Faculty Collaboration Database

Dietary Caffeine Synergizes Adverse Peripheral and Central Responses to Anesthesia in Malignant Hyperthermia Susceptible Mice. Mol Pharmacol 2020 Oct;98(4):351-363

Date

08/09/2020

Pubmed ID

32764093

Pubmed Central ID

PMC7491310

DOI

10.1124/mol.120.119412

Scopus ID

2-s2.0-85091126379 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. 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 MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (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 MH susceptibility 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 at a human-relevant 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.

Author List

Aleman M, Zhang R, Feng W, Qi L, Lopez JR, Crowe C, Dong Y, Cherednichenko G, Pessah IN

Author

Colleen Crowe MD Associate Professor in the Emergency Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Caffeine
Dantrolene
Disease Models, Animal
Drug Synergism
Electroencephalography
Female
Halothane
Heterozygote
Humans
Injections, Intraperitoneal
Male
Malignant Hyperthermia
Mice
Muscle Fibers, Skeletal
Mutation
Ryanodine Receptor Calcium Release Channel