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Biomedical subjects

F Wappler

Publications and source records attributed to F Wappler.

104 records · Page 6Linked to original sources
PubMed1996

Effects of the serotonin2 receptor agonist DOI on skeletal muscle specimens from malignant hyperthermia-susceptible patients.

BACKGROUND: Administration of serotonin2 (5-HT2) receptor agonists in pigs triggers malignant hyperthermia (MH) and psychotic-like behavior. Both can be reduced by 5-HT2 receptor antagonists. Furthermore, an increase in the plasma concentration of 5-HT has been found during onset of halothane-induced MH in pigs. Therefore, in this study, the in vitro effects of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were investigated in muscle specimens from MH-susceptible (MHS) and -negative (MHN) patients. METHODS: After MH classification using the caffeine-halothane contracture test (CHCT), surplus muscle specimens from 23 MHS and 17 MHN patients were used to examine the effects of DOI. In the first study, DOI was added to the bath in a concentration of 0.02 mM. In a second experiment, muscles were preincubated for 60 min with 0.02 mM DOI, and subsequently, halothane was added incrementally to the organ bath (0.11-0.22-0.44 mM) for 15 min according to the CHCT protocol. The in vitro effects of DOI on contracture development and muscle twitch were measured for 120 min in both investigations. RESULTS: Muscle specimens form all patients developed contractures after administration of DOI, characterized by a significantly earlier development of contracture in MHS (16.8 +/- 1.7 min) than in MHN (66.3 +/- 5.8 min) muscles (P < 0.05). There was no overlap between the groups in the range of times. The onset of contracture development after DOI was prolonged by halothane in specimens from MHN patients (89.7 +/- 5.6 min) but not MHS patients. Preincubation with DOI increased the halothane-induced contractures in specimens from MHS patients compared to the results of the CHCT. The contracture development in specimens from MHS patients was larger than from MHN patients. At the end of the experiment, contractures had reached a maximum of 12.9 +/- 1.1 mN in specimens from MHS and 5.3 +/- 0.6 mN in MHN patients (P < 0.05). The additional administration of halothane led to significantly increased contractures in specimens from MHS individuals (15.9 +/- 0.9 mN) at 120 min. However, the contracture development decreased significantly to 3.1 +/- 0.4 mN in MHN muscles. Muscle twitch after DOI administration was reduced significantly in specimens from MHS and MHN patients. CONCLUSIONS: A functional or structural altered serotonin system might be involved in the development of MH in humans.

Adolescent↗
PubMed1995

C1840-T mutation in the human skeletal muscle ryanodine receptor gene: frequency in northern German families susceptible to malignant hyperthermia and the relationship to in vitro contracture response.

In swine, a point mutation in the ryanodine receptor gene can account for all cases of malignant hyperthermia (MH). The frequency of a corresponding mutation in humans (C1840-T) and its relationship to the in vitro contracture profile is unknown. We screened 192 patients from 28 unrelated northern German families for the C1840-T mutation in the human ryanodine receptor gene and tested for MH susceptibility using the in vitro contracture test (IVCT) according to the European MH Protocol. In our patients 106 revealed MH susceptible (MHS), 56 MH nonsusceptible and 30 MH equivocal status following IVCT. In each family one or two individuals had developed clinical signs of MH or a MH crisis. All of these patients were classified MHS. The C1840-T mutation was found in 2 of 28 families (7.1%). All eight individuals of the two families characterized by this mutation revealed MHS status following IVCT. The thresholds for halothane- and caffeine-induced contractures as well as the contracture profiles following cumulative (0.4-10.0 mumol/l every 3 min) and bolus (10 mumol/l) administration of ryanodine were found to be similar in MHS patients with and without the C1840-T mutation. In conclusion, the C1840-T mutation in the human ryanodine receptor gene is a rare abnormality in MHS families. Similar contracture profiles in the presence and absence of this mutation might imply no major functional role with respect to the contracture response. At present, molecular genetic analysis cannot replace IVCT to discover MH susceptibility in humans.

