Protective effects of calcium channel blockers on acute bromobenzene toxicity to isolated rat hepatocytes. Inhibition of phenylephrine-induced calcium oscillations.
METHODS
Protective effects of verapamil, nifedipine, diltiazem, and ethylene glycol tetraacetic acid (EGTA) on acute bromobenzene (BB) toxicity to rat hepatocytes were evaluated, and cytosolic [Ca2+]i was monitored in single BB-exposed rat hepatocytes. Additionally, the effect of nifedipine on phenylephrine-stimulated calcium oscillations was investigated.


RESULTS
BB at 0.8-2.4 mM increased the lactate dehydrogenase (LDH) leakage rate dose-dependently. Pretreatment with verapamil (25-35 microM), nifedipine (35-45 microM), diltiazem (25 microM), or EGTA (1.5-5 mM) markedly attenuated the BB-induced (1.6 mM) LDH leakage rate during 2 h of incubations. BB did not cause any detectable acute change in [Ca2+]i. BB interfered with phenylephrine-stimulated calcium oscillations, by blocking the oscillations in 58% of the cells and reducing the oscillation frequency in the rest. Nifedipine (100 and 200 microM) blocked the phenylephrine-induced calcium oscillations completely in 55% and 88% of the cells, respectively.


CONCLUSIONS
The findings demonstrate that verapamil, nifedipine, diltiazem, and EGTA significantly protect rat hepatocytes against BB toxicity. BB interferes with phenylephrine-stimulated calcium oscillations. Nifedipine inhibits the oscillations at doses higher than those exerting a protective effect.
Wu
J
J
Dept. of Histology and Cell Biology, University Hospital, University of Umeå, Sweden.
Danielsson
A
A
Lindström
P
P
Karlsson
K
K
Sehlin
J
J
D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity*; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004110:Diltiazem / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
D001969:Bromobenzenes; D002121:Calcium Channel Blockers; D010656:Phenylephrine; D004533:Egtazic Acid; D014700:Verapamil; D007770:L-Lactate Dehydrogenase; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium