The aim of this study was to evaluate the effect of two models of hypertension on serum ADMA concentrations and whether the changes of serum ADMA concentrations are reversible by removing the cause of hypertension. Materials and Methods. 48 male wistar rats were randomly assigned into four groups: control, deoxycorticosterone acetate salt (DOCA-Salt), sham, and two kidneys one clip (2K1C). After 12 weeks, in half of the animals ( each group), serums were taken and direct blood pressure was measured. Then, DOCA injection was withdrawn and the animals received tap water and, in 2K1C group, renal clips were removed. After 12 weeks, direct blood pressure was measured and blood samples were taken. Results. Serum ADMA concentration in DOCA-Salt group was slightly higher than control, although it was not statistically significant. In 2K1C hypertensive group, serum ADMA concentration was significantly elevated compared to sham group ( ). Unclipping and reversal of hypertension returned serum ADMA level to sham group. There was a weak positive correlation between systolic blood pressure and serum ADMA concentration. Conclusion. increased serum ADMA concentration during hypertension is dependent on the model of hypertension, and removing the cause of hypertension could reduce it 1. Introduction Endothelial dysfunction is a major risk factor for cardiovascular disease which is accompanied with reduced nitric oxide (NO) bioavailability [1]. NO has several vascular protective effects including vasodilation, inhibition of platelet aggregartion, smooth muscle cell proliferation, and leukocyte adhesion [2]. Studies indicated that reduced bioavailability of NO by NO synthase inhibitor or increased NO degradation causes endothelial dysfunction [3]. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase and influence NO production [4]. ADMA is produced by protein arginine methyltransferase enzyme (PRMT) and competes with L-arginine, NO precursor, for all the three isoforms of NO synthase [5]. As an NO synthase inhibitor, ADMA has an important role in vascular homeostasis. There is a correlation between ADMA levels and cardiovascular morbidity and mortality [6, 7]. ？ADMA is associated by cardiovascular risk factors such as atherosclerosis, hypertension, and diabetes [8]. Elevated level of ADMA has been demonstrated in hyperlipidemia, diabetes mellitus, and peripheral artery disease [9]; however, there is a controversy on the effect of hypertension on serum ADMA concentration. Some clinical studies reported a relationship between hypertension and high
References
[1]
F. Perticone, A. Sciacqua, R. Maio et al., “Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension,” Journal of the American College of Cardiology, vol. 46, no. 3, pp. 518–523, 2005.
[2]
A. Cengel and A. Sahinarslan, “Nitric oxide and cardiovascular system,” Anadolu Kardiyoloji Dergisi, vol. 6, no. 4, pp. 364–368, 2006.
[3]
J. P. Cooke, “Does ADMA cause endothelial dysfunction?” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 9, pp. 2032–2037, 2000.
[4]
T. Teerlink, “Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance,” Clinical Chemistry and Laboratory Medicine, vol. 43, no. 10, pp. 1130–1138, 2005.
[5]
P. Vallance and J. Leiper, “Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 6, pp. 1023–1030, 2004.
[6]
R. H. B？ger, “Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials,” Vascular Medicine, vol. 10, no. 1, pp. S19–S25, 2005.
[7]
J. Wang, A. S. Sim, X. L. Wang, C. Salonikas, D. Naidoo, and D. E. L. Wilcken, “Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease,” Atherosclerosis, vol. 184, no. 2, pp. 383–388, 2006.
[8]
R. H. B？ger, “The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor,” Cardiovascular Research, vol. 59, no. 4, pp. 824–833, 2003.
[9]
K. Krzyzanowska, F. Mittermayer, M. Wolzt, and G. Schernthaner, “ADMA, cardiovascular disease and diabetes,” Diabetes Research and Clinical Practice, vol. 82, no. 2, pp. S122–S126, 2008.
[10]
A. Surdacki, M. Nowicki, J. Sandmann et al., “Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension,” Journal of Cardiovascular Pharmacology, vol. 33, no. 4, pp. 652–658, 1999.
[11]
D. Wang, S. Strandgaard, J. Iversen, and C. S. Wilcox, “Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension,” American Journal of Physiology, vol. 296, no. 2, pp. R195–R200, 2009.
