doi: 10.1161/01.CIR.0000121686.53780.84
(Circulation. 2004;109:e174.)
© 2004 American Heart Association, Inc.
Correspondence |
Estrogen and Asymmetric Dimethylarginine in Postmenopausal Women
Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan, tsudak{at}mail.wakayama-med.ac.jp
To the Editor:
We read with great interest the recent article by Holden et al1 dealing with the relationship between estrogen and asymmetric dimethylarginine (ADMA) metabolism in postmenopausal women. The results of their study demonstrated that hormone replacement therapy significantly decreased plasma ADMA levels in postmenopausal women. In an in vitro study, Holden et al1 observed that estrogen increased the activity of dimethylarginine dimethylaminohydrolase activity in endothelial cells. They proposed that estrogen can alter the catabolism and release of ADMA, which might partially contribute to the positive effect of estrogen on NO synthesis.
Several studies have already reported that ADMA might have a crucial role in cardiovascular regulations. It was demonstrated that inhibition of NO bioavailability by ADMA and a subsequent reduction in endothelial function might contribute to the increase in blood pressure during salt intake in normotensive postmenopausal women not receiving estrogen.2 Similarly, it was reported that there was a significant inverse correlation between plasma ADMA and flow-mediated dilatation of brachial artery, indicating that ADMA might be related to a decline in endothelial vasodilator function.3 In a previous study, we showed that estrogen-induced improvement of membrane fluidity of erythrocytes was mediated by NO production, which was counteracted by ADMA in postmenopausal women.4 The finding suggests that ADMA might actively participate in the regulation of cell membrane function in postmenopausal women. Because the deformability and microviscosity of erythrocyte membranes may be highly dependent on the membrane fluidity, the reduction in membrane fluidity could cause a disturbance in the blood rheological behavior and in the microcirculation, which might contribute to the pathophysiology of hypertension.
Recently, Achan et al5 demonstrated that intravenous infusion of ADMA increased blood pressure and systemic vascular resistance and decreased heart rate and cardiac output in humans. Therefore, we would like to know whether the hormone replacement therapy–induced decrease in plasma ADMA level might be accompanied by the changes in blood pressure and cardiac function. It would be important to assess more precisely whether ADMA may be involved in the cardiovascular disorders in postmenopausal women.
References
1. Holden DP, Cartwright JE, Nussey SS, et al. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation. 2003; 108: 1575–1580.
2. Scuteri A, Stühlinger MC, Cooke JP, et al. Nitric oxide inhibition as a mechanism for blood pressure increase during salt loading in normotensive postmenopausal women. J Hypertens. 2003; 21: 1339–1346.[CrossRef][Medline] [Order article via Infotrieve]
3. Stühlinger MC, Oka RK, Graf EE, et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia. Role of asymmetric dimethyl arginine. Circulation. 2003; 108: 933–938.
4. Tsuda K, Kinoshita Y, Kimura K, et al. Electron paramagnetic resonance investigation on modulatory effect of 17ß-estradiol on membrane fluidity of erythrocytes in postmenopausal women. Arterioscler Thromb Vasc Biol. 2001; 21: 1306–1312.
5. Achan V, Broadhead M, Malaki M, et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003; 23: 1455–1459.
Response
Departments of Obstetric and Gynaecology, Royal Sussex County Hospital, Brighton, UK
Departments of Biochemistry and Immunology, St George’s Hospital Medical School, London, UK
Oncology, Gastroenterology, Endocrinology, and Medicine, St George’s Hospital Medical School, London, UK
We thank Drs Tsuda and Nishio for their interest in our paper on estradiol effects on dimethylarginine dimethylaminohydrolase (DDAH) activity and the metabolism of asymmetric dimethylarginine (ADMA).1 We previously showed a correlation between serum ADMA concentrations and blood pressure in pregnancy,2 a state associated with high concentrations of circulating estrogens. In the present study, we examined whether estrogen had a direct role in the regulation of ADMA metabolism. Our results both from cell culture and from women using estrogen replacement therapy demonstrated the effect of estradiol on ADMA physiology. Some of these results have been independently confirmed.3
We were intrigued by the finding that estradiol affects erythrocyte membrane fluidity in an NO-dependent manner, attenuated by ADMA.4 There is, to our knowledge, a single report in the literature that erythrocytes contain DDAH.5 In our clinical study, we did not examine changes in blood pressure or cardiovascular function during estrogen therapy, whereas unfortunately Tsuda and co-workers did not measure erythrocyte DDAH activity in their study. Therefore, it is clear that only when these parameters are measured in the same study will we be in a position to comment fully on the various contributions of estrogen to ADMA/DDAH regulation and physiology in the cardiovascular system.
References
1. Holden DP, Cartwright JE, Nussey SS, et al. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation. 2003; 108: 1575–1580.
2. Holden DP, Fickling SA, Whitley GS, et al. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol. 1998; 178: 551–556.[CrossRef][Medline] [Order article via Infotrieve]
3. Post MS, Verhoeven MO, van der Mooren MJ, et al. Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women. J Clin Endocrinol Metab. 2003; 88: 4221–4226.
4. Tsuda K, Kinoshita-Shimamoto Y, Mabuchi Y, et al. Hormone replacement therapy improves membrane fluidity of erythrocytes in postmenopausal women: an electron paramagnetic resonance investigation. Am J Hypertens. 2003; 16: 502–507.[CrossRef][Medline] [Order article via Infotrieve]
5. Kang ES, Cates TB, Harper DN, et al. 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]
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