Inositol-1,4,5-trisphosphate and malignant hyperthermia

Scholz, Jens; Troll, U.; Esch, Jochen Schulte am; Hartung, E.; Patten, Monica; Sandig, P; Schmitz, Wilhelm

doi:10.1016/0140-6736(91)93052-b

Cited by 31 publications

(22 citation statements)

References 9 publications

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“…Alterations in these systems, for example, serotonin [4] or inositolpolyphosphates [5,23], have been found to be associated with MH. Also, the cAMP system seems to be altered in MH.…”

Section: Discussionmentioning

confidence: 98%

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Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine

Fiege

Wappler

Weißhorn

et al. 2005

European Journal of Anaesthesiology

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Background and objective: The phosphodiesterase-III (PDE-III) inhibitor enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of enoximone or caused by inhibition of PDE-III remained unclear. Therefore, the effects of the PDE-III inhibitor amrinone in porcine MH normal (MHN) and MHS skeletal muscles were investigated.Methods: MH-trigger-free general anaesthesia was performed in eight MHS and eight MHN swine. The MH status of the swine was determined by detection of the Arg615-Cys point mutation on chromosome 6 indicating MH susceptibility. Skeletal muscle specimens were excised for the in vitro contracture tests with amrinone. Amrinone was added cumulatively every 5 min to muscle specimens in order to obtain organ bath concentrations between 20 and 400 µmol L Ϫ1 . The in vitro effects of amrinone on muscle contractures and twitches were measured.Results: Amrinone-induced contractures in all skeletal muscle preparations. MHS muscles developed contractures at significantly lower bath concentrations of amrinone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 80, 100, 150, 200 and 400 µmol L Ϫ1 amrinone. Muscle twitches remained unchanged up to and including 200 µmol L Ϫ1 amrinone.Conclusions: Inhibition of PDE-III in general elicited higher contractures in MHS than in MHN muscles. Therefore, a contribution of PDE-III and the cyclic adenosine monophosphate (cAMP) system in the pathophysiology of MH must be suspected.Malignant hyperthermia (MH) is a potentially lethal myopathy that is often inherited as an autosomal dominant trait [1]. It is widely accepted that susceptibility to MH is caused by abnormal Ca 2ϩ metabolism within the skeletal muscle fibre [2,3]. Ca 2ϩ homoeostasis in skeletal muscles is regulated by a variety of intracellular second messenger systems. Alterations in some of the second messenger systems, for example, serotonin [4] or inositolpolyphosphates [5] have been found to be associated with MH. Also the cyclic adenosine monophosphate (cAMP) system seems to be affected in MH. In skeletal muscle cells from MH susceptible (MHS) patients and animals higher cAMP concentrations were measured compared to MH normal (MHN) [6][7][8].

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“…Alterations in these systems, for example, serotonin [4] or inositolpolyphosphates [5,23], have been found to be associated with MH. Also, the cAMP system seems to be altered in MH.…”

Section: Discussionmentioning

confidence: 98%

“…Ca 2ϩ homoeostasis in skeletal muscles is regulated by a variety of intracellular second messenger systems. Alterations in some of the second messenger systems, for example, serotonin [4] or inositolpolyphosphates [5] have been found to be associated with MH. Also the cyclic adenosine monophosphate (cAMP) system seems to be affected in MH.…”

mentioning

confidence: 98%

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine

Fiege

Wappler

Weißhorn

et al. 2005

European Journal of Anaesthesiology

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“…This hypothesis was confirmed by studies which revealed that the InsP 3 receptor shares considerable structural and functional homologies with the ryanodine receptor (Mignery et al 1989). Furthermore, the basal concentrations of InsP 3 in skeletal and cardiac muscles of MHS swine and humans were found to be significantly elevated (Foster et al 1989;Scholz et al 1991;Wappler et al 1997a), and it has been suggested that an increased activity of phospholipase C might cause the increase of InsP 3 concentrations (Fletcher and Wieland 1994). Further investigations have shown significant differences in the threshold for InsP 3 -induced release of Ca 2+ between muscle fibers of MHS and MHN (López et al 1995); the magnitude of the effect of InsP 3 on [Ca 2+ ] i was greater in MHS than in MHN muscle preparations.…”

Section: Discussionmentioning

confidence: 98%

“…Various hypotheses have been discussed to account for the increase of intracellular Ca 2+ levels, e.g. a defect in Ca 2+ release channels of the sarcoplasmic reticulum (ryanodine receptor; Mickelson et al 1988;Fill et al 1990), an abnormality in the excitation-contraction coupling mechanisms (Pessah et al 1996), or alterations in the inositol phosphate metabolism of skeletal muscle cells (Foster et al 1989;Scholz et al 1991;Wappler et al 1997a).…”

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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“…There is increasing evidence for a pathogenetical role of inositol phosphates (IPs) which play an important role in Ca 2+ mobilization in skeletal muscle (Steinmann 1994). Thus, increased levels of the second messenger 1,4,5 IP3 and that of other IPs have been demonstrated in skeletal muscle of human MHS individuals and of MHS pigs even in the absence of triggering agents (Foster et al 1989;Scholz et al 1991Scholz et al , 1993Tonner et al 1995). Actually, MHS skeletal muscles exhibit a higher responsiveness to IP3-induced release of Ca 2+ (Lopez et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia

Richter

Scholz

Löscher

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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Recent studies have shown a significant increase of inositol phosphates (IPs) in skeletal muscle during episodes of halothane-induced malignant hyperthermia (MH) in pigs. After treatment with dantrolene and disappearance of MH crisis the IP concentrations returned to basal levels. In order to examine if the increase of IPs during halothane-induced MH may be related to an enhanced IP synthesis in response to activation of 5-HT2 (5-hydroxytryptamine) receptors, the effects of ritanserin, a selective 5-HT2 receptor antagonist, on IP levels were investigated. Biopsies of skeletal muscle of the hindlimbs were obtained in random order and IPs were determined in homozygous MH-susceptible (MHS) and MH-non-susceptible (MHN) swine in the following order: (1) basal, (2) after treatment with ritanserin (2.0 mg/kg), (3) after halothane challenge (3 vol% for 20 min). Basal concentrations of all IPs were higher in MHS than in MHN swine. Ritanserin did not cause any significant changes of IP levels compared to the basal concentrations in MHS and MHN pigs. In MHS pigs, ritanserin did not prevent a halothane-induced MH-crisis. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 levels were increased in MHS (during MH crisis) vs. basal concentrations, whereas no changes were found in MHN pigs. Since the increases of IP levels in MHS pigs during MH crisis found in the present study were comparable to those without pretreatment with ritanserin, shown by recent studies, it may be concluded that ritanserin does not prevent the increase of IPs during a halothane-induced MH. Thus, the present data indicate that increases of IP levels during halothane-induced MH in swine are due to other mechanisms than 5-HT mediated enhancement of IP synthesis.

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Inositol-1,4,5-trisphosphate and malignant hyperthermia

Cited by 31 publications

References 9 publications

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine

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

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia

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