Imipramine-induced cardiac depression is responsible for the increase in intracellular magnesium and the activation of ERK 1/2 in rats.
Imipramine, an antidepressant drug, can cause potentially lethal cardiotoxic side effects including hypotension, ventricular tachycardia, and decreased cardiac output. This study investigated the mechanism responsible for imipramine-induced cardiac depression in rats. The left ventricular developed pressure (LVDP), velocity of the change in pressure (dP/dt), and heart rate (HR) accompanied with the total magnesium efflux ([Mg](e)) were measured in Langendorff-perfused intact rats hearts. Intracellular ionized magnesium concentrations ([Mg(2+)]( i)) were measured using Mag-fura 2 AM in a single H9c2 cell. The activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2) was analyzed by Western blot. Imipramine induced reversible decreases in LVDP, dP/dt, and HR, which were accompanied by increases in [Mg](e). Imipramine also induced activation of ERK 1/2 and increase in the [Mg(2+)]( i), which was inhibited PD98059, ERK 1/2 inhibitor. These results suggest that imipramine-induced cardiac depression may be partly due to increases of [Mg(2+)](i) that are accompanied by the activation of ERK 1/2 in rats.
Lee
Mun-Young
MY
Department of Pharmacology and Toxicology, College of Veterinary Medicine, Chonbuk National University, Jeonju, Republic of Korea.
Kim
Shang-Jin
SJ
Kim
Jin-Shang
JS
Kang
Hyung-Sub
HS
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D000929:Antidepressive Agents, Tricyclic; D005419:Flavonoids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D008274:Magnesium; D007099:Imipramine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one