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.
Wappler
F
F
Department of Anesthesiology, University-Hospital Eppendorf, Hamburg, Germany.
Roewer
N
N
Köchling
A
A
Scholz
J
J
Löscher
W
W
Steinfath
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008305:Malignant Hyperthermia / Q000209:etiology / Q000503:physiopathology*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000662:Amphetamines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D006221:Halothane