Ritanserin attenuates the in vitro effects of the 5-HT2 receptor agonist DOI on skeletal muscles from malignant hyperthermia-susceptible patients

Wappler, Frank; Scholz, Jens; Oppermann, Stefan; Richthofen, V. von; Steinfath, Markus; Esch, Jochen Schulte am

doi:10.1016/s0952-8180(97)00008-1

Cited by 12 publications

(5 citation statements)

References 30 publications

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“…One potential mechanism for psychedelic-mediated hyperthermia is 5-HT 2A Rmediated skeletal muscle contraction (Guillet-Deniau et al, 1997;Wappler et al, 1997;Hajduch et al, 1999). The prominent SERT activity of several substituted tryptamines that were characterized in this study also highlights a potential role for substituted tryptamine-induced 5-HT syndrome in mediating psychedelic-induced hyperthermia.…”

Section: Discussionmentioning

confidence: 58%

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter

Kozell

Eshleman

Swanson

et al. 2023

J Pharmacol Exp Ther

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Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied, under medical guidance, as potential treatments of psychiatric disorders.Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use. Using HEK cells stably expressing 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors (5-HT 1A R, 5-HT 2A R, 5HT 2C R respectively) or the serotonin transporter (SERT), we measured affinities, potencies and efficacies of 21 substituted tryptamines. With the exception of two 4-acetoxy compounds, substituted tryptamines exhibited affinities and potencies less than one micromolar at the 5-HT 2A R, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT 2C R, 5-HT 1A R, and SERT. Sorting by the ratio of 5-HT 2A to 5-HT 2C , 5-HT 1A , or SERT affinity revealed chemical determinants of selectivity. We found that while 4-substituted compounds exhibited affinities that ranged across a factor of 100, they largely exhibited high selectivity for 5-HT 2A Rs versus 5-HT 1A Rs and 5-HT 2C Rs. 5-substituted compounds exhibited high affinities for 5-HT 1A Rs, low affinities for 5-HT 2C Rs, and a range of affinities for 5-HT 2A Rs, resulting in selectivity for 5-HT 2A Rs versus 5-HT 2C Rs but not versus 5-HT 1A Rs.Additionally, a number of psychedelics bound to SERT, with non-ring substituted tryptamines most consistently exhibiting binding. Interestingly, substituted tryptamines and known psychedelic standards exhibited a broad range of efficacies, which were lower as a class at 5-HT 2A Rs compared to 5-HT 2C Rs and 5-HT 1A Rs. Conversely,

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Section: Discussionmentioning

confidence: 58%

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter

Kozell

Eshleman

Swanson

et al. 2023

J Pharmacol Exp Ther

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“…The contractures developed faster in MHS than in MHN specimens, and the threshold for halothane was markedly decreased following pretreatment of MHS preparations with 5-HT 2 receptor agonists. These effects could be reduced or completely counteracted by dantrolene and ritanserin (Wappler et al 1997b(Wappler et al , 1997c. Ritanserin is a potent and long-acting antagonist at the 5-HT 2 receptor; however, it has been shown that ritanserin acts also as an excellent antagonist at the 5-HT 1C receptor (Hoyer et al 1989).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the contracture threshold for halothane was markedly decreased following pretreatment of MHS preparations with 5-HT 2 receptor agonists. The in vitro effects of 5-HT 2 receptor agonists on muscle specimens from MHS patients could be reduced or completely counteracted by dantrolene (Wappler et al 1997b), as well as with the 5-HT 2 receptor antagonist ritanserin (Wappler et al 1997c). Furthermore, in vitro studies have shown that halothane-induced increase of calcium levels in MHS muscles could be reduced by pretreatment with ketanserin (Ooms et al 1983).…”

Section: Introductionmentioning

confidence: 99%

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients

Wappler

Scholz

Fiege

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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Administration of 5-HT2 receptor agonists induced malignant hyperthermia (MH) in susceptible pigs. Furthermore, the 5-HT2 receptor antagonist ritanserin prevented 5-HT-induced porcine MH. It has been shown that 5-HT2 receptor agonists induce marked contractures in skeletal muscle specimens from MH susceptible (MHS) but not in specimens from normal patients. The purpose of this study was to investigate the effects of ritanserin on halothane-induced contractures in muscle specimens from MHS patients. Twenty-five patients aged 8-56 years (29.5+/-13.6) classified as MHS by the in vitro contracture test (IVCT) with halothane and caffeine according to the protocol of the European MH Group participated in this study. Muscle specimens were pretreated with ritanserin 10 micromol/l (n= 14), 20 micromol/l (n=14) and 100 micromol/l (n=12) for 10 min and subsequently halothane was added incrementally (0.11-0.22-0.44 mmol/l) to the tissue bath as described in the European MH protocol. The results of the halothane contracture test were used as control. Following administration of halothane, muscle contractures reached a maximum of 16.9+/-4.2 mN. Ritanserin led to a significant inhibition of halothane-induced contractures in MHS muscles. Following pretreatment with ritanserin, halothane-induced contracture maximum was significantly smaller with 7.5+/-3.1 mN after 10 micromol/l ritanserin, 4.9+/-1.5 mN after 20 micromol/l ritanserin and 0.5+/- 0.2 mN after 100 micromol/l ritanserin than without pretreatment. Administration of ritanserin induced at all concentrations a decrease in muscle twitch height. Increase in muscle twitch following halothane was reduced in a concentration-dependent manner by ritanserin. The presented findings indicate that 5-HT might be involved in the mechanisms of halothane-induced MH in humans. Further studies have to determine the pathophysiological role of the 5-HT system in MH, and whether ritanserin could be an alternative for treatment or prevention of halothane-induced MH.

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“…The results of in vitro experiments in skeletal muscle preparations from MH patients with 5‐HT‐receptor agonists and antagonists provide evidence that 5‐HT might also be involved in the mechanisms of MH in humans [58–60]. Based on the findings of these investigations, it is suggested that a functional or structurally altered 5‐HT system might be involved in the development of MH.…”

Section: Serotonin Systemmentioning

confidence: 99%

Malignant hyperthermia

Wappler¹

2001

Eur J Anaesthesiol

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Malignant hyperthermia is an autosomal-dominant inherited disorder of the skeletal muscle cell characterized by a hypermetabolic response to all commonly used inhalational anaesthetics and depolarizing muscle relaxants. The clinical syndrome includes muscle rigidity, hypercapnia, tachycardia and myoglobinuria as result of increased carbon dioxide production, oxygen consumption and muscle membrane breakdown. In human beings and animals susceptible to malignant hyperthermia, it is generally accepted that an increase in the level of myoplasmic free calcium is the cause of the syndrome. Various hypotheses have been proposed to account for the increase of intracellular calcium levels, e.g. a defect in the calcium release channel of the sarcoplasmic reticulum (ryanodine receptor), an abnormality of the excitation-contraction coupling mechanisms, or alterations in second messenger systems of skeletal muscles. This review gives an overview of the main features of this disease and recent advances in research including pathophysiology, treatment, diagnosis and genetics as well as association with other disorders.

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Ritanserin attenuates the in vitro effects of the 5-HT2 receptor agonist DOI on skeletal muscles from malignant hyperthermia-susceptible patients

Cited by 12 publications

References 30 publications

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients

Malignant hyperthermia

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Ritanserin attenuates the in vitro effects of the 5-HT2 receptor agonist DOI on skeletal muscles from malignant hyperthermia-susceptible patients

Cited by 12 publications

References 30 publications

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2AReceptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2AReceptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients

Malignant hyperthermia

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Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter