Failure of calcium antagonistic agents to prevent hepatotoxicity induced by diclofenac.
Diclofenac (0.5-2 mM) dose- and time-dependently reduces the viability of isolated hepatocytes. This effect cannot be counteracted by the calcium channel blockers diltiazem (0.05-0.1 mM) and verapamil (0.05-0.5 mM), the calmodulin antagonist calmidazolium (0.01 mM) or Quin 2-AM (0.1 mM), an intracellular calcium chelating agent. On the contrary, verapamil even accentuates the toxic effects of diclofenac. It is concluded from these results, that diclofenac causes cell damage by other mechanisms than calcium overload.
Institute for Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
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Schmitz
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Lepper
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Estler
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004008:Diclofenac / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D004008:Diclofenac; D014700:Verapamil; D004110:Diltiazem