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PIII‐11
Author(s) -
Chopra N.,
Nagase H.,
Taff J. L.,
Hlaing T.,
Knollmann B. C.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.219
Subject(s) - trifluoperazine , promethazine , endoplasmic reticulum , calcium , ryanodine receptor 2 , medicine , cardiology , chemistry , pharmacology , calmodulin , ryanodine receptor , biochemistry
BACKGROUND Ca 2+ storage in the sarcoplasmic reticulum (SR) is pivotal for normal function of the heart. Mutations in the major SR Ca 2+ storage protein, calsequestrin (CSQ), cause ventricular arrhythmias. In vitro data suggest that certain cardiotoxic drugs inhibit Ca 2+ binding to recombinant CSQ, which in turn may disrupt SR function. Here, we test the hypothesis that tricyclic antidepressants and phenothiazines decrease SR Ca 2+ storage capacity of intact myocytes. METHODS Intracellular[Ca 2+ ] was measured in isolated murine cardiac myocytes loaded with fluorescent Ca 2+ indicator (Fura‐2). SR Ca 2+ storage capacity was determined by rapid caffeine application. Concentration‐response curves were constructed for each test drug (Amitriptyline, AMT, Promethazine, PMZ, and Trifluoperazine, TFP) and Emax and IC50 estimated by logistic regression analysis. RESULTS After 6 min exposure at 10 μM, AMT and TFP reduced SR Ca 2+ storage by 38% and 50% respectively, whereas PMZ had no effect (n = 5–15 cells each). After longer exposure, AMT reduced SR Ca storage capacity with an Emax of 42% and IC50 of 1 μM. PMZ had a significantly lower Emax (28%) and higher IC50(41 μM), p<0.01. Longer exposure to TFP was not tolerated. CONCLUSION All test drugs decreased SR Ca 2+ storage capacity in a time and concentration dependent fashion, but with significantly different efficacy and potency. Thus, the observed cardiotoxicity of such drugs could be related to depressed CSQ function potentially inducing ventricular arrhythmias. Clinical Pharmacology & Therapeutics (2005) 79 , P60–P60; doi: 10.1016/j.clpt.2005.12.219