Biochemical changes in malignant hyperthermia susceptible swine: cyclic AMP, inositol phosphates, α1, β1‐ and β2‐adrenoceptors in skeletal and cardiac muscle

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Abstract
It has been presumed that alteration in the concentrations of second messengers leads to alterations in the function of the ryanodine receptor. Consequently, we have determined the basal content of cyclic AMP and inositol phosphates in skeletal and cardiac muscle of malignant hyperthermia (MH) susceptible (MHS) and healthy normal control (MHN) swine. Since α,‐ and β‐adrenoceptors are linked to these second messenger systems, the densities of α1,‐ and β‐adrenoceptors were also determined. In skeletal as well as cardiac muscle, a higher basal concentration of almost all of the inositol phosphates was found. Of all inositol phosphates measured, the presumed second messenger inositol 1,4,5‐trisphosphate (1,4,5‐IP3) was mostly concentrated in both tissues. Each MHS sample contained more 1,4,5,‐IP3 than the highest value observed in MHN muscle, indicating that a threshold of 1,4,5‐IP3 concentration for determination of MHS or MHN status can be defined. In addition, MHS skeletal muscle contained more cAMP than MHN, whereas there was no difference between MHS and MHN in cardiac muscle. The changes observed in the different inositol phosphate and cAMP contents were not accompanied by an altered α1,‐ or β‐adrenoceptor density in skeletal or cardiac muscle between MHS and MHN. However, the total number of β‐adrenoceptors of MHN and MHS was significantly higher in cardiac (about 80 fmol/mg protein) than skeletal muscles (about 30 fmol/ mg protein). The cardiac muscles revealed about 80% β1,‐ and 20% β2‐adrenoceptors, whereas skeletal muscles were characterised by over 95% β2‐adrenoceptors. In conclusion, the present study supports the view that altered second messenger systems and, thereby, altered intracellular calcium regulations are at least in part involved in the modulation and development of MH. Moreover, in addition to the skeletal muscle, multiple other organs, e.g. heart, may be affected in MH.