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Further characterization of a rat model of amiodarone-induced pulmonary toxicity (AIPT).

Taylor-MD; Van Dyke-K; Bowman-L; Miles-PR; Castranova-V; Reasor-MJ
Toxicologist 2000 Mar; 54(1):18
The antiarrhythmic drug amiodarone (AD) is limited in use by its pulmonary toxicity involving inflammation and fibrosis. The goal of this study was to further characterize an animal model of AIPT and to examine the possible mechanisms involved in the progression of toxicity. Male F344 rats were instilled intratracheally with AD (6.25 mg/kg with a 3.125 mg/mL solution) in sterile water or the sterile water vehicle on day 0 and again on day 2, a protocol that leads to the development of pulmonary fibrosis on day 28 in the AD-treated animals. To study the initial events leading to this endpoint, animals were killed on days 3, 5, 6, 7, or 10 and bronchoalveolar lavage (BAL) was performed. Recovery of alveolar macrophages and eosinophils was increased on days 3 and 5, while neutrophil recovery was significantly elevated only on day 3. Potential oxidant production of BAL cells (total cells x PMA-stimulated luminol-dependent chemihuninescence [total counts/10(6) cells/20 min]) was markedly elevated in AD-treated rats on day 3. BAL cells recovered from AD-treated and control rats on day 3 were cultured overnight. Cells from AD treated rats produced more nitric oxide (NO) breakdown products in the culture media than cells from control animals, indicating an increased cellular production of NO as a result of AD treatment. These findings indicate that this model exhibits a transient pulmonary inflammation soon after the adminstrations of the drug with the potential for elevated oxidant production in the lungs. Therefore, oxidant mechanisms may be involved in the development of AIPT in this model.
Models; Laboratory-animals; Animal-studies; Animals; Toxic-effects; Toxins; Pulmonary-system-disorders; Respiratory-system-disorders; Fibrosis; Models; Pulmonary-system-disorders; Respiratory-system-disorders; Pulmonary-function
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The Toxicologist. Society of Toxicology 39th Annual Meeting, March 19-23, 2000, Philadelphia, Pennsylvania