Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Oct 2002
Nitric oxide is not involved in the endotoxemia-induced alterations in Ca2+ and ryanodine responses in mouse diaphragms.
Lipopolysaccharide (LPS, endotoxin)-induced diaphragmatic contractile dysfunction and sarcolemmal injury in animals has been identified. However, the precise nature of sepsis-related alterations in diaphragm myofiber function and the activity of Ca(2+) release from sarcoplasmic reticulum of skeletal muscle remain unclear. The present study investigated the in vivo effects of LPS on the Ca(2+)-dependent mechanical activity and ryanodine response in mouse diaphragm and Ca(2+) release from isolated sarcoplasmic reticulum membrane vesicles, and aimed to examine the role of nitric oxide (NO) in these responses. ⋯ Moreover, LPS treatment resulted in a significant expression of mRNA for iNOS in mouse diaphragms. The inhibitory effects on Ca(2+)- and ryanodine responses by LPS could be prevented by treatment with polymyxin B (LPS neutralizer) and pentoxifylline, but not by treatment with dexamethasone, N(G)-nitro- L-arginine or aminoguanidine (NOS inhibitors). These results imply that the NO-related pathway may not be involved in the dysfunction of the Ca(2+) release mechanism in the sarcoplasmic reticulum of mouse diaphragm during endotoxemia.
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Naunyn Schmiedebergs Arch. Pharmacol. · Oct 2002
Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family.
Malignant hyperthermia (MH) is a potentially lethal inherited pharmacogenetic syndrome due to a dysfunction of the intracellular calcium regulation of skeletal muscle following administration of volatile anaesthetics and depolarizing muscle relaxants. The ryanodine receptor of skeletal muscle (RYR1), which is an intracellular calcium release channel, has been proposed to be a candidate structure for the MH defect. In some families with a history of MH a C1840-T nucleotide exchange has been found in the RYR1 gene which cosegregates with the MH susceptible phenotype. ⋯ This person was classified as MH susceptible according to the in vitro contracture test protocol. None of the other family members (6 MH susceptible and 9 MH non-susceptible persons), including the parents of the child carrying the mutation, presented the C to T nucleotide exchange at position 1840. This novel observation clearly demonstrates that only the detection of the C1840-T mutation may lead to the diagnosis of MH susceptibility, but missing the mutation does not justify diagnosing a patient as non-susceptible within a single pedigree.