LACK OF PROPHYLACTIC OR THERAPEUTIC EFFICACY OF 5-HT2A RECEPTOR ANTAGONISTS IN HALOTHANE-INDUCED PORCINE MALIGNANT HYPERTHERMIA

During halothane-induced malignant hyperthermia (MH), plasma levels of serotonin (5-hydroxytryptamine, 5-HT) increase in pigs. Administratio n of 5-HT agonists which stimulate the 5-HT2A subreceptor triggers MH in susceptible pigs. A possible link between MH induced by 5-HT2A rece ptor agonists and halothane could be an increase of second messengers such as phosphoinositides (inositol polyphosphates), which have recent ly been implicated in the abnormal regulation of skeletal muscle calci um release in MH. If so, antagonists of 5-HT2A receptors which are lin ked to phosphoinositide turnover should be capable of preventing, reta rding or attenuating halothane-induced MH. This possibility was invest igated in the present study in MH susceptible pigs, using dantrolene f or comparison. Development of MH triggered by a halothane challenge (i nhalation of 3% halothane for 15 min) was completely prevented by dant rolene, 3.5 mg/i.v., whereas the 5-HT2A receptor antagonists ritanseri n (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 ketan serin where given in combination with hyperventilation after developme nt of MH, dantrolene exerted therapeutic efficacy, whereas neither rit anserin nor ketanserin were effective treatments. The data indicate th at 5-HT is not critically involved in the mechanisms of halothane-indu ced MH, at least under the conditions of the present experimental stud y.