TY - JOUR
T1 - Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs
AU - Kennedy, Thomas P.
AU - Gordon, Gary B.
AU - Paky, Andreas
AU - McShane, Alan
AU - Adkinson, N. Franklin
AU - Peters, Stephen P.
AU - Friday, Karen
AU - Jackman, Warren
AU - Mario Sciuto, A.
AU - Gurtner, Gail H.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1988/7
Y1 - 1988/7
N2 - Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean ± SEM) (from 13.6 ± 1.2 to 40.6 ± 9.5 mm Hg, p < 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 μM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (ΔW) of 5.7 ± 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (ΔW = 0.7 ± 0.3 g/min, p < 0.05). pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., ΔW = 0.05 ± 0.02 g/min, p < 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, ΔW = 0.6 ± 0.2 g/min, p < 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, ΔW = 0.1 ± 0.08 g/min, p < 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2 −), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.
AB - Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean ± SEM) (from 13.6 ± 1.2 to 40.6 ± 9.5 mm Hg, p < 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 μM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (ΔW) of 5.7 ± 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (ΔW = 0.7 ± 0.3 g/min, p < 0.05). pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., ΔW = 0.05 ± 0.02 g/min, p < 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, ΔW = 0.6 ± 0.2 g/min, p < 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, ΔW = 0.1 ± 0.08 g/min, p < 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2 −), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.
KW - Amiodarone
KW - Glutathione disulfide
KW - Oxidants
KW - Superoxide anion
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U2 - 10.1097/00005344-198807000-00004
DO - 10.1097/00005344-198807000-00004
M3 - Article
C2 - 2459531
AN - SCOPUS:0023921169
SN - 0160-2446
VL - 12
SP - 23
EP - 36
JO - Journal of cardiovascular pharmacology
JF - Journal of cardiovascular pharmacology
IS - 1
ER -