- Email: [email protected]
The beneficial effects of angiotensin-converting enzyme inhibitors on serum asymmetric dimethylarginine levels in the patients with cardiovascular disease
Letters to the Editor
[5]
[6]
[7]
[8]
[9]
[10]
[11]
And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. Cole TG, Ferguson CA, Gibson DW, Nowatzke WL, Bachorik PS, Ross JW. Optimization of beta-quantification methods for highthroughput applications. Clin Chem 2001;47(4):712–21. Yan SK, Ren FQ, Song YH, Lin QS. Determination of cholesterol in lipoprotein fractions by agarose gel electrophoresis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2001 23(1):93–6. Friedewald WT, Levy RJ, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–509. Usui S, Kakuuchi H, Okamoto M. Differential reactivity of two homogeneous LDL-cholesterol methods to LDL and VLDL subfractions, as demonstrated by ultracentrifugation and HPLC. Clin Chem 2002;48:1946–54. Greg Miller W, Parvin P, Waymack F, et al. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem 2002;48:489–98. Warnick GR, Knopp RH, Fitzpat rick V, Bronson L. Estimating lowdensity lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. Clin Chem 1990;36:15–9. Bachorik PS. Measurement of low-density lipoprotein cholesterol. In: Rifai N, Warnick GR, Dominiczak MH, editors. Handbook of lipoprotein testing. Washington, DC: AACC Press; 1997. p. 145–60.
107
[12] Okada M, Matsui H, Ito Y, et al. Low-density lipoprotein cholesterol can be chemically measured: a new superior method. J Lab Clin Med 1998:132. [13] Esteban-Salán M, Guimón-Berdesi A, Viuda-Unzueta JM, et al. Analytical and clinical evaluation of two homogeneous assays for LDL-cholesterol in hyperlipidemic patients. Clin Chem 2000;46:1121–31. [14] Scharnagl H, Nauck M, Wieland H, Marz W. The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin Chem Lab Med 2001;39:426–31. [15] Onat A, Yıldı rım B, Uslu N, Gürbüz N, Kelefl I, Çetinkaya A. Investigations plasma lipoproteins and apolipoproteins in Turkish adults: overall levels, associations with other risk parameters and HDL's role as a marker of coronary risk in women. Türk Kardiyol Dern Aras 1999;27:72–9. [16] Onat A. Risk factors and cardiovascular disease in Turkey. Atherosclerosis 2001;156:1–10. [17] Yuksel HK, Coskun A, Duran S, Yavuz O. Preliminary results of HDL levels in the Duzce region (Turkey): normal rather than low. Anadolu Kardiyol Derg 2006;6(2):174–5. [18] Bijtster P. A multi-cent re evaluation of the measurement of high density lipoprotein cholesterol by the Reflotron assay. Eur J Clin Chem Clin Biochem 1993;31(3):173–8. [19] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.141
The beneficial effects of angiotensin-converting enzyme inhibitors on serum asymmetric dimethylarginine levels in the patients with cardiovascular disease Turgay Celik a,⁎, Atila Iyisoy a , Cagdas Yuksel b , Bekim Jata a a
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, 06018 Etlik-Ankara, Turkey b Sarikamis Army District Hospital, Department of Cardiology, Sarikamis, Turkey Received 16 June 2008; accepted 26 November 2008 Available online 21 December 2008
Keywords: Asymmetric dimethylarginine; Angiotensin-converting enzyme inhibitors
We have read with great interest the study published in the recent issue of the Journal, by Kawata et al. [1]. In that study measurements of serum asymmetric dimethylarginine (ADMA) and coronary flow velocity reserve (CFVR) using
⁎ Corresponding author. Tel.: +90 312 3044268; fax: +90 312 3044250 E-mail address: [email protected] (T. Celik).
transthoracic Doppler echocardiography were performed at baseline and after 4 weeks of temocapril therapy in 18 patients with type 2 diabetes. Although blood pressure, fasting blood sugar and lipid profiles remained unchanged, serum ADMA concentrations decreased significantly and CFVR increased significantly after the treatment. Moreover, a strong correlation was observed between the difference of ADMA and that of CFVR. Temocapril reduced serum
108
Letters to the Editor
ADMA concentrations, improved CFVR beyond its blood pressure lowering effect. They conclude that their results suggest that decrease in ADMA by temocapril treatment is related to improvement of coronary circulation as determined by CFVR in patients with type 2 diabetes. There is abundant evidence that the endothelium plays a pivotal role in the maintenance of vascular tone and structure. Dysfunction of the endothelial L-arginine–nitric oxide pathway is a common mechanism by which several cardiovascular risk factors mediate their deleterious effects on the vascular wall [2]. There is a growing clinical evidence to support the hypothesis that ADMA, an endogenous inhibitor of nitric oxide synthase is a new independent cardiovascular risk factor [3]. Asymmetric dimethylarginine mediates endothelial dysfunction in coronary artery disease, lipid disorders, chronic heart failure, diabetes mellitus and arterial hypertension [3]. Angiotensin-converting enzyme inhibitors (ACEI) improve endothelial function in hypertensive patients, proving that the activation of the renin–angiotensin– aldesterone system (RAAS) may contribute to the endothelial dysfunction in the patients with hypertension [4]. Ito et al. the mechanisms for the increased ADMA levels in hypertensive patients [5]. Patients with essential hypertension were randomized to an ACEI treatment group (perindopril, 4 mg/ day), an AT1 receptor antagonist treatment group (losartan, 50 mg/day) or a beta-blocker treatment group (bisoprolol, 5 mg/day) for 4 weeks. Before and after the treatment, blood pressure (BP), serum concentration of ADMA and plasma concentration of von Willebrand factor (vWF) were measured. Perindopril, losartan and bisoprolol decreased BP to a similar extent, and