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Henk P. M. Vijverberg – One of the best experts on this subject based on the ideXlab platform.
Potentiation and inhibition of neuronal nicotinic receptors by Atropine: competitive and noncompetitive effects.Molecular pharmacology, 1997Co-Authors: R Zwart, Henk P. M. VijverbergAbstract:
Atropine, the classic muscarinic receptor antagonist, inhibits ion currents mediated by neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. At the holding potential of -80 mV, 1 microM Atropine inhibits 1 mM acetylcholine-induced inward currents mediated by rat alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7 nicotinic receptors by 12-56%. Inward currents induced with a low agonist concentration are equally inhibited (alpha3beta2, alpha3beta4), less inhibited (alpha2beta4, alpha7), or potentiated (alpha4beta2, alpha4beta4) by 1 microM Atropine. Effects on the more sensitive alpha4beta4 nicotinic receptors were investigated in detail by systematic variation of acetylcholine and Atropine concentrations and of membrane potential. At high agonist concentration, Atropine inhibits alpha4beta4 nicotinic receptor-mediated ion current in a noncompetitive, voltage-dependent way with IC50 values of 655 nM at -80 mV and of 4.5 microM at -40 mV. At low agonist concentration, 1 microM Atropine potentiates alpha4beta4 nicotinic receptor-mediated ion current. This potentiating effect is surmounted by high concentrations of acetylcholine, indicating a competitive interaction of Atropine with the nicotinic receptor, and potentiation is also reversed at high Atropine concentrations. Steady state effects of acetylcholine and Atropine are accounted for by a model for combined receptor occupation and channel block, in which Atropine acts on two distinct sites. The first site is associated with noncompetitive ion channel block. The second site is associated with competitive potentiation, which appears to occur when the agonist recognition sites of the receptor are occupied by acetylcholine and Atropine. The apparent affinity of Atropine for the agonist recognition sites of the alpha4beta4 nicotinic acetylcholine receptor is estimated to be 29.9 microM.
Roger W Beuerman – One of the best experts on this subject based on the ideXlab platform.
molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts prior to and after induction of experimental myopia with Atropine treatmentMolecular Vision, 2011Co-Authors: Veluchamy A Barathi, Roger W BeuermanAbstract:
Purpose: To investigate the effect of Atropine on the development of spectacle lens induced myopia in the mouse and to determine if the level of mRNAs for the muscarinic receptor subtypes (M1 – M5) is affected by Atropine treatment. Methods: Experimental myopia was developed in Balb/CJ (BJ) mice by placing −10 diopter spectacle lens on post-natal day 10 over the right eyes of 150 mice (n=10 in each group, 5 repetitions) for six weeks. After 2 weeks of lens wearing, the Atropine group received a daily sub-conjunctival injection (10 µl) of 1% Atropine sulfate and the saline group received daily 10 µl of 0.9% normal saline for 4 weeks. In addition, myopia was developed in C57BL/6 (B6) mice by placing −10 D spectacle lens on post-natal day 10 over the right eyes of 60 mice (n=10 in each group, 2 repetitions) for six weeks with and without Atropine treatment. Refraction and axial length was measured at 2, 4, and 6 weeks after treatments. RT–PCR and northern blots were performed using specific primers for M1-M5, and products sequenced. Real-time PCR was used to quantify message levels. Results: Axial length of myopic eyes was 111% of their controls without Atropine treatment and 103% of controls after Atropine (p<0.01). Refraction shifted from myopic to emmetropic after Atropine was administered in both pigmented and non-pigmented eyes. Corneal thickness, anterior chamber depth, corneal curvature and retinal thickness were not significantly different with and without Atropine treatment (p=0.14). The lens thickness and vitreous chamber depth were significantly reduced after receiving Atropine (p<0.05). Real-time PCR showed that message levels for M1, M3, and M4 were upregulated in myopic sclera after Atropine treatment, but M2 and M5 showed little change. Conclusions: The present study shows that 1% Atropine reduces myopia progression in both pigmented and non-pigmented mice eyes. Axial length and vitreous chamber depth appear to be the main morphological parameters related to myopia. The results suggest that Atropine may act on one or more muscarinic receptors to differentially regulate expression levels of specific receptors.
Ruwan K Perera – One of the best experts on this subject based on the ideXlab platform.
Atropine augments cardiac contractility by inhibiting camp specific phosphodiesterase type 4Scientific Reports, 2017Co-Authors: Ruwan K Perera, Thomas H Fischer, Michael Wagner, Matthias Dewenter, Christiane Vettel, Nadja I Bork, Lars S Maier, Marco Conti, J WessAbstract:
Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. However, many cardiac effects of Atropine cannot be adequately explained solely by its antagonism at muscarinic receptors. In isolated mouse ventricular cardiomyocytes expressing a Forster resonance energy transfer (FRET)-based cAMP biosensor, we confirmed that Atropine inhibited acetylcholine-induced decreases in cAMP. Unexpectedly, even in the absence of acetylcholine, after G-protein inactivation with pertussis toxin or in myocytes from M2- or M1/3-muscarinic receptor knockout mice, Atropine increased cAMP levels that were pre-elevated with the β-adrenergic agonist isoproterenol. Using the FRET approach and in vitro phosphodiesterase (PDE) activity assays, we show that Atropine acts as an allosteric PDE type 4 (PDE4) inhibitor. In human atrial myocardium and in both intact wildtype and M2 or M1/3-receptor knockout mouse Langendorff hearts, Atropine led to increased contractility and heart rates, respectively. In vivo, the Atropine-dependent prolongation of heart rate increase was blunted in PDE4D but not in wildtype or PDE4B knockout mice. We propose that inhibition of PDE4 by Atropine accounts, at least in part, for the induction of tachycardia and the arrhythmogenic potency of this drug.