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Toxicol In Vitro. 2010 Apr;24(3):960-72. doi: 10.1016/j.tiv.2009.12.027. Epub 2010 Jan 11.

Altered cytosolic Ca2+ dynamics in cultured Guinea pig cardiomyocytes as an in vitro model to identify potential cardiotoxicants.

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1
Safety Pharmacology, Department of Toxicology and Pathology, Non-Clinical Safety, Hoffmann-La Roche, Inc, Nutley, NJ 07110, USA.

Abstract

Altered intracellular calcium (Ca(i)(2+)) handling by cardiomyocytes has been implicated in drug-induced cardiomyopathy and arrhythmogenesis. To explore whether such alterations predict cardiotoxicity, Ca(i)(2+) imaging was conducted in cultured, spontaneously contracting Guinea pig cardiomyocytes to characterize the effects of 13 cardiotoxicants and 2 safe drugs. All cardiotoxicants perturbed Ca(i)(2+) at therapeutically relevant concentrations. The cytotoxic chemotherapeutics doxorubicin and epirubicin, known to cause cardiomyopathy, preferentially reduced Ca(i)(2+) transient amplitude and sarcoplasmic reticulum (SR) Ca(2+) content, whereas Torsade de Pointes (TdP) inducers and potent hERG channel blockers (amiodarone, cisapride, dofetilide, E-4031 and terfenadine) predominately suppressed diastolic Ca(i)(2+) and contraction rate, and prolonged Ca(i)(2+) transient duration. The molecularly targeted cancer therapeutics, sunitinib and imatinib, exhibited profound effects on Ca(i)(2+), combining effects of cytotoxic chemotherapeutics, TdP inducers and potent hERG channel blockers. TdP inducers lacking direct hERG inhibition, ouabain and pentamidine, significantly elevated Ca(i)(2+) transient amplitude and SR Ca(2+) content while aconitine primarily accelerated automaticity and elevated diastolic Ca(i)(2+) similar to ouabain. Finally, amoxicillin and aspirin did not exert any significant effects on Ca(i)(2+) at concentrations up to 100 microM. These results suggest that detecting altered Ca(i)(2+) handling in cultured cardiomyocytes may be used as an in vitro model for early cardiac drug safety assessment.

PMID:
20064605
DOI:
10.1016/j.tiv.2009.12.027
[Indexed for MEDLINE]
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