Characterization of muscarinic receptors that mediate contraction of guinea‐pig isolated trachea to choline esters: effect of removing epithelium

Morrison, Keith J.; Vanhoutte, Paul M.

doi:10.1111/j.1476-5381.1992.tb14393.x

Cited by 11 publications

(4 citation statements)

References 26 publications

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“…ACh was less potent in producing contraction in the presence than in the absence of the endothelium, while the response to carbachol was unaltered. Similar differential changes in the contractile response to ACh and carbachol upon removal of the epithelium were observed in the guineapig trachea, where these resutls were ascribed to differences in the abilities of these choline esters to diffuse to the muscarinic receptor sites in the epithelium intact preparations (Morrison & Vanhoutte, 1992). The endothelium might act as a barrier for ACh in lamb coronary arteries.…”

Section: Discussionsupporting

confidence: 49%

Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries

Simonsen

Prieto

Rivera

et al. 1993

British J Pharmacology

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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 jm), 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 (MI 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 concentrationdependent, 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 (10-9-1-' 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 MI-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-' 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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Section: Discussionsupporting

confidence: 49%

Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries

Simonsen

Prieto

Rivera

et al. 1993

British J Pharmacology

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“…Error bars indicate s.e.mean ( n = 4). Carbachol activates M 3 receptors in guinea‐pig trachea (Morrison and Vanhoutte, 1992).…”

Section: Resultsmentioning

confidence: 99%

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

Jones

Woodward

2010

British J Pharmacology

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BACKGROUND AND PURPOSESurprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E2 (DX-DM PGE2) on pig cerebral artery when used as a selective EP3 receptor agonist. This study investigated the selectivity profile of DX-DM PGE2, focusing on the interaction between its EP3 and TP (thromboxane A2-like) agonist activities. EXPERIMENTAL APPROACHContraction of guinea-pig trachea (EP1 system) and aorta (EP3 and TP systems) was measured in conventional organ baths. KEY RESULTSStrong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE2 (EP3 agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE2 induced strong contraction, which on the basis of treatment with (DG)-3ap (EP3 antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP3 and TP receptors. EP3/TP self-synergism also accounted for contraction induced by PGF2a and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE2 also showed significant EP1 agonism on guinea-pig trachea as defined by the EP1 antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations Ն3 mM. CONCLUSIONS AND IMPLICATIONSEP3/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP3 agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP3 system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed. AbbreviationsFA, free acid form of a C1-ester or C1-amide prostanoid; nH, Hill slope for a sigmoidal log concentration-response curve; pA2, negative logarithm of the molar concentration of antagonist producing a dose ratio of 2; pEC50, negative logarithm of the agonist concentration inducing 50% maximum response; PGE2, prostaglandin E2; pIC50, negative logarithm of the molar concentration producing 50% inhibition of an established response; TXA2, thromboxane A2 IntroductionProstaglandin E2 (PGE2) has a broad range of actions including excitation of smooth muscle cells mediated by prostanoid EP1 and EP3 receptors and inhibition mediated by EP2 and EP4 subtypes (see Coleman et al., 1994; receptor nomenclature follows Alexander et al., 2009). Its contractile action on pig BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) isolated cerebral artery has been linked to activation of both EP1 and EP3 receptors operating through the phosphatidyl inositol pathway (Jadhav et al., 2004). We had two major concerns about this study. First, very high concentrations (30-300 mM) of the EP1 antagonist AH-6809 (Coleman et al., 1985;1987) were used to identify the EP1 component and also to gauge the selectivity of 11-deoxy-16,16-dimethyl PGE2 (DX-DM PGE...

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“…In the former tissue, honokiol and magnolol have no noteworthy effects, while Fagron and KPC are reversible non‐competitive muscarinic antagonists. As in guinea pig trachea, CCh‐mediated contraction is mediated by M 3 ‐receptors and is independent by the presence of epitelium (Kj & Pm, 1992), we can speculate that the antagonist effects elicited by Fagron and KPC occur at M 3 receptors as well. This mechanism is of clinical interest owing to the M 3 ‐mediated deleterious acetylcholine effects on the airways, which entail an increased release of pro‐inflammatory mediators from bronchial epithelial cells and cells of the immune system (Gosens et al, 2004).…”

Section: Discussionmentioning

confidence: 74%

Magnolia officinalis L. bark extract and respiratory diseases: From traditional Chinese medicine to western medicine via network target

Fontana

Mattioli

Biotti

et al. 2023

Phytotherapy Research

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The understanding of the use of Magnolia officinalis L. (Magnoliaceae) as a possible dietary supplement for supporting the treatment of airway pathologies might be of clinical interest. Two commercially available bark extracts (M. officinalis extract [MOE]) were characterized by quantitation in honokiol and magnolol content by means of high-performance liquid chromatography with UV detection. MOE effects, as well as those of the reference compounds per se, on some targets connected to airway pathologies (antibacterial-and lung and trachea relaxing-activities) were investigated. Results showed that MOE possessed interesting antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae. This was accompanied by a spasmolytic and antispasmodic activity, possibly owing to its ability to concurrently modulate different targets such as H 1 -, β 2 -and muscarinic receptors and L-type calcium channels involved in bronchodilation. All these effects were directly related to the MOE content in honokiol and magnolol. In conclusion, the properties of MOE highlighted here strongly encourage its application as dietary supplement in the treatment of airway diseases.

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Characterization of muscarinic receptors that mediate contraction of guinea‐pig isolated trachea to choline esters: effect of removing epithelium

Cited by 11 publications

References 26 publications

Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries

Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

Magnolia officinalis L. bark extract and respiratory diseases: From traditional Chinese medicine to western medicine via network target

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Characterization of muscarinic receptors that mediate contraction of guinea‐pig isolated trachea to choline esters: effect of removing epithelium

Cited by 11 publications

References 26 publications

Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries

Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries

Interaction of prostanoid EP3 and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE2

Magnolia officinalis L. bark extract and respiratory diseases: From traditional Chinese medicine to western medicine via network target

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Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