Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle

Doods, Henri; Entzeroth, Michael; Ziegler, H.; Mayer, Norbert Michael; Holzer, Peter

doi:10.1016/0014-2999(94)90202-x

Cited by 31 publications

(25 citation statements)

References 18 publications

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“…[3][4][5]7,9,12 Previous studies, including our own laboratory, have employed doses of atropine as much as 10,000 times or higher than theoretically required for binding at the M 4 receptors or 17,500 times or higher than required for binding at the M 1 receptor 5,43,44 based on published receptor affinity values. 45 Consequently, a number of studies have questioned whether muscarinic antagonist drug effects on myopia inhibition are working via retinal receptors and proposed either a nonreceptoral mechanism of action or at muscarinic receptors in the sclera. 16,46,47 The present study utilized highly selective muscarinic antagonists (MT3 and MT7) in an animal model that has both M 4 and M 1 receptors, and used doses to provide physiologically relevant concentrations at the receptor binding site for ocular-based receptors, specifically retinal-based receptors.…”

Section: Evidence For a Receptoral-based Mechanism Of Muscarinic Antamentioning

confidence: 99%

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Arumugam

McBrien²

2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The broadband muscarinic antagonist atropine is effective in stopping the progression of myopia in animals and humans. The partially selective M 1 /M 4 antagonist pirenzepine also slows progression of myopia, although not as effectively as atropine. Due to the supra maximal doses utilized in these studies, it is unclear if this antimyopia effect occurs through a receptoral-based mechanism, and if so, which receptors are involved. Studies in chicks indicate the involvement of the M 4 muscarinic receptor. The current study investigated the effect of the highly selective muscarinic antagonists Muscarinic Toxin 3 (MT3) (M 4 selective) and Muscarinic Toxin 7 (MT7) (M 1 selective) on experimental myopia in a mammalian model. METHODS.Tree shrews (n ¼ 23) underwent daily intravitreal injections of MT3, MT7, or vehicle (phosphate buffered saline) for five days in the treated eye, combined with deprivation of vision with a translucent occluder (MD). The contralateral eye was unocccluded and underwent intravitreal injections of vehicle for the same period. Two additional groups (n ¼ 10) underwent daily intravitreal injections of MT7 or vehicle for 10 days in the treated eye combined with negative lens (À9.5 diopter [D]) defocus (LIM). The control eye was injected with saline and wore a plano lens. RESULTS. Both MT3 and MT7 treatment reduced the development of deprivation-induced myopia (treated-control eye [T-C]; vehicle-MD; À4.3 6 0.6 D versus MT3-MD; À0.7 6 0.2 D and MT7-MD; À0.7 6 0.4 D; P < 0.001). MT7 treatment was effective at inhibiting lens-induced myopia (T-C; vehicle-LIM; À4.6 6 0.5 D versus MT7-LIM; 0.2 6 0.2 D; P < 0.05). CONCLUSIONS. The findings demonstrate that inhibition of formdeprivation myopia by muscarinic antagonists involves both M 4 and M 1 muscarinic receptor signaling pathways in mammals. (Invest Ophthalmol Vis Sci. 2012;53:5827-5837) DOI: 10.1167/iovs.12-9943T he broadband muscarinic antagonist, atropine, has been shown to prevent the development of myopia in humans. [1][2][3] In addition, atropine and the partially selective muscarinic antagonist, pirenzepine, have been shown to reduce the development of myopia in several animal models, including rhesus monkeys, 4 chicks, 5,6 and tree shrews. 7,8 However, the disadvantage of atropine is that it is a nonselective muscarinic antagonist and has unwanted ocular and gastric adverse effects. Studies of pirenzepine, a partially selective M 1 /M 4, 6,7,9 and himbacine, a partially selective M 4 /M 2 antagonist, 10 have shown them to be effective at slowing the progression of myopia. However, the specific site of action of these antagonists remains unclear, partly due to the lack of specificity and high doses required to inhibit myopia. Although pirenzepine is termed an M 1 selective antagonist, it also demonstrates subtype cross-reactivity to other receptors causing significant increase in pupil diameter in tree shrews, 7 significant increase in pupil size and decrease in accommodation in rhesus monkeys, 11 and blurred near vision in human childr...

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Section: Evidence For a Receptoral-based Mechanism Of Muscarinic Antamentioning

confidence: 99%

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Arumugam

McBrien²

2012

Invest. Ophthalmol. Vis. Sci.

