Dantrolene

The porcine stress syndrome is a major cause of poor meat quality and death in the pork industry. It is known to be more prevalent in some pig strains than others,1 and susceptible animals can be identified by a challenge with halothane, which results in striking elevation in body temperature. This scenario parallels the clinical entity of familial malignant hyperthermia on exposure to general anesthetics, which was one of the earliest recognized human pharmacogenetic syndromes. We now know that affected pigs and people share the same molecular mechanism, mutations in the sarcoplasmic reticulum (SR) calcium release channel of skeletal muscle encoded by RYR1 .2,3 In the pig world, selective breeding programs have been used to develop strains resistant to malignant hyperthermia. In humans, malignant hyperthermia is an anesthetic emergency and is treated by immediate intravenous administration of dantrolene, which is effective and thought to be safe. Chronic oral dantrolene is also approved to treat severe muscle spasticity, and, in this setting, the limiting toxicity is hepatitis, which can be fulminant and fatal in up to 1% of exposed subjects.Article see p 875Abrupt membrane depolarization (excitation) in skeletal or in cardiac muscle results in calcium release from SR stores via ryanodine receptor (RyR) calcium release channels, and the ensuing rise in intracellular calcium then activates the contractile apparatus. The details of the way in which excitation couples to contraction differs somewhat in the 2 types of muscle (in the heart, but not in skeletal muscle, calcium influx via voltage-gated Cav1.2 channels is required to activate RyR channels; Figure), and there are different genes encoding the channels, RYR1 in skeletal muscle and RYR2 in cardiac muscle. Early studies of the mechanism of action of dantrolene highlighted its ability to decouple excitation from contraction in skeletal muscle, …