3,5‐Di‐t‐Butylcatechol as a Ryanodine Receptor Agonist in Rat Intact Skeletal Muscle Fibers

Abstract

Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I‐III Regulatory, Quality, ManufacturingPostmarketing Phase IV 3,5‐Di‐t‐butylcatechol (DTCAT) stimulates the rat skeletal muscle sarcoplasmic reticulum ryanodine receptor (RyR). In the present study, its effects on the contractile response of diaphragm preparation were characterized using electrically stimulated phrenic nerve–diaphragm preparations and diaphragm strips. DTCAT reduced, concentration‐dependently, twitch contraction of the phrenic nerve–diaphragm preparation evoked by both direct and indirect stimulation and increased spontaneous tone. Twitch amplitude reduction was irreversible, while the increase of spontaneous tone was only partially reversible upon DTCAT washout. In diaphragm strips, caffeine > 4‐chloro‐m‐cresol >> 3,5‐diisopropylcatechol ≅ ryanodine > DTCAT enhanced spontaneous tone, whereas quercetin reduced it with all the compounds reducing twitch amplitude. DTCAT‐induced contracture was partly dependent on extracellular Ca2+ influx and antagonized by a Cd2+/La3+ mixture. In intact skeletal muscle preparations, DTCAT behaved as a RyR agonist.