IN VITRO EFFECTS OF SEROTONIN RECEPTOR AGONISTS ON SKELETAL MUSCLE 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.

Download Full-text

In vitro effects of 4-chloro-3-ethylphenol in skeletal muscle preparations from malignant hyperthermia susceptible and normal swine

European Journal of Anaesthesiology ◽

10.1097/00003643-200202000-00011 ◽

2002 ◽

Vol 19 (2) ◽

pp. 135-140 ◽

Cited By ~ 1

Author(s):

M. U. Gerbershagen ◽

F. Wappler ◽

M. Fiege ◽

R. Weihorn ◽

P. A. Alberts ◽

...

Keyword(s):

Skeletal Muscle ◽

Malignant Hyperthermia ◽

Malignant Hyperthermia Susceptible ◽

In Vitro Effects

Download Full-text

In vitro effects of 4-chloro-3-ethylphenol in skeletal muscle preparations from malignant hyperthermia susceptible and normal swine

European Journal of Anaesthesiology ◽

10.1017/s0265021502000248 ◽

2002 ◽

Vol 19 (02) ◽

pp. 135 ◽

Cited By ~ 1

Author(s):

M. U. Gerbershagen ◽

F. Wappler ◽

M. Fiege ◽

R. Weißhorn ◽

P. A. Alberts ◽

...

Keyword(s):

Skeletal Muscle ◽

Malignant Hyperthermia ◽

Malignant Hyperthermia Susceptible ◽

In Vitro Effects

Download Full-text

5HT1A Serotonin Receptor Agonists Inhibit Plasmodium falciparum by Blocking a Membrane Channel

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.12.3806-3809.2003 ◽

2003 ◽

Vol 47 (12) ◽

pp. 3806-3809 ◽

Cited By ~ 8

Author(s):

Christopher P. Locher ◽

Peter C. Ruben ◽

Jiri Gut ◽

Philip J. Rosenthal

Keyword(s):

Serotonin Receptor ◽

Surface Membrane ◽

Resistant Isolate ◽

Neurological Involvement ◽

Membrane Channel ◽

Transport Pathway ◽

Human Lung Fibroblast ◽

Receptor Agonists ◽

Serotonin Receptor Agonists

ABSTRACT Toidentify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels.

Download Full-text