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(Stroke. 2006;37:2871.)
© 2006 American Heart Association, Inc.

Letters to the Editor

Response to Letter by Tsuda

Jan T. Kielstein, MD

Department of Nephrology, Medical School, Hannover, Germany, Stanford University, School of Medicine, Division of Cardiovascular Medicine, Stanford, Calif

Frank Donnerstag, MD

Department of Neuroradiology, Medical School, Hannover, Germany

Sandra Gasper, MD; Jan Menne, MD Danilo Fliser, MD

Department of Nephrology, Medical School, Hannover, Germany

Anousheh Kielstein, MD

Addiction Pharmacology Research Laboratory at California Pacific Medical Center Research Institute, San Francisco, Calif

Jens Martens-Lobenhoffer, PhD; Fortunato Scalera, PhD Stefanie M. Bode-Boger, MD, MPH

Institute of Clinical Pharmacology, University Hospital, Magdeburg, Germany

John Cooke, MD, PhD

Stanford University, School of Medicine, Division of Cardiovascular Medicine, Stanford, Calif

Response:

We thank Dr Tsuda for the interest in our article on the effects of acute ADMA infusion on vascular stiffness and cerebral perfusion and for expanding the discussion on ADMA beyond the well established effects of ADMA on different vascular beds in humans.¹ Although not part of our study, the interaction between corpuscular blood components and the endothelium are important because they influence the microcirculation. Preclinical and clinical data suggest that ADMA is able to influence properties and behavior of corpuscular blood components. Dr Tsuda and his group showed that elevated ADMA levels in hypertensive men are associated with lower membrane fluidity of erythrocytes.² Kang et al³ reported that ADMA is metabolized in human erythrocytes. In a very elegant study Billecke et al⁴ recently analyzed in detail how the whole blood, a 5-kg constantly moving tissue (in a 70-kg human), contributes to the regulation of ADMA levels. Rat erythrocytes were not only able to hydrolyze ADMA but also to liberate large amounts of ADMA. But also white leukocytes are affected by ADMA. When Chan et al cocultured monocytes with ADMA, exposed endothelial cells became hyperadhesive.⁵ These data suggest that ADMA may simultaneously increase vascular adhesion and vasoconstriction with adverse consequences on vascular patency.

A secondary analysis of our data, which Dr Tsuda asked for, showed that there was a weak correlation between baseline total cerebral blood flow and baseline ADMA levels (r²=0.261, P=0.025) and a stronger correlation between ADMA and baseline augmentation index (r²=0.316, P=0.015). The limited number of subjects studied does not, however, allow a meaningful multivariate analysis so that this univariate analysis should be interpreted cum grano salis. ADMA has an irresistible appeal as a biomarker for cardiovascular risk and unifying mediator of atherosclerosis and beautifully fits in our current understanding of the pathophysiology of this multifaceted disease. There is, however, the ultimate test ADMA has to take: reducing ADMA should ideally translate into decreased morbidity and mortality, a lesson the rise and fall of acknowledgement of homocysteine as a cardiovascular risk factor should have taught us.

Acknowledgments

Disclosures

None.

References

1. Kielstein JT, Tsikas D, Fliser D. Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur J Clin Pharmacol. 2006; 62 (Suppl 13): 39–44.[CrossRef]

2. Tsuda K, Nishio I. An association between plasma asymmetric dimethylarginine and membrane fluidity of erythrocytes in hypertensive and normotensive men an electron paramagnetic resonance investigation. Am J Hypertens. 2005; 18: 1243–1248.[CrossRef][Medline] [Order article via Infotrieve]

3. Kang ES, Cates TB, Harper DN, Chiang TM, Myers LK, Acchiardo SR, Kimoto M. An enzyme hydrolyzing methylated inhibitors of nitric oxide synthase is present in circulating human red blood cells. Free Radic Res. 2001; 35: 693–707.[Medline] [Order article via Infotrieve]

4. Billecke SS, Kitzmiller LA, Northrup JJ, Whitesall SE, Kimoto M, Hinz AV, D’Alecy LG. Contribution of Whole Blood to the Control of Plasma Asymmetrical Dimethylarginine. Am J Physiol Heart Circ Physiol. 2006; 291: H1788–H1796.[Abstract/Free Full Text]

5. Chan JR, Boger RH, Bode-Boger SM, Tangphao O, Tsao PS, Blaschke TF, Cooke JP. Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol. 2000; 20: 1040–1046.[Abstract/Free Full Text]

Related Article:

Asymmetric Dimethylarginine and Cerebrovascular Disorders in Humans

Kazushi Tsuda
Stroke 2006 37: 2870. [Extract] [Full Text] [PDF]

This Article Extract Full Text (PDF) All Versions of this Article: 37/12/2871    most recent 01.STR.0000248205.20996.3fv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kielstein, J. T. Articles by Cooke, J. Search for Related Content PubMed PubMed Citation Articles by Kielstein, J. T. Articles by Cooke, J. Related Collections Related Article