Adolescent↗
PubMed1995

[Effects of serotonin 2 receptor agonists on skeletal muscle preparations in patients with a disposition toward malignant hyperthermia].

In pigs genetically susceptible to malignant hyperthermia (MH), it has been shown that serotonin (5-HT2) receptor agonists can induce MH and "psychotic" behaviour. Both can be prevented by 5-HT2 receptor antagonists. Furthermore, free levels of serotonin in plasma increased concomitantly with clinical and laboratory parameters during halothane-induced MH in pigs. In this study the in vitro-effects of the 5-HT2 receptor agonist1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) were investigated in muscle specimens of MH-susceptible (MHS) and normal (MHN) patients. METHODS. Muscle biopsies were obtained from 37 patients aged 5-69 years (23.6 +/- 5.3 years) with clinical suspicion for MH. The patients were first classified as MHS, MHN or MHE (MH equivocal) by the in vitro contracture test (IVCT) according to the European MH protocol. After MH classification, surplus muscle specimens were subjected to the DOI study. DOI was added to the organ bath in a concentration of 0.02 mmol/l. The in vitro effects on contracture development and muscle twitch were observed for 120 min. RESULTS. Muscle specimens of all patients developed contractures after administration of DOI. However, DOI produced an earlier development of contracture in MHS (17.0 +/- 1.8 min; n = 17) than in MHN (64.7 +/- 5.9 min; n = 15) muscles. In MHS muscles, contractures were more distinct than in MHN muscles; at the end of the experiment, contractures had reached a maximum of 12.5 +/- 0.9 mN in MHS and 5.1 +/- 0.7 mN in MHN muscles. Muscle twitch following DOI administration was reduced significantly in both MHS and MHN muscles. The results of four MHE muscles were comparable with MHS. CONCLUSION. The present study supports the assumption that an altered serotonin system might be involved in the development of MH. In further studies it should investigated whether 5-HT2 receptors of skeletal muscles from MHS subjects are disordered in function or structure. 5-HT2 receptor agonists should be considered as MH-triggering agents.

Adolescent↗
PubMed1995

Alterations of inositol polyphosphates in skeletal muscle during porcine malignant hyperthermia.

Malignant hyperthermia (MH) may result from increased intracellular calcium concentrations. Increased 1,4,5-IP3 concentrations could mediate this increase in Ca2+. In this study we measured inositol polyphosphates in selectively bred MH susceptible (MHS) and MH non-susceptible (MHN) swine. MH crisis was induced by halothane challenge, and dantrolene was administered in order to measure inositol polyphosphates after MH reversal. Muscle biopsies of skeletal muscles of the hind limbs were obtained in random order and inositol polyphosphates determined by high pressure liquid chromatography using a metal dye detection method. Inositol polyphosphates were determined in three groups: (1) MHS vs MHN basal, (2) during MH crisis induced by halothane and (3) following treatment with dantrolene after halothane challenge. Clinical variables (P(_)VO2, P(-)VCO2, PE'CO2 and pH) indicated that MH was readily induced in MHS swine. Basal concentrations of all inositol polyphosphates were higher in MHS swine compared with MHN swine. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 concentrations increased in MHS animals compared with the respective baseline values, whereas no changes in MHN animals could be detected. Dantrolene administration decreased inositol polyphosphate concentrations in MHS swine. MHN swine showed no changes in inositol polyphosphates after dantrolene. These findings indicate that inositol polyphosphates may be involved in metabolic changes after triggering and treatment of MH.

Anesthetics, Inhalation↗
PubMed1995

Modulation of ryanodine-induced contractures in human skeletal muscle pretreated with dantrolene.

