Inositol 1,4,5-trisphosphate synthesis in mononuclear white blood cells ofmalignant hyperthermia-susceptible and normal human beings, following in vitro exposure to halothane, caffeine and ryanodine

Despite a plethora of findings associated with the pathophysiology of malig nant hyperthermia (MH), the in vitro contracture test (IVCT) is the only re liable test for diagnosis of this heterogeneous syndrome in man. An increas e of 1,4,5-IP3 (inositol 1,4,5-trisphosphate), a second messenger involved in cellular calcium homeostasis, has been observed in muscle tissue of MH s usceptible (MHS) patients. The aim of this study was to evaluate if the kno wn differences of 1,4,5-IP3 content in muscle tissue might be reproduced in mononucleated white blood cells (MWBCs). Subsequently, MWBCs of 23 healthy controls and 12 patients with a clinical suspicion for MH disposition were isolated and screened for 1,4,5-IP3 content. An IVCT according to the prot ocol of the European Malignant Hyperpyrexia Group (EMHG) was performed on m uscle specimens of 12 patients. Eight MHN and four MHS individuals were dia gnosed. Additionally, 1,4,5-IP3 synthesis in MWBCs was detected following i n vitro exposure to IVCT test substances halothane (2%), caffeine (1-30 mM) , and ryanodine (1-5 mu M). A broad inter-individual variability of 1,4,5-I P3 content was observed in MWBCs of all volunteers, but no differences were detected between MHS and MHN individuals. These findings are in strong con trast to those observed in muscle tissue. In vitro exposure of isolated MWB Cs to halothane, caffeine and ryanodine yielded no statistically significan t differences between groups. A time- and concentration-dependent increase in cellular 1,4,5-IP3 content could be induced in some but not all individu als of both groups. Since no correlation was obtained between induction of 1,4,5-IP3-synthesis following in vitro exposure of MWBCs to MH test substan ces and MH disposition, this study was terminated. We conclude from our dat a that the detection of 1,4,5-IP3 synthesis in MWBCs is not suitable for di agnosis of MH disposition. It remains questionable whether an altered 1,4,5 -IP3 metabolism in MWBCs is involved in pathologic cascades of MH. Therefor e, other cell tissues should be evaluated in further studies to clarify the role of the 1,4,5-IP3 metabolism in MH.