TY - JOUR T1 - Dietary caffeine synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.120.119412 SP - mol.120.119412 AU - Monica Aleman AU - Rui Zhang AU - Wei Feng AU - Lihong Qi AU - Jose Lopez AU - Chelsea Crowe AU - Yao Dong AU - Gennady Cherednichenko AU - Isaac N. Pessah Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/08/10/mol.120.119412.abstract N2 - Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia susceptibility (MHS). Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MHS. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MHS mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 MHS mice (HET) are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane maintenance anesthesia (HAL) under experimental conditions that maintain normal core body temperature. HET receiving CAF (plasma CAF 893ng/ml) have significantly shorter times to respiratory arrest compared to WT, without altering blood chemistry, displaying hyperthermia or muscle rigor. Bolus dantrolene i.p. (DAN) before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline EEG total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF+HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MHS exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations.SIGNIFICANCE STATEMENT Dietary caffeine attaining a human relevant plasma dose synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice. Synergism of these drugs can be attributed to their actions at ryanodine receptors. ER -