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

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 alpha 1- and beta-adrenoceptors are linked to these second messenger systems, the densities of alpha 1- and beta-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 alpha 1- or beta-adrenoceptor density in skeletal or cardiac muscle between MHS and MHN. However, the total number of beta-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% beta 1- and beta 2- and 20% beta 2-adrenoceptors, whereas skeletal muscles were characterized by over 95% beta 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine

“…Additionally, during and after physical exercise the cAMP concentrations in blood serum increased more and were prolonged in MHS compared to MHN patients [24]. Furthermore, a higher cAMP content in skeletal muscle was also found in MHS compared to MHN swine [8]. However, whether the changes in the cAMP system were causal MH-mechanisms or secondary changes cannot be clarified yet.…”

“…Also the cyclic adenosine monophosphate (cAMP) system seems to be affected in MH. In skeletal muscle cells from MH susceptible (MHS) patients and animals higher cAMP concentrations were measured compared to MH normal (MHN) [6][7][8].…”

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

“…IPs were determined with high pressure liquid chromatography (HPLC) as described in detail elsewhere (Scholz et al 1993;Tonner et al 1995).…”

“…There is increasing evidence for a pathogenetical role of inositol phosphates (IPs) which play an important role in Ca 2+ mobilization in skeletal muscle (Steinmann 1994). Thus, increased levels of the second messenger 1,4,5 IP3 and that of other IPs have been demonstrated in skeletal muscle of human MHS individuals and of MHS pigs even in the absence of triggering agents (Foster et al 1989;Scholz et al 1991Scholz et al , 1993Tonner et al 1995). Actually, MHS skeletal muscles exhibit a higher responsiveness to IP3-induced release of Ca 2+ (Lopez et al 1995).…”

Effects of Theophylline on Anesthetized Malignant Hyperthermia‐Susceptible Pigs

“…Alterations in some second-messenger systems have been found to be associated with MH [2, 3]; the cyclic AMP (cAMP) system also seems to be affected in MH. In skeletal-muscle cells from MH-susceptible (MHS) patients and animals, higher cAMP levels were measured compared to normal (MHN) subjects [4–7]. …”