Dantrolene seems to be the causal therapy in malignant hyperthermia (MH) crisis but the complex mechanisms of MH and dantrolene therapy are still not fully understood. The influence of dantrolene on ryanodine-induced contractures has been reported in animal studies only. In the present study 20 patients from 17 families were tested for MH using the protocol of the European Malignant Hyperthermia Group. In addition ryanodine-induced contractures were evaluated following bolus application of 10.0 mumol.l-1 ryanodine. After pretreatment with 1 mumol.l-1 dantrolene ryanodine-provoked contractures developed significantly later in MHS (15.8 +/- 1.8 min) and MHN (46.0 +/- 4.2 min) muscle specimens than after ryanodine alone (MHS 4.8 +/- 0.7 min. (MHN 13.7 +/- 0.9 min). They were no longer observed in either group after pretreatment with 5 mumol.l-1 dantrolene. We conclude that dantrolene is able to attenuate ryanodine-induced contractures dose-dependently, and therefore it is speculated that dantrolene could specifically act at the ryanodine receptor binding site.

Adolescent↗
PubMed1994

High-purity ryanodine and 9,21-dehydroryanodine for in vitro diagnosis of malignant hyperthermia in man.

Susceptibility to malignant hyperthermia (MH) is currently diagnosed by the in vitro contracture test (IVCT) in skeletal muscle. However, this test does not possess absolute specificity. Thus, in addition to the established procedure, the "ryanodine contracture test" has been proposed to improve discrimination between MH-susceptible (MHS) and normal (MHN) patients. In all previous studies, the ryanodine used was a mixture consisting of high-purity ryanodine (HPR) and 9,21-dehydroryanodine (DHR). Therefore, in this study the effects of both substances were investigated in concentrations of 2, 5 and 10 mumol litre-1. With all concentrations, contractures appeared earlier in MHS than in MHN muscles, but these differences were significant at all contracture levels with HPR only. Moreover, with the smallest concentration (2 mumol litre-1), the best discrimination between MHS and MHN was observed. Classification of MH-equivocal patients (MHE) as MHS or MHN seems to be possible with the use of ryanodine-induced contractures. The contracture test with HPR should therefore be added to the established procedure of the IVCT.

Adolescent↗
PubMed1993

[High purity ryanodine for in vitro diagnosis of malignant hyperthermia].

OBJECTIVE AND STUDY DESIGN: The identification of disposition for malignant hyperthermia (MH) is performed by the halothane-caffeine contracture test in skeletal muscle. However, testing currently renders about 14% of the patients MH equivocal (MHE). To reduce this number the "ryanodine contracture test" has been proposed in addition to the established procedure. As all ryanodine preparations used until now are combinations of ryanodine and dehydroryanodine, we investigate in this study the effects of the now available high-purity ryanodine (HPR) in concentrations of 2,5 and 10 mumol/l. RESULTS: With all concentrations contractures appeared significantly earlier in MHS (malignant hyperthermia susceptible) than in MHN (malignant hyperthermia non-susceptible). However, only at 2 mumol/l a time overlap between both groups was not observed. By defining a time interval for MHS and MHN, three of the MHE patients could be assigned to MHS and three to MHN following their ryanodine-induced contractures. CONCLUSION: The ryanodine contracture test should be added to the current diagnostics of malignant hyperthermia.

Adolescent↗
PubMed1993

Accelerated contractures after administration of ryanodine to skeletal muscle of malignant hyperthermia susceptible patients.

A genetic disorder of the calcium releasing ryanodine receptor has recently been postulated in malignant hyperthermia (MH) and ryanodine-induced contractures differ between subjects who are malignant hyperthermia susceptible (MHS) and non-susceptible (MHN). We tested 39 patients from 26 families for MH, using the procedure of the European Malignant Hyperthermia Group. A ryanodine contracture test was performed by both cumulative (0.4-10.0 mumol litre-1 every 3 min) and bolus (10.0 mumol litre-1) application. Contracture with cumulative ryanodine application started significantly earlier in MHS (9.6 (SEM 0.5) min) than in MHN patients (24.6 (1.3) min). A significant difference in start of contracture between MHS (4.8 (0.6) min) and MHN (14.5 (0.6) min) patients occurred also after bolus application of ryanodine. The ryanodine contracture test seems to be a potentially specific in vitro diagnostic test for MH.

Adolescent↗