Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of serotonin (5-HT) were determined in platelet-free and platelet-rich plasma before and during the onset of halothane-induced malignant hyperthermia (MH) in genetically MH-susceptible pigs. During MH onset, the free (i.e. physiologically active) levels of 5-HT in plasma rose concomitantly with the increases in muscle tone, body temperature, venous pCO2 and plasma lactate. Since pharmacological stimulation of 5-HT2 receptors has recently been shown to trigger MH in susceptible pigs, the finding of increased 5-HT plasma levels during onset of halothane-induced MH may indicate that 5-HT is involved in the mechanisms by which volatile anesthetics trigger this myopathic syndrome.
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PMID:Increase of serotonin in plasma during onset of halothane-induced malignant hyperthermia in pigs. 142 84

Succinylcholine (Sch) which is a cholinergic neuromuscular blocker has been known to occasionally lead to episodes of malignant hyperthermia in swine and humans. In order to find whether it produces any hyperthermic effects through action on medial preoptic area, experiments were carried on by administering intracerebrally the chemical into the medial preoptic area through an in-dwelling cannula-cum-electrode in the free moving rat. The changes in body temperature and the local EEG were studied. For comparison purpose, the effects of carbachol, atropine and phenylephrine were also studied. Further, in the curarized state of no muscular activity, the effect of SCh on the preoptic area was again tested and also the changes in the other autonomic parameters of heart rate and galvanic skin resistance (GSR) were studied. It was observed that SCh given into preoptic area caused a clear hyperthermic effect. The effect was countered by prior administration of atropine into the site. After SCh the local EEG changed into a high amplitude slow wave format. The heart rate was not altered but the GSR increased by two-fold. Carbachol caused a rise in body temperature, heart rate and also GSR. SCh also caused a reduction in noradrenaline content of the hypothalamus by 23% while no change in dopamine and serotonin occurred. Serotonin increased by 28% in the brainstem with no change in the other amines. Septum showed an increase of noradrenaline and dopamine contents by 40% and 25% respectively. Keeping in view the monoaminergic connections and thermoregulatory role of the preoptic area, one may postulate that SCh could inhibit the warm sensors and the controls of the dual sympathetic mechanism which normally leads to an increase of sudomotor activity and a decrease of vasomotor activity, the inhibition resulting in rise of body temperature.
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PMID:Effects of succinylcholine and related substances administered into the medial preoptic area on the local EEG, body temperature, heart rate, galvanic skin resistance and biogenic amines. 384 71

During halothane-induced malignant hyperthermia (MH), plasma levels of serotonin (5-hydroxytryptamine, 5-HT) increase in pigs. Administration of 5-HT agonists which stimulate the 5-HT2A subreceptor triggers MH in susceptible pigs. A possible link between MH induced by 5-HT2A receptor agonists and halothane could be an increase of second messengers such as phosphoinositides (inositol polyphosphates), which have recently been implicated in the abnormal regulation of skeletal muscle calcium release in MH. If so, antagonists of 5-HT2A receptors which are linked to phosphoinositide turnover should be capable of preventing, retarding or attenuating halothane-induced MH. This possibility was investigated in the present study in MH susceptible pigs, using dantrolene for comparison, Development of MH triggered by a halothane challenge (inhalation of 3% halothane for 15 min) was completely prevented by dantrolene, 3.5 mg/i.v., whereas the 5-HT2A receptor antagonists ritanserin (0.5-10 mg/kg i.v.) or ketanserin (0.5-10 mg/kg i.v.) exerted no prophylactic effect. In pigs in which dantrolene, ritanserin or ketanserin where given in combination with hyperventilation after development of MH, dantrolene exerted therapeutic efficacy, whereas neither ritanserin nor ketanserin were effective treatments. The data indicate that 5-HT is not critically involved in the mechanisms of halothane-induced MH, at least under the conditions of the present experimental study.
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PMID:Lack of prophylactic or therapeutic efficacy of 5-HT2A receptor antagonists in halothane-induced porcine malignant hyperthermia. 784 74

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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PMID:Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia. 893 57

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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PMID:5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients. 1055 Dec 74

Numerous medical conditions present with acute and severe autonomic and muscular overactivity. These syndromes include Neuroleptic Malignant Syndrome, Serotonin Syndrome, Dysautonomia (or paroxysmal sympathetic storms) following acquired brain injury, Autonomic Dysreflexia, Parkinsonian-Hyperpyrexia Syndrome, Malignant Catatonia, intrathecal baclofen withdrawal, Malignant Hyperthermia, Stiff Man Syndrome and Irukandji Syndrome. In their worst forms, each of these syndromes are relatively rare, are treated by different medical specialties and show widely varying pathophysiology. Most are considered to be medical emergencies and share significant mortality rates. Previous authors have noted similarities between some of these conditions, prompting the suggestion that a single common mechanism may underlie their clinical presentation. However, the development of such an integrative model has not occurred. This paper presents a short review of the clinical syndromes, grouped by the location of pathology and mechanism of action. From this background, an integrative framework termed the excitatory:inhibitory ratio (EIR) model is presented. The EIR model consists of two inter-related networks operating at spinal and brainstem levels. The model is evaluated against pre-clinical scientific research, known pathways, each disorder's pathophysiology (where this is known) and variable severity, and used to explain the reasons behind the efficacy of current treatment regimes. Circumstantial evidence for an expanded aetiology for Malignant Hyperthermia is provided and generic treatment strategies for a number of other conditions are suggested. Finally, minor modifications to this model provide a basis to begin to explain less severe, regional "overlap" syndromes.
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PMID:The excitatory:inhibitory ratio model (EIR model): An integrative explanation of acute autonomic overactivity syndromes. 1758 40

Maintaining a body temperature within a narrow range is vital for the survival of all mammals, including humans. With the help of optogenetics, a better understanding of the thermoregulatory organs and pathways is achieved. Optogenetic activation of the GABAergic neurons in the ventral part of the lateral preoptic nucleus (VLPO) leads to decrease in the body temperature. On the other hand, number of drugs could alter the thermoregulatory balance, leading to a hyperthermic state, such as serotonin syndrome (SS). SS is a potentially life-threatening clinical condition that occurs as a result of a drug-induced increase in the intrasynaptic serotonin (5-hydroxytryptamine, 5-HT) levels due to overdose of a single drug or due to interaction between two or more drugs with serotonergic mechanism of action. In this hypothesis, we propose a novel method for the treatment of hyperthermia, a core clinical sign of serotonin syndrome, through deep brain stimulation (DBS). An electrode is stereotactically placed in the VLPO, which may lead to reduction of the core body temperature. If proven effective, this technique should be left as a salvage method for reduction of hyperthermia, where the drug treatment is insufficient or ineffective. This technique could be used for the treatment of other syndromes, where hyperthermia takes a central place, including malignant hyperthermia, neuroleptic malignant syndrome, etc. DBS, on the other hand, could be used alone to induce hyperthermia in patients with malignant diseases. Hyperthermia improves the immune response, improves the drug penetration and stop the repair of already damaged tumor cells after chemotherapy or radiotherapy.
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PMID:Deep brain stimulation as a possible treatment of hyperthermia in patients with serotonin syndrome. 3279 90