Abstract
Amiodarone (AM), a potent antidysrhythmic agent, can cause potentially life-threatening pulmonary fibrosis. In the present investigation of mechanisms of initiation of AM lung toxicity, we found that 100 μM AM decreased mitochondrial membrane potential in intact hamster lung alveolar macrophages and preparations enriched in isolated alveolar type II cells and nonciliated bronchiolar epithelial (Clara) cells, following 2 h of incubation. This was followed by a drop in cellular ATP content (by 32–77%) at 4 to 6 h, and 30 to 55% loss of viability at 24 h. Supplementation of incubation media with 5.0 mM glucose or 2.0 mM niacin did not reduce AM-induced ATP depletion or cell death in macrophages, and the mitochondrial permeability transition inhibitor cyclosporin A (1.0 μM) did not affect AM cytotoxicity. At 50 μM, the AM metaboliteN-desethylamiodarone (DEA) produced effects similar to those of AM, but more rapidly and extensively, with the Clara cell-enriched preparation being particularly susceptible. In isolated whole lung mitochondria, DEA was accumulated to a greater extent than AM. Both AM and DEA inhibited complex I- and complex II-supported respiration, but DEA inhibited complex II to a greater degree than AM. These results demonstrate that AM and DEA disrupt mitochondrial membrane potential prior to ATP depletion and subsequent lung cell death, that DEA is more potent than AM, and that the mitochondrial permeability transition is not involved in mitochondrial perturbation by AM. This suggests that AM- and DEA-induced perturbations of mitochondrial function may initiate AM-induced pulmonary toxicity.
Footnotes
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This research was supported by Canadian Institutes of Health Research (CIHR) Grant MT-13257. M.W.B. and J.W.C. are recipients of CIHR Studentships.
- Abbreviations:
- AM
- amiodarone
- AIPT
- amiodarone-induced pulmonary toxicity
- DEA
- desethylamiodarone
- JC-1
- 1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide
- FCCP
- carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone
- RCR
- respiratory control ratio
- HPLC
- high-performance liquid chromatography
- ANOVA
- analysis of variance
- MPT
- mitochondrial permeability transition
- Received March 2, 2001.
- Accepted May 22, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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