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(Circulation. 2003;108:1493.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Evidence for Dysregulation of Dimethylarginine Dimethylaminohydrolase I in Chronic Hypoxia–Induced Pulmonary Hypertension

Lesley J. Millatt, PhD; Guy StJ. Whitley, PhD; Dechun Li, MD, PhD; James M. Leiper, PhD; Helmy M. Siragy, MD; Robert M. Carey, MD; Roger A. Johns, MD

From the Departments of Anesthesiology (L.J.M.) and Internal Medicine (H.M.S., R.M.C.), University of Virginia Health System, Charlottesville; the Department of Cellular and Molecular Sciences, St George’s Hospital Medical School, London, UK (G.S.W.); the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Md (D.L., R.A.J.); and the Centre for Clinical Pharmacology, University College, London, UK (J.M.L.).

Correspondence to Roger A. Johns, MD, Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, 600 North Wolfe St, Blalock 1415, Baltimore, MD 21287-4965. E-mail rajohns{at}jhmi.edu

Received October 8, 2002; de novo received April 1, 2003; accepted May 6, 2003.

Background— Chronic hypoxia–induced pulmonary hypertension is associated with increased pulmonary expression of nitric oxide synthase (NOS) enzymes. Nevertheless, some reports have indicated decreased pulmonary production of NO in the disease. To address this paradox, we determined pulmonary concentrations of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) in the hypoxia-induced pulmonary hypertension rat model. In addition, we determined whether dysregulation of the ADMA-metabolizing enzyme dimethylarginine dimethylaminohydrolase I (DDAH I) plays a role in this disease.

Methods and Results— Adult male rats were exposed for 1 week to either normoxia or hypoxia (10% oxygen). Lung tissues were used for Western blot analysis of endothelial NOS and DDAH I expression, measurement of lung NO and ADMA content, and in vitro assay of DDAH enzyme activity. Western blot analysis revealed a 1.9-fold increase in endothelial NOS protein and a 37% decrease in DDAH I protein in the lungs of hypoxia-exposed rats. Both pulmonary DDAH enzyme activity and NO content were significantly decreased in the hypoxic group (by 37% and 22%, respectively), but pulmonary ADMA concentrations were increased by 2.3-fold compared with the normoxic group.

Conclusions— These data demonstrate that the rat chronic hypoxia–induced pulmonary hypertension model is associated with increased pulmonary concentrations of the NOS inhibitor ADMA. Moreover, pulmonary hypertensive rats exhibit reduced pulmonary expression and activity of the ADMA-metabolizing enzyme DDAH I. The decreased DDAH I and increased ADMA concentrations may therefore contribute to pulmonary hypertension via the competitive inhibition of pulmonary NOS enzymes.

Key Words: hypertension, pulmonary • hypoxia • asymmetric dimethylarginine • nitric oxide • nitric oxide synthase

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