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Role of calcium and phospholipase in potassium antimonyl tartrate-induced cardiac myocyte toxicity.
Wey-H; Richards-D; Mathias-P; Tirmenstein-M; Walker-C; Toraason-M
Toxicologist 1995 Mar; 15(1):310
Exposure of rat cardiac myocytes to potassium antimonyl tartrate (PAT) has been shown to cause oxidative stress and toxicity. This study investigates the roles of intracellular calcium (Ca2+i) and phospholipase (PLPase) activation in PAT-induced toxicity. Myocytes isolated from rat neonates were cultured on plastic culture dishes or glass coverslips and were used after 2-3 days in culture. Toxicity and lipid peroxidation were assessed by release of lactate dehydrogenase (LDH) and thiobarbituric acid reactive substances (TBARS), respectively. Ca2+i was monitored on an inverted phase contrast microscope with the fluorescent probe fura-2. ATP content was measured by extraction and HPLC analysis. Exposure to 200 JLM PAT for 4 hrs resulted in a 50-60% release of LDH (% of total) and a 10-fold increase in TBARS release. In individual fura-2 loaded myocytes, 200 JLM PAT increased Ca2+i by approximately 75% by3 hours, whereas, exposure to 500 JLM PAT resulted in Ca2+i overload (greater than 10-fold increase). Preloading of myocytes with the Ca2+ chelator BAPTA (10 JLM) prevented the effects of PAT on LDH and TBARS release, but PAT exposure in calcium-free/EGTA medium did not prevent toxicity, suggesting release from intracellular Ca2+ stores. Co-exposure to the PLPase inhibitor mepacrine also prevented PAT toxicity. After 6 hrs exposure to PAT (200 JLM) in the presence of mepacrine (50 JLM) LDH release was still prevented, but myocytes were hypercontracted, suggesting an elevated Ca2+i. PAT-induced ATP loss was partially prevented by BAPTA and mepacrine. These results link elevated Ca2+i and activation of PLPase with PAT-induced myocyte cell death and suggest that increased Ca2+i precedes phospholipase activation.
Exposure-assessment; Exposure-limits; Cellular-reactions; Animal-studies; Laboratory-animals; Calcium-compounds
Issue of Publication
The Toxicologist. Society of Toxicology 34th Annual Meeting, March 5-9,1995, Baltimore, Maryland
Page last reviewed: April 12, 2019
Content source: National Institute for Occupational Safety and Health Education and Information Division