Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro.

The antiarrhythmic amiodarone (AM) and its metabolite desethylamiodarone (Des) are known to cause AM-induced pulmonary toxicity, but the mechanisms underlying this disorder remain unclear. We hypothesized that AM might cause AM-induced pulmonary toxicity in part through the induction of apoptosis or necrosis in alveolar epithelial cells (AECs). Two models of type II pneumocytes, the human AEC-derived A549 cell line and primary AECs isolated from adult Wistar rats, were incubated with AM or Des for 20 h. Apoptotic cells were determined by morphological assessment of nuclear fragmentation with propidium iodide on ethanol-fixed cells. Necrotic cells were quantitated by loss of dye exclusion. Both AM and Des caused dose-dependent necrosis starting at 2.5 and 0.1 microg/ml, respectively, in primary rat AECs and at 10 and 5 microg/ml in subconfluent A549 cells (P < 0.05 and P < 0.01, respectively). AM and Des also induced dose-dependent apoptosis beginning at 2.5 microg/ml in the primary AECs (P < 0.05 for both compounds) and at 10 and 5 microg/ml, respectively, in the A549 cell line (P < 0.01). The two compounds also caused significant net cell loss (up to 80% over 20 h of incubation) by either cell type at drug concentrations near or below the therapeutic serum concentration for AM. The cell loss was not due to detachment but was blocked by the broad-spectrum caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone. Furthermore, the angiotensin-converting enzyme inhibitor captopril (500 ng/ml) and the angiotensin-receptor antagonist saralasin (50 microg/ml) significantly inhibited both the induction of apoptosis and net cell loss in response to AM. These results are consistent with recent work from this laboratory demonstrating potent inhibition of apoptosis in human AECs by captopril (Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, Flynn K, and Filippatos G. Am J Physiol Lung Cell Mol Physiol 275: L1013-L1017, 1998). They also suggested that the accumulation of AM and/or its primary metabolite Des in lung tissue may induce cytotoxicity of AECs that might be inhibitable by angiotensin-converting enzyme inhibitors or other antagonists of the renin-angiotensin system.

Results of Stent Supported Percutaneous Transluminal Coronary Angioplasty in Octogenarians With Coronary Artery Disease.

Between January 1995 and July 1998, percutaneous transluminal coronary angioplasty was performed on 27 lesions in 24 octogenarians. Half of the patients were African American. Women comprised 67% of the study group. Patients with unstable angina and myocardial infarction constituted 54% of the cohort. Two-thirds of the patients (83%) had single vessel disease with predominant class A and B lesion complexity of the angioplasty site. Acute success rate was 92%. Stents were successfully placed in 11 subjects (46%). None had acute myocardial infarction, emergency coronary artery bypass surgery, or stroke as a complication of the procedure. One patient presenting with acute myocardial infarction complicated by cardiogenic shock, died. Significant bleeding complications requiring blood transfusions occurred in 17% of patients. Of the patients, 23 (96%) were discharged in a clinically stable condition. Follow up during a two year period was completed in 21 patients (88%). One patient died of cancer. Four subjects (19%) underwent repeat percutaneous transluminal coronary angioplasty. One other patient had recurrent chest pain requiring multiple hospitalizations. The remaining 16 patients (76%) remained free of recurrence of angina. We concluded that percutaneous transluminal coronary angioplasty with stent placement can be performed in octogenarians with a high rate of clinical and angiographic success with an acceptable range of morbidity and mortality, and favorable long term (two year) outcome. (c) 2000 by CVRR, Inc.

Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism.

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.