Beneficial effects of amiodarone in heart failure: interaction with β-adrenoceptors rather than G proteins

Schnabel, Petra; Mies, Florian; Maack, Christoph; Rosenkranz, Stephan; Zolk, Oliver; Böhm, Michael

doi:10.1016/s0014-2999(99)00101-6

Cited by 7 publications

(5 citation statements)

References 14 publications

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“…Its beneficial anti-arrhythmic effects are attributed to inhibition of sodium, calcium, and potassium currents, while side effects are thought to be related in part to its lipophilicity and its structural similarity to thyroxine. It has been shown to potently inhibit H 3 histamine receptors [22] and to alter adrenergic receptor signaling [23,24] . Early studies reported that amiodarone inhibited radioligand binding to muscarinic receptors [25,26] , a property that we have attributed to an allosteric interaction [17,21] .…”

Section: Discussionmentioning

confidence: 99%

Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

et al. 2016

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We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone's most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M₁, M₃, and M₅ receptors. Furthermore, the quaternary analog N-ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone also modulates Gq-mediated responses at M₁ and M₃, although in a more discriminating manner. For example, dronedarone markedly enhances pilocarpine-stimulated release of arachidonic acid from CHO cells, via the M₃ receptor subtype, but does not affect the acetylcholine-stimulated response. Such probe-dependent effects are diagnostic of an allosteric interaction. In comparison to these effects at M₃, dronedarone is strongly inhibitory toward both pilocarpine and acetylcholine at the M₁ subtype. The effects of dronedarone are consistent with an interaction at the amiodarone site: dronedarone inhibits the enhancement of acetylcholine's response produced by amiodarone at the M₃ subtype; also, NEA reverses the enhancement of pilocarpine's response at M₃ produced by either dronedarone or amiodarone. In studies with the M₁-selective allosteric agonist 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), amiodarone enhanced the maximal response observed, whereas dronedarone was inhibitory. On the other hand, benzyl quinolone carboxylic acid, the well-known allosteric ligand that dramatically enhances the potency of acetylcholine at the M₁ subtype, had no effect on the response profile of AC-260584. In summary, dronedarone acts at M₁ and M₃ muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site.

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Section: Discussionmentioning

confidence: 99%

Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

et al. 2016

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“…Along side with that, its pharmacological effects are not restricted with blockade of potassium channel, but have a complex influence on electric parameters of the cardiomyocytes membranes [7]. Amiodarone is able to inhibit partially sodium and calcium channels as well as to block β-adrenoceptors [5][6][7][8][9][10][11]. It's considered that this antiarrhythmic drug shows high antiarrhythmic efficacy owing to these properties.…”

Section: Introductionmentioning

confidence: 99%

Amiodarone Modulation of Intracellular Transport of Calcium Ions in Cardiomyocites

Kondratyeva¹,

Afanasiev²,

Popov³

et al. 2012

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The influence of amiodarone on intracellular transport of calcium ion in cardiomyocytes of rat was investigated. The experiments were performed on isolated papillary muscles of Wistar rats. Force-frequency dependence (0.7, 1, 2, 3, 4 Hz), extrasystolic and postextrasystolic contractions and post-rest (4-60 s) reactions of rat myocardium after amiodarone treatment (1 μM) were investigated. Decay potentiation coefficient of contraction force was estimated. Results. The analyses of force-frequency dependence has shown that amiodarone prevent the decreasing of the force contraction at increasing of the stimulation frequency. Amiodarone promotes increase of the time constant t1(T50), that indicate the drug promotes acceleration of Са2+ transport inside the SR resulting increase of Са2+ in the places of its release from the sarcoplasmic reticulum (SR). Treatment of papillary muscle with amiodarone decreased amplitude of extrasystolic contractions. As known, postextrasystolic and post-rest reactions of myocardium characterize the SR function. We have found amiodarone increased potentiation of postextrasystolic and post-rest contractions. Preliminary caffeine perfusion of muscles preparations cancelled the amiodarone-induced increasing postextrasystolic and post-rest potentiation. However, potentiation decay coefficient before and after treatment with amiodarone didn’t have difference. Conclusions, amiodarone influences on intracellular calcium ions homeostasis by modulation SR functions related with most likely are stipulated either by activation of Са2+ transport from uptake sites to release sites or by prevent of Са2+ leakage from the SR

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“…Studies have shown that amiodarone interacts with several ion channels, inhibiting sodium, calcium, and potassium currents (Kodama et al, 1997) and that it alters adrenergic receptor signaling (Yin et al, 1994;Schnabel et al, 1999). Amiodarone also has been found to inhibit the binding of antagonists to muscarinic receptors (Cohen-Armon et al, 1984;Colvin et al, 1989).…”

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confidence: 99%

Novel Allosteric Effects of Amiodarone at the Muscarinic M₅Receptor

Stahl¹,

Ellis²

2010

J Pharmacol Exp Ther

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Allosteric sites on muscarinic receptors may present superior therapeutic targets for several central nervous system disorders, due to the potential of allosteric ligands to provide more selective modulation and to preserve the spatiotemporal patterning that is characteristic of synaptic transmission. We have found that the antiarrhythmic drug amiodarone interacts allosterically with M 1 and M 5 muscarinic receptors. At both M 1 and M 5 , amiodarone was only able to partially inhibit the binding of the orthosteric antagonist [3 H]N-methylscopolamine (NMS). In addition, amiodarone was able to alter the rate of dissociation of [ 3 H]NMS from M 1 and M 5 receptors. These findings suggest that NMS and amiodarone are able to bind to the receptor simultaneously. The pharmacology of the effect on NMS dissociation demonstrated that amiodarone was not interacting at the "common" site at which gallamine, obidoxime, and many other muscarinic allosteric ligands are known to bind. In functional studies, amiodarone enhanced the ability of acetylcholine (at EC 20 ) to activate the M 5 receptor; however, under the same conditions, amiodarone did not enhance M 1 activation. More detailed studies at M 5 found that the effect of amiodarone was to enhance the efficacy of acetylcholine, without increasing its potency. This report describes the first demonstration of allosteric enhancement of efficacy at the M 5 receptor, and the first demonstration of enhancement of efficacy but not potency at any muscarinic receptor. In summary, amiodarone has been shown to be a novel positive allosteric modulator of muscarinic receptors that is selective for the M 5 subtype, relative to M 1 .

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Beneficial effects of amiodarone in heart failure: interaction with β-adrenoceptors rather than G proteins

Cited by 7 publications

References 14 publications

Dronedarone Modulates M<sub>1</sub> and M<sub>3</sub> Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Dronedarone Modulates M<sub>1</sub> and M<sub>3</sub> Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Amiodarone Modulation of Intracellular Transport of Calcium Ions in Cardiomyocites

Novel Allosteric Effects of Amiodarone at the Muscarinic M₅Receptor

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Beneficial effects of amiodarone in heart failure: interaction with β-adrenoceptors rather than G proteins

Cited by 7 publications

References 14 publications

Dronedarone Modulates M<sub>1</sub> and M<sub>3</sub> Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Dronedarone Modulates M<sub>1</sub> and M<sub>3</sub> Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Amiodarone Modulation of Intracellular Transport of Calcium Ions in Cardiomyocites

Novel Allosteric Effects of Amiodarone at the Muscarinic M5Receptor

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Novel Allosteric Effects of Amiodarone at the Muscarinic M₅Receptor