title: Tricyclic antidepressant amitriptyline alters sarcoplasmic reticulum calcium handling in ventricular myocytes.
abstract: Tricyclic antidepressants such as amitriptyline (AMT) have been reported to have adverse side effects on cardiac performance. AMT effects on Ca handling in ventricular myocytes, however, are not well understood. Therefore, we investigated AMT action on sarcoplasmic reticulum (SR) Ca release in ventricular myocytes, ryanodine receptor (RyR) activity, and Ca uptake by SR microsomes. In permeabilized myocytes, AMT transiently increased free luminal Ca concentration ([Ca]) followed by marked depletion. AMT (10 microM) caused a rapid and a transient increase of Ca spark frequency, followed by a significant suppression of spark activity. The latter was associated with a decrease of Ca spark amplitude and SR Ca load to 87 and 60%, respectively. AMT (10 microM) completely abolished propagation of spontaneous Ca waves. Higher concentrations of AMT (0.1-1 mM) evoked SR Ca release reminiscent of the effect of caffeine (20 mM) and caused almost complete depletion of SR Ca content. Studies on single calsequestrin-free RyR channels revealed that AMT increased the mean open time and open probability (Po) in a dose-dependent fashion (dissociation constant = 4.2 microM). High concentrations of AMT (> 25 microM) evoked frequent long openings with Po reaching very high levels (> 0.70). In studies with cardiac SR microsomes, AMT slowed the rate of ATP-dependent Ca uptake. We conclude that AMT affects SR Ca handling in ventricular myocytes by multiple mechanisms, including direct stimulation of RyRs and inhibition of SR Ca uptake. These effects could contribute to AMT cardiotoxicity.
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical Center, 1750 W. Harrison Ave., Chicago, IL 60612, USA.
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Zima
authors.forename: Jia
authors.initials: J
authors.lastname: Qin
authors.forename: Michael
authors.initials: M
authors.lastname: Fill
authors.forename: Lothar A
authors.initials: LA
authors.lastname: Blatter
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000639:Amitriptyline / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology* / Q000633:toxicity; D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D002155:Calsequestrin / Q000378:metabolism; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008861:Microsomes; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; D000639:Amitriptyline; D002110:Caffeine; D000255:Adenosine Triphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
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