[12]
R. Schnabel, S. Blankenberg, E. Lubos et al., “Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study,” Circulation Research, vol. 97, no. 5, pp. e53–59, 2005.
[13]
A. Meinitzer, U. Seelhorst, B. Wellnitz et al., “Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (The Ludwigshafen Risk and Cardiovascular Health Study),” Clinical Chemistry, vol. 53, no. 2, pp. 273–283, 2007.
[14]
F. Diekmann, R. Zart, C. Thone-Reineke, C. Bauer, H. H. Neumayer, and B. Hocher, “Regulation of the renal endothelin system in the two-kidney, one clip renal hypertensive rat,” Journal of Cardiovascular Pharmacology, vol. 36, no. 5, pp. S191–S194, 2000.
[15]
C. Veeramani, B. Aristatle, G. Pushpavalli, and K. V. Pugalendi, “Antihypertensive efficacy of Melothria maderaspatana leaf extract on sham-operated and uninephrectomized DOCA-salt hypertensive rats,” Journal of Basic and Clinical Physiology and Pharmacology, vol. 21, no. 1, pp. 27–41, 2010.
[16]
I. Palomo, A. Contreras, L. M. Alarcón et al., “Elevated concentration of asymmetric dimethylarginine (ADMA) in individuals with metabolic syndrome,” Nitric Oxide, vol. 24, no. 4, pp. 224–228, 2011.
[17]
J. A. Chirinos, R. David, J. A. Bralley et al., “Endogenous nitric oxide synthase inhibitors, arterial hemodynamics, and subclinical vascular disease: the PREVENCION study,” Hypertension, vol. 52, no. 6, pp. 1051–1059, 2008.
[18]
M. P. Siroen, T. Teerlink, R. J. Nijveldt, H. A. Prins, M. C. Richir, and P. A. van Leeuwen, “The clinical significance of asymmetric dimethylarginine,” Annual Review of Nutrition, vol. 26, pp. 203–228, 2006.
[19]
A. J. Cardounel, H. Cui, A. Samouilov et al., “Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial no production and vascular function,” Journal of Biological Chemistry, vol. 282, no. 2, pp. 879–887, 2007.
[20]
M. G. Modena, L. Bonetti, F. Coppi, F. Bursi, and R. Rossi, “Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women,” Journal of the American College of Cardiology, vol. 40, no. 3, pp. 505–510, 2002.
[21]
J. M. Leiper, J. Santa Maria, A. Chubb et al., “Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases,” Biochemical Journal, vol. 343, no. 1, pp. 209–214, 1999.
[22]
J. M. Sasser, N. C. Moningka, M. W. Cunningham Jr., B. Croker, and C. Baylis, “Asymmetric dimethylarginine in angiotensin II-induced hypertension,” American Journal of Physiology, vol. 298, no. 3, pp. R740–R746, 2010.
[23]
M. F. Chen, X. M. Xie, T. L. Yang et al., “Role of asymmetric dimethylarginine in inflammatory reactions by angiotensin II,” Journal of Vascular Research, vol. 44, no. 5, pp. 391–402, 2007.
[24]
K. Sydow and T. Münzel, “ADMA and oxidative stress,” Atherosclerosis Supplements, vol. 4, no. 4, pp. 41–51, 2003.
[25]
J. F. Reckelhoff and J. C. Romero, “Role of oxidative stress in angiotensin-induced hypertension,” American Journal of Physiology, vol. 284, no. 4, pp. R893–R912, 2003.
[26]
C. Delles, M. P. Schneider, S. John, M. Gekle, and R. E. Schmieder, “Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical NG, NG-dimethylarginine in human essential hypertension,” American Journal of Hypertension, vol. 15, no. 7, pp. 590–593, 2002.
[27]
A. Ito, K. Egashira, T. Narishige, K. Muramatsu, and A. Takeshita, “Renin-angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension,” Japanese Circulation Journal, vol. 65, no. 9, pp. 775–778, 2001.
[28]
H. Wang and J. Liu, “Plasma asymmetric dimethylarginine and L-arginine levels in Chinese patients with essential hypertension without coronary artery disease,” Journal of Cardiovascular Disease Research, vol. 2, no. 3, pp. 117–120, 2012.