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“…(Proska & Tuoek, 1994). About ten fold higher concentrations of alcuronium were needed to achieve the same slow rates of dissociation in the M4-like fraction as compared to the M2-like fraction (Table 5 (Tietje et al, 1990;Tietje & Nathanson, 1991) (Doods et al, 1994). -In cells transfected with chick genes, M4 receptors had a five fold lower affinity for AF-DX116 than the M2 receptors (Tietje & Nathanson, 1991).…”

Section: Effect Of Alcuronium On the Dissociation Of [3h]-nmsmentioning

confidence: 99%

“…On the other hand, the affinity of the M4 subtype for pirenzepine appeared 10 times (Waelbroeck et al, 1990;Lazarenio et al, 1990), 6 times (Wess et al, 1991) or 3 times higher (Doods et al, 1994) (Waelbroeck et al, 1990), 8 times lower (Ellis et al, 1991), or 7 times lower (Lazareno et al, 1990) receptors. The high affinity of chick cardiac receptors for pirenzepine has been observed repeatedly (Brown et al, 1985;Lindmar & Loffelholz, 1987;Jeck et al, 1988;Choo et al, 1988;Lazareno et al, 1990;Tietje & Nathanson, 1991), although low affinity was found by Sorota et al (1986).…”

Section: Effect Of Alcuronium On the Dissociation Of [3h]-nmsmentioning

confidence: 99%

Two populations of muscarinic binding sites in the chick heart distinguished by affinities for ligands and selective inactivation

Jakubík

Tuček

1994

British J Pharmacology

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Both populations have high affinities for pirenzepine, but the affinity of the former (major) population is lower (pKi = 7.99) than that of the latter (minor) population (pKi = 10.14). 2 Since it has been shown earlier that two mRNAs for muscarinic receptors are expressed in the chick heart, one of them close to the genetically defined m2 and the other to the m4 subtype, we propose that the major population of binding sites with high affinities for AF-DX1 16

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“…This suggests that in the present study both the PTX-sensitive and PTX-insensitive G proteins may be linked to the M3 receptors which are thought to be the predominant receptors involved with contraction in this smooth muscle. However M2 receptors associated with PTXsensitive G proteins may also have a role in the agonist induced increases in the levels of inositol phosphates (Thomas et al, 1993 (Caulfield, 1993;Doods et al, 1994;Eglen et al, 1994).…”

Section: Toxin Treatmentmentioning

confidence: 99%

G‐protein involvement in muscarinic receptor‐stimulation of inositol phosphates in longitudinal smooth muscle from the small intestine of the guinea‐pig

Prestwich

Bolton

1995

British J Pharmacology

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1 Aluminium fluoride (AlF), pertussis toxin (PTX) and cholera toxin (ChTX) have been used to examine the involvement of G-proteins during muscarinic acetylcholine receptor (AChR) stimulation of inositol phospholipid hydrolysis in fragments of longitudinal smooth muscle from the small intestine of the guinea-pig. 4 PTX had no effect on basal levels of any of the [3H]-inositol phosphates but reduced the effects of CCh on these; ChTX had no effects on either basal or CCh-stimulated levels. 5 It was concluded that muscarinic AChR-stimulated increases in the levels of [3H]-inositol phosphates occur via both a PTX-sensitive G-protein and a PTX-insensitive mechanism. The actions of AIF may suggest the involvement of an inhibitory G-protein in the regulation of muscarinic AChR-stimulated inositol phospholipid turnover.

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Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle

Cited by 31 publications

References 18 publications

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Two populations of muscarinic binding sites in the chick heart distinguished by affinities for ligands and selective inactivation

G‐protein involvement in muscarinic receptor‐stimulation of inositol phosphates in longitudinal smooth muscle from the small intestine of the guinea‐pig

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Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle

Cited by 31 publications

References 18 publications

Muscarinic Antagonist Control of Myopia: Evidence for M4and M1Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Muscarinic Antagonist Control of Myopia: Evidence for M4and M1Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Two populations of muscarinic binding sites in the chick heart distinguished by affinities for ligands and selective inactivation

G‐protein involvement in muscarinic receptor‐stimulation of inositol phosphates in longitudinal smooth muscle from the small intestine of the guinea‐pig

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Product

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Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew