Published online before print August 21, 2006, doi: 10.1161/01.HYP.0000239812.05676.1d
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(Hypertension. 2006;48:E21.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
Response to Cigarettes and ADMA: The Smoke Hasn’t Cleared Yet
Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, Melbourne, Australia
Vascular Pharmacology, Baker Heart Research Institute, Melbourne, Australia
Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, Melbourne, Australia
As acknowledged by Kielstein and coauthors, our recent study1 sought to investigate in detail the complex nature of the adverse effects of cigarette smoking on endothelial function. Using both in vivo and in vitro methodology we demonstrated that components of cigarette smoke, most likely reactive oxygen species, exerted inhibitory effects on several elements of the L-arginine:NO pathway, which cumulatively resulted in reduced production of NO. Among the numerous potential targets we demonstrated inhibition of type 1 cationic amino acid transporter (the key L-arginine transporter), the endothelial isoform of NO synthase and dimethylarginine dimethylaminohydrolase. As such, our clinical observations of elevated asymmetrical dimethyl-arginine (ADMA) and reduced N-hydroxy-arginine levels were entirely consistent with our biochemical studies.
Although much has been made of the observed association between alterations in plasma ADMA levels and cardiovascular risk,2 it remains controversial as to whether the modest elevations in ADMA observed in our study or in other risk factor studies truly indicate a pathophysiologic role. In this context, although large-scale observational studies can provide value in the identification of clinical useful risk markers and in the generation of mechanistic hypotheses, these ultimately require more deliberate focused studies as we performed. In the large-scale study3 cited by Kielstein and coauthors, the interpretation of the impact of smoking status on arginine metabolism is clouded by the marked heterogeneity of the study population. For example, it was not possible to evaluate the influence of statins in that study, despite evidence that statins reduce ADMA levels.4 Furthermore, Kielstein and colleagues5,6 showed that ADMA only exerted hemodynamic effects when infused at doses resulting in nonclinical high plasma ADMA levels.
Accordingly, we suggest that the precise determination of the pathophysiologic basis of vascular disease, such as that induced by smoking, can only be determined by rigorously designed clinical and basic research, designed specifically to complement each other.
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Acknowledgments |
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Disclosures
None.
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References |
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 Top References |
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1. Zhang WZ, Venardos K, Chin-Dusting J, Kaye DM. Adverse effects of cigarette smoke on NO bioavailability. role of arginine metabolism and oxidative stress. Hypertension. 2006; 48: 278–285.
2. Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004; 109: 1813–1818.
3. Eid HM, Arnesen H, Hjerkinn EM, Lyberg T, Seljeflot I. Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Metabolism. 2004; 53: 1574–1579.[CrossRef][Medline] [Order article via Infotrieve]
4. Lu TM, Ding YA, Leu HB, Yin WH, Sheu WH, Chu KM. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol. 2004; 94: 157–161.[CrossRef][Medline] [Order article via Infotrieve]
5. Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation. 2004; 109: 172–177.
6. Kielstein JT, Peter C, Adams C. Cigarettes and ADMA: the smoke hasn’t cleared yet. Hypertension. 2006; 48: e20.[Medline] [Order article via Infotrieve]
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