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(Circulation. 2003;108:3042.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis

Genetic and Physiological Evidence

Hayan Dayoub, MD^*; Vinod Achan, MD^*; Shanthi Adimoolam, PhD; Johannes Jacobi, MD; Marcus C. Stuehlinger, MD; Bing-yin Wang, MD, PhD; Philip S. Tsao, PhD; M. Kimoto, PhD; Patrick Vallance, MD; Andrew J. Patterson, MD, PhD; John P. Cooke, MD, PhD

From the Program in Vascular Medicine and Biology (H.D., S.A., J.J., M.C.S., V.-y.W., P.T., J.P.C.) and Department of Anesthesiology (A.J.P.), Stanford University School of Medicine, Stanford, Calif; Centre for Clinical Pharmacology (V.A., P.V.), Department of Medicine, University College London, UK; and Department of Nutritional Science (M.K.), Okayama Prefectural University, Kuboki, Japan.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford CA 94305-5246. E-mail john.cooke{at}stanford.edu

Received September 17, 2001; de novo received July 18, 2003; revision received August 13, 2003; accepted August 14, 2003.

Background— NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis.

Methods and Results— We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production.

Conclusions— DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.

Key Words: nitric oxide • endothelium • blood pressure • risk factors • vasodilation

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