Summary
Amiodarone HCl (AD) is a very effective antiarrhythmic drug, but its use is often associated with serious pulmonary complications. It is shown to induce lung phospholipidosis. Nevertheless, the effects of this drug on pulmonary surfactant which is composed of about 75% phospholipids and which prevents alveolar collapse is not known. Therefore, we have examined the effect of AD on the intra- and extracellular surfactant pools and on the levels of phosphatidylcholine (PC), the primary constituent of pulmonary surfactant.
Male Wistar rats were fed AD (175 mg/kg) by oral gavage for three weeks. At the end of the experimental period, the rats were killed, the lungs removed and perfused, and surfactant isolated. Some lungs were prepared for ultrastructural examination. Phospholipid was assayed in the intra- and extracellular surfactant.
Amiodarone produced a significant increase in both the intra- and extracellular sufactant phospholipid along with an appreciable change in the phospholipid profile. Also, the drug seemed to increase the number of lamellar inclusions in the surfactant producing type II alveolar cells. These data suggest that administration of AD leads to an increase in the lung surfactant phospholipid levels and lamellar bodies in alveolar type II cells.
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References
Bitterman P, Adelberg S, Crystal RG (1983) Mechanism of pulmonary fibrosis: spontaneous release of the alveolar macrophage derived growth factor in the interstitial lung disorders. J Clin Invest 72:1808–1813
Carvajal RE, Gonzales R, Vargas AF, Selman M (1982) Cell mediated immunity against connective tissue in experimental pulmonary fibrosis. Lung 160:131–137
Dake MD, Madison JN, Mantogomery CK, Shellito JE, Hinchcliffe WA, Winkler ML, Baindton DF (1985) Electron microscopic demonstration of lyososomal inclusion bodies in lung, liver, lymph nodes and blood leucocytes of patients with amiodarone pulmonary toxicity. Am J Med 78:506–512
D'Amico DJ, Kenyon KR, Ruskin JN (1981) Amiodarone keratopathy. Arch Ophthalmol 99:257–261
Diegelmann RF, Kaplan AM, McCoy BJ, Cohen IK (1979) Macrophage stimulation of fibroblast proliferation and collagen synthesis in vivo and in vitro. Proceedings of the Eleventh International Congress of Biochemistry, p 502
Fiske CH, Subbarow Y (1925) The colorimetric determination of phosphorus. J Biol Chem 66:375–380
Hostetler KY (1984) Molecular studies of the induction of cellular phospholipidosis by cationic amphiphilic drugs. Fed Proc 43:2582–2585
Hostetler KY, Reasor MJ, Walker ER, Yazaki PJ, Frazee BW (1986) Role of phospholipase A inhibition in amiodarone pulmonary toxicity in rats. Biochim Biophys Acta 875:400–405
Hostetler KY, Giordano JR, Jellison EJ (1988) In vitro inhibition of lysosomal phospholipase A1 of rat lung by amiodarone and desethylamiodarone. Biochim Biophys Acta 959:316–321
Joshi UM, Kodavanti PRS, Coudert B, Dwyer TM, Mehandale HM (1988) Types of interaction of amphiphilic drugs with phospholipid vesicles. J Pharmacol Exp Ther 246:150–157
Joshi UM, Kodavanti PR, Lockard VG, Mehendale HM (1989) Fluorescence studies on binding of amphiphilic drugs to isolated lamellar bodies relevance to phospholipidosis. Biochim Biophys Acta 1004:309–320
Kacew S (1987) Cationic amphiphilic drug — induced renal cortical lysosomal phospholipidosis: an in vitro comparative study with gentamicin and chlorphentermine Toxicol Appl Pharmacol 91:469–476
Kacew S (1988) Role of phospholipase C in chlorphentermine — induced pulmonary phospholipidosis in rat. Proc Soc Exp Biol Med 188:35–39
Katyal SC, Estes LW, Lombardi B (1977) Method for the isolation of surfactant from homogenates and lavages of lung of adult, new born and fetal rats. Lab Invest 36:585–592
Kodavanti UP, Mehendale HM (1990) Cationic amphiphilic drug and phospholipid storage disorder. Pharm Rev 42:327–352
Kodavanti UP, Mehendale HM (1991) Amiodarone — and desethylamiodarone — induced pulmonary phospholipidosis, inhibition of phospholipases in vivo and alteration of 14C — amiodarone uptake by perfused lung. Am J Respir Cell Mol Biol 4:369–378
Leibovich SJ, Ross R (1976) A macrophage dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Pathol 84:501
Liu FLW, Cohen RD, Downar E, Butany JW, Edelson JD, Rebuck AS (1986). Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax 41:100–105
Lullmann H, Lullmann-Rauch R, Wassermann O (1978) Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27:1103–1108
Marchilinski FE, Gansler TS, Waxman HL, Josephson ME (1982) Amiodarone pulmonary toxicity. Ann Intern Med 97:839–845
Martin WJ II, Howard DM (1985) Amiodarone induced lung toxicity: in vitro evidence for the direct toxicity of the drug. Am J Pathol 120:344–350
Miles PR, Bowman L, Tucker J, Reasor MJ, Wright JR (1986) Alterations in rat alveolar surfactant phospholipids and proteins induced by administration of chlorphentermine. Biochim Biophys Acta 877:167–178
Reasor MJ (1981) Drug — induced lipidosis and the alveolar macrophage. Toxicology 20:1–31
Singh BN (1983) Amiodarone: Historical development and pharmacological profile. Am Heart J 106:788–797
Valimaki M, Pelliniemi TT and Niinikoski J (1975) Oxygen induced changes in pulmonary phospholipids in the rat. J Appl Physiol 39:780–787
Van Zandwijk N, Darmanata J, Duren D, Alberts C, Durrer D, Wagenvoort C (1983) Amiodarone pneumonitis. Eur J Respir Dis 64:313–317
Wahl SM, Wahl LM, McCarthy JB (1978) Lymphocyte mediated activation of fibroblast proliferation and collagen production. J Immunol 121:942–946
Wilson BD, Jaworski AJ, Donner ME, Lippmann ML (1989) Amiodarone — induced pulmonary toxicity in the rat. Lung 167:301–311
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Correspondence to N. Devaraj at the above address
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Padmavathy, B., Devaraj, H. & Devaraj, N. Amiodarone — induced changes in surfactant phospholipids of rat lung. Naunyn-Schmiedeberg's Arch Pharmacol 347, 421–424 (1993). https://doi.org/10.1007/BF00165393
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DOI: https://doi.org/10.1007/BF00165393