Search

Industrial exposure and pharmaceutical use of antimony compounds have been linked to altered cardiovascular function and pathology. Antimony compounds induce hypotension, bradycardia, and cardiac arrhythmias, all of which can arise from aberrations in myocyte regulation of intracellular free calcium concentration ([Ca2+]i). To determine if trivalent antimony affects [Ca2+]i during excitation-contraction, we developed an in vitro cardiac myocyte model that was exposed for 24 hr to potassium antimonyl tartrate (PAT) at 0-10 microM. Control myocytes received sodium potassium tartrate. Concentrations of up to 10 microM PAT were without effect on total DNA and protein content of cultures, indicating that PAT exposures were not overtly toxic. However, spontaneous beating rates of myocytes were significantly reduced by 5 and 10 microM PAT. Myocytes were paced by electric field stimulation at 0.5 Hz, and the effect of PAT on [Ca2+]i transients during excitation-contraction was monitored with fura-2. PAT (2-8 microM) significantly reduced systolic [Ca2+]i in a concentration-dependent fashion, but was without effect on diastolic [Ca2+]i or on the first derivative of the transient rise (d[Ca2+]i/dt). Myocytes from control cells responded to epinephrine (10(-8)-10(-5) m) in concentration-dependent fashion with elevated systolic [Ca2+]i and an increase in the rate of decay of transients. In PAT-exposed myocytes, the systolic response was blunted while the decay rate was enhanced. PAT-exposed cells also exhibited a reduced basal [Ca2+]i when depolarized by 90 mm KCl and a reduced caffeine-releasable Ca2+ pool of the sarcoplasmic reticulum. Both control and PAT-treated cells responded to ryanodine in a comparable fashion. Results indicate that a nonlethal exposure to PAT reduces Ca2+ availability during excitation-contraction. Decreased influx of Ca2+ across the sarcolemma and enhanced removal of Ca2+ appear to be responsible., (Copyright 1997 Academic Press.)

The metabolism of the reproductive toxicant bis(2-methoxyethyl) ether was studied in male Sprague-Dawley rats, and the principal metabolite (2-methoxyethoxy)acetic acid and its metabolic precursor 2-(2-methoxyethoxy)ethanol were evaluated separately as testicular toxicants. For the metabolism study, rats were given single po doses of [1,2-ethylene-14C]bis(2-methoxyethyl) ether at 5.1 or 0.051 mmol/kg body wt. Within 96 hr, approximately 86 to 90% of the radioactivity was excreted in the urine. Urinary metabolites were separated by high-performance liquid chromatography and isolated for characterization by gas chromatography-mass spectrometry. The principal urinary metabolite, accounting for 67.9 +/- 3.3% of the administered high dose and 70.3 +/- 1.3% of the low dose, was identified as (2-methoxyethoxy)acetic acid. A second metabolite, representing 6.2 +/- 0.8% of the high dose and 5.8 +/- 0.8% of the low dose, was identified as methoxyacetic acid, a previously recognized testicular toxicant. In the toxicity study, (2-methoxyethoxy)acetic acid and 2-(2-methoxyethoxy)ethanol were administered to rats at 5.1 mmol/kg body wt by gavage as single daily doses for as many as 20 consecutive days. The testes of rats killed 24 hr after the administration of even numbered doses showed no gross or microscopic abnormalities. These results are in contrast to the previously reported testicular atrophy evoked after as few as 8 daily doses of the parent compound, bis(2-methoxyethyl) ether, tested under the same experimental conditions. Thus, the testicular toxicity reported for bis(2-methoxyethyl) ether could be explained by the presence of a minor metabolite, methoxyacetic acid.