Inositol 1,4,5,-Trisphosphate Phosphatase Deficiency and Malignant Hyperpyrexia in Swine

Foster, Paul S.; Claudianos, Charles; Gesini, E.; Hopkinson, K.C.; Denborough, M. A.

doi:10.1016/s0140-6736(89)90182-7

Cited by 65 publications

(34 citation statements)

References 17 publications

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“…However, it must be linked to a dysregulation of intracellular Ca 2ϩ homeostasis. We think that it is the result of a chronic alteration of intracellular Ca 2ϩ release or leak combined with a resetting of the set point and/or a deficiency in the Ca 2ϩ transport by the SR and/or the plasma membrane (9,11,12,29,34,38) The enhanced sensitivity of MHS muscle cells to caffeine and 4-CmC has been observed by numerous groups (16,22,45,48,51), and thus similar behavior in MHS myoballs was expected. However, the mechanism for this increased sensitivity has been the subject of debate.…”

Section: Discussionmentioning

confidence: 54%

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca²⁺]_i

López¹,

Linares²,

Pessah³

et al. 2005

American Journal of Physiology-Cell Physiology

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[Ca 2ϩ ]i, and reduced the amount of Ca 2ϩ release associated with exposure to any given concentration of caffeine or 4-CmC to MHN levels. These results suggest that the differences in the response of MHS skeletal myoballs to caffeine and 4-CmC may be mediated at least in part by the chronic high resting [Ca 2ϩ ]i levels in these cells. calcium homeostasis; 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid MALIGNANT HYPERTHERMIA (MH) is a potentially fatal pharmacogenetic myopathy of humans and several large mammals, including swine, dog, and horse. It can be induced by volatile anesthetics and/or depolarizing muscle relaxants (1, 33, 37). While in swine susceptibility to the syndrome has been associated with a single point mutation (Arg615Cys) in the Ca 2ϩ release channel at the sarcoplasmic reticulum (ryanodine receptor 1, RyR1) (13, 32), in humans at least 42 MH mutations have been identified at 34 different RyR1 residues and two MH mutations at one residue in the skeletal dihydropyridine receptor (DHPR) (21,33,37 (17,26). In addition, it was previously shown that skeletal muscle from MHS individuals and animals have a lower pharmacological threshold and an exaggerated response at submaximal concentrations of caffeine (22, 45) and 4-chloro-m-cresol (4-CmC) (44, 48) than do those with MH-nonsusceptible (MHN) muscle. This enhanced sensitivity is widely used as part of the clinical diagnosis of MH susceptibility in humans and has been confirmed experimentally in swine (16,21). The molecular and cellular basis for heightened sensitivity to pharmacological agents in MHS has remained unclear (33, 37). Evidence of chronically elevated resting [Ca 2ϩ ] i has been presented on the basis of direct measurements with Ca 2ϩ -selective electrodes in isolated human and swine skeletal muscle fibers (28, 30). However, the extent to which high [Ca 2ϩ ] i contributes to sensitizing responses to caffeine and 4-CmC is not known.The purpose of the present study was to address the question of whether the enhanced intracellular Ca 2ϩ release at submaximal concentrations of caffeine and 4-CmC (44,45,48) in MHS cells is related to chronic elevation in resting [Ca 2ϩ ] i in affected muscle cells. To do so, resting [Ca 2ϩ ] i of MHS myoballs was decreased nearly to MHN levels by loading them with the Ca 2ϩ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid (BAPTA) and then reexamining the responses to caffeine and 4-CmC. Our results suggest that the enhanced intracellular Ca 2ϩ release at submaximal concentrations of caffeine and 4-CmC was closely associated with the high resting [Ca 2ϩ ] i observed in these cells. MATERIALS AND METHODSMuscle cell preparations. Muscle biopsies were obtained from the hindlimb muscles of newborn (4 -8 days) Yorkshire (MHN; n ϭ 4) and Poland China (MHS; n ϭ 5) swine. Susceptibility to MH was determined using polymerase chain reaction genotyping as previously described (33, 37). Hindlimb muscle was removed while the animals were anesthetized with the nontriggering age...

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Section: Discussionmentioning

confidence: 54%

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca²⁺]_i

López¹,

Linares²,

Pessah³

et al. 2005

American Journal of Physiology-Cell Physiology

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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: 96%

“…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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“…increased Ca 2+ stimulation of Ca 2+ activated phosholipase C isoforms may lead to abnormal elevations of IPs. Furthermore, halothane has been shown to inhibit the activity of inositol 1,4,5-trisphosphatase (IP35-ase), a degrading enzyme of IPs in MHS skeletal muscles (Foster et al 1989 basal conditions may be also based on reduced IP35-ase activity, observed in skeletal muscles of MHS pigs in the absence of triggering agents (Foster et al 1989). These findings, however, do not exclude an additional involvement of enhanced synthesis of IPs by activation of receptors which are G-protein-linked or coupled to tyrosine kinases (Berridge, 1993;Foster, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…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 Phosphatase Deficiency and Malignant Hyperpyrexia in Swine

Cited by 65 publications

References 17 publications

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca²⁺]_i

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca²⁺]_i

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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Inositol 1,4,5,-Trisphosphate Phosphatase Deficiency and Malignant Hyperpyrexia in Swine

Cited by 65 publications

References 17 publications

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2+]i

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2+]i

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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Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca²⁺]_i

Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca²⁺]_i