Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia

Abstract

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.

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients

“…The latter results indicate that increases in inositol polyphosphate concentrations during halothane-induced porcine MH might also be due to other mechanisms than 5-HT-mediated enhancement of inositol polyphosphate synthesis. As indicated by the present data, the lack of efficacy of ritanserin on halothane-induced MH (Löscher et al 1994) and the failure to prevent the halothane-induced increase of inositol phosphate levels (Richter et al 1996) could be related to the high dose of the trigger (3 v/v halothane for 15-20 min) or to insufficient doses of ritanserin (2.5 mg/kg i.v.) used in the in vivo experiments.…”

“…Dantrolene reversed the increase in inositol polyphosphates in the MHS group to values close to control concentrations before halothane administration. However, in a recent study ritanserin did not prevent the increase of inositol polyphosphates during a halothane-induced MH in swine (Richter et al 1996). The latter results indicate that increases in inositol polyphosphate concentrations during halothane-induced porcine MH might also be due to other mechanisms than 5-HT-mediated enhancement of inositol polyphosphate synthesis.…”

Attenuation of serotonin–induced contractures in skeletal muscle from malignant hyperthermia–susceptible patients with dantrolene

“…However, in direct contrast, it has been shown that the serotonin2 receptor antagonist ritanserin exerted no prophylactic or therapeutic efficacy in halothaneinduced porcine MH (29), and that ritanserin could not prevent an increase of inositol polyphosphates during halothane-induced MH (30). The authors concluded that serotonin seems not to be critically involved in the enhancement of inositol polyphosphates in halothane-induced MH, whereas in MH triggered by serotonin2 receptor agonists this mechanism might play an important role.…”

Pathophysiological role of the serotonin system in malignant hyperthermia

“…22 However, ritanserin did not prevent the increase in IP concentration during halothane-induced MH in pigs. 13 This result indicates that increases in IP concentration during halothane-induced porcine MH might be due to mechanisms other than a 5-HT-mediated increase in IP synthesis. The lack of effect of ritanserin on halothane-induced MH 12 and the failure to prevent the halothane-induced increase in IP levels 13 could be related to the high dose of the trigger or to insuf®cient doses of ritanserin used in the in vivo experiments.…”

“…12 Furthermore, ritanserin was ineffective in preventing anaesthetic-induced MH crises as well as halothane-mediated increases in inositol polyphosphates in MH pigs. 13 The reason for the contradictory results of these in vivo experiments remains unclear. Possible explanations include different durations of exposure to the trigger substances and concentrations of halothane, the additional administration of succinylcholine and the use of different breeds of pig.…”