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(Circulation. 2004;109:1278-1283.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

L-Arginine Transport in the Human Coronary and Peripheral Circulation

S.E.S. Miner, MD; A. Al-Hesayen, MD; S. Kelly, RN; T. Benson, RN; J.J. Thiessen, PhD; V.R. Young, PhD; J.D. Parker, MD

From the Departments of Medicine and Pharmacy (J.J.T.), Mount Sinai Hospital and University Health Network, University of Toronto, Ontario, Canada, and the Department of Laboratory and Human Nutrition and Clinical Research Center, Massachusetts Institute of Technology, Cambridge (V.R.Y.).

Correspondence to John D. Parker, MD, FRCP(C), Toronto General Hospital, 200 Elizabeth St, Eaton North 13-212, Toronto, Ontario, Canada, M5G 2C4. E-mail jdp{at}ca.inter.net

Received January 22, 2003; de novo received August 11, 2003; revision received November 24, 2003; accepted December 1, 2003.

Background— Nitric oxide synthase (NOS) uses arginine for the production of nitric oxide (NO). High intracellular concentrations of arginine suggest that NOS activity should be independent of plasma arginine supply. However, under certain conditions, increased plasma arginine concentrations appear to be associated with increased NOS activity. The purpose of this study was to explore arginine transport within the human coronary and peripheral circulation

Methods and Results— Mass-labeled ¹⁵N₂-arginine was infused to steady state before cardiac catheterization in 31 patients. After diagnostic angiography, a catheter was placed in the coronary sinus. The transcardiac concentration gradient (aorta-coronary sinus) of ¹⁵N₂-arginine was used as a measure of arginine transport at baseline and during infusions of acetylcholine and N^G-monomethyl-L-arginine (L-NMMA). No gradient was detected at rest. During the infusion of acetylcholine, a significant gradient was detected (2.5±1.2 µmol/L, P=0.01) corresponding to a fractional extraction of 11.7±7.5%. This is consistent with in vitro studies that suggest that stimulation of NOS induces arginine transport. During the infusion of L-NMMA, the concentration of ¹⁵N₂-arginine increased in the coronary sinus, producing a gradient of -3.9±1.3 µmol/L (P=0.0002), corresponding to a fractional production of 20.5±5.0%. This is consistent with in vitro studies that suggest that L-NMMA induces the efflux of arginine from the cell to the extracellular space via transporter-mediated transstimulation.

Conclusions— The use of steady-state ¹⁵N₂-arginine to examine transorgan L-arginine gradients represents a novel tool for the study of L-arginine transport and the mechanisms of endothelial and NOS dysfunction.

Key Words: nitric oxide synthase • coronary disease • endothelium

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