexahydrosiladiphenidol (p-F-HHSiD) inhibited responses with pA2 values of 9.41 +/- 0.23, 7.17 +/- 0.07, 6.94 +/- 0.18 respectively. The M2 muscarinic receptor antagonist, AF-DX 116, the M2/M4 muscarinic receptor antagonist, himbacine, and the M1 muscarinic receptor antagonist, pirenzepine, yielded pA2 values of 7.36 +/- 0.43, 7.47 +/- 0.14 and 7.23 +/- 0.48 respectively. The non-selective antagonist, atropine, had a pA2 of 8.72 +/- 0.28. 4. In longitudinal muscle 4-DAMP, HHSiD, p-F-HHSiD, AF-DX 116, himbacine and pirenzepine gave pA2 values of 9.09 +/- 0.16, 7.45 +/- 0.43, 7.44 +/- 0.21, 6.44 +/- 0.1, 7.54 +/- 0.40, 6.87 +/- 0.38 respectively. Atropine yielded a pA2 value of 8.60 +/- 0.08. 5. The pharmacological profile of antagonist affinities at the muscarinic receptor population responding to muscarinic agonist-evoked contraction is similar to that widely accepted as characterizing the activation of an M3 muscarinic receptor subtype, although pA2 values of some antagonists are lower than that seen in other investigations.
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PMID:Characterization of muscarinic receptors mediating contractions of circular and longitudinal muscle of human isolated colon. 856 13


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