Inositol 1,4,5-trisphosphate in blood and skeletal muscle in human malignant hyperthermia

The in vitro contracture test (IVCT) is the only available diagnostic method at present for evaluation of malignant hyperthermia (MH) susceptibility. However, the disadvantage of the IVCT is that it is invasive. Several studies suggest that an altered inositol phosphate system is involved in the development of MH. A greater concentration of inositol 1,4,5-trisphosphate (1,4,5-IP3) was found in MH susceptible (MHS) than in normal (MHN) skeletal muscles. In this study the concentrations of 1,4,5-IP3 in blood samples and skeletal muscle specimens of identical patients were measured in an attempt to define susceptibility to MH. Muscle biopsies were obtained from 34 patients with clinical suspicion of MH. Patients were first classified as MHS (n=19), MHN (n=8) or MH equivocal (MHE; n=7) by the standard IVCT. For detection of 1,4,5-IP3 concentrations, blood samples were obtained and an additional muscle specimen was excised. After sample preparation, concentrations of 1,4,5-IP3 were measured using radioimmunoassay. In blood samples, concentrations of 1,4,5-IP3 were similar in all individuals tested for MH susceptibility and in control patients not tested for MH susceptibility (n=44). In skeletal muscle, 1,4,5-IP3 concentrations were significantly higher in MHS than in MHE or MHN patients, respectively. Each MHS sample contained more 1,4,5-IP3 than the highest concentration measured in MHN muscle. Defining arbitrary thresholds for 1,4,5-IP3 concentration in skeletal muscles in order to discriminate between MHS and MHN status, it was possible to assign three MHE patients to MHS and four to MHN. This study supports the hypothesis that an altered inositol phosphate system might be involved in MH. However, measurement of 1,4,5-IP3 concentration in a simple blood sample preparation is not reliable for MH susceptibility screening.