either perindopril or losartan, but not bisoprolol, significantly decreased serum ADMA and plasma vWF. These findings suggest that the RAAS may contribute to the mechanism of increased serum ADMA as well as to the endothelial injury observed in hypertensive patients. They conclude that the vasculoprotective actions of ACEI or AT1 receptor antagonists may be explained at least in part by amelioration of the endothelial injury through a decrease in the serum ADMA concentration. Angiotensin II increases reactive oxygen species (ROS) formation by vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [6]. Due to inactivation of dimethylarginine dimethylaminohydrolase (DDAH) by ROS, ACEI and AT1 receptor antagonist might improve ADMA metabolism by ameliorating oxidative stress. In fact, in some studies serum markers of oxidative stress have been reduced by these drugs [5,7]. In a nicely designed study, [8] Napoli et al. compared the effects of two ACE inhibitors: zofenopril containing reduced sulfhydryl groups and thus possesses direct radical-scavenging properties, and enalapril, which does not contain –SH groups and has no antioxidant activity. They demonstrated that zofenopril was much more effective in reducing ADMA concentration [8]. On the other hand, no change in serum lipid peroxidation products was observed in patients treated with ACEI in other studies [9]. One can claim
that RAAS blockade could decrease ADMA by lowering blood pressure since shear stress increases ADMA and symmetric dimethylarginine (SDMA) formation by endothelial cells. Simultaneous depression of both ADMA and SDMA [10] would be consistent with this possibility. However, it was reported that [9] ACEI or AT1 receptor antagonist decreased ADMA despite having no effect on blood pressure. Furthermore, it was found that only perindopril but not bisoprolol reduces ADMA in hypertensive patients despite similar decrease in blood pressure [5] suggesting that effect on blood pressure does not play an essential role. No changes in renal function were observed in most studies in which the patients treated with an ACEI or AT1 receptor antagonist. In fact, treatment with perindopril reduced plasma ADMA but had no effect on urinary ADMA in patients with type 2 diabetes [9]. In conclusion, ACEI and AT1 receptor antagonists are the drugs most consistently shown to reduce ADMA level in humans. Unfortunately, most of the human studies addressing the effect of pharmacotherapy on ADMA metabolism were accomplished on small patient subgroups and were relatively shortlasting. Besides, L-arginine was rarely measured in most studies, whereas L-arginine/ADMA ratio may be more important for NO synthase function than ADMA itself, and arginine concentration may be either increased [11] or decreased [12] by pharmacotherapy. We strongly believe that agents affecting ADMA more specifically (protein arginine methyltransferases inhibitors or dimethylarginine dimethylaminohydrolase inducers) deserve further investigation. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [13].
References [1] Kawata T, Daimon M, Hasegawa R, et al. Effect of angiotensinconverting enzyme inhibitor on serum asymmetric dimethylarginine and coronary circulation in patients with type 2 diabetes mellitus. Int J Cardiol 2009;132:286–8. [2] Böger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. J Nutr 2004;134(10 Suppl):2842S–7S. [3] Szuba A, Podgórski M. Asymmetric dimethylarginine (ADMA) a novel cardiovascular risk factor—evidence from epidemiological and prospective clinical trials. Pharmacol Rep 2006;58:16–20 Suppl. [4] Rizzoni D, Muiesan ML, Porteri E, et al. Effects of long-term therapy with lisinopril on resistance arteries of hypertensive patients with left ventricular hypertrophy. J Hypertens 1997;15:197–204. [5] Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Renin– angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Jpn Circ J 2001;65:775–8. [6] Kalinowski L, Malinski T. Endothelial NADH/NADPH dependent enzymatic sources of superoxide production: relationship to endothelial dysfunction. Acta Biochim Pol 2004;51:459–69. [7] Fu YF, Xiong Y, Guo Z. A reduction of endogenous asymmetric dimethylarginine contributes to the effect of captopril on endothelial dysfunction induced by homocysteine in rats. Eur J Pharmacol, 2005;508:167–75.
Letters to the Editor [8] Napoli C, Sica V, de Nigris F, Pignalosa O, Condorelli M, Ignarro LJ, et al. Sulfhydryl angiotensin converting enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension. Am Heart J 2004;148:e5. [9] Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. Circ J 2002;66:811–5. [10] Closs EI, Basha FZ, Habermeier A, Förstermann U. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1997;1:65–73.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.109
109
[11] Dierkes J, Westphal S, Martens-Lobenhoffer J, Luley C, Bode-Böger SM. Fenofibrate increases the L-arginine: ADMA ratio by increase of L-arginine concentration but has no effect on ADMA concentration. Atherosclerosis 2004;173:239–44. [12] Holven KB, Haugstad TS, Holm T, Aukrust P, Ose L, Nenseter MS. Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 2003;89:359–63. [13] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
[5]
[6]
[7]
[8]
[9]
[10]
[11]
And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. Cole TG, Ferguson CA, Gibson DW, Nowatzke WL, Bachorik PS, Ross JW. Optimization of beta-quantification methods for highthroughput applications. Clin Chem 2001;47(4):712–21. Yan SK, Ren FQ, Song YH, Lin QS. Determination of cholesterol in lipoprotein fractions by agarose gel electrophoresis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2001 23(1):93–6. Friedewald WT, Levy RJ, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–509. Usui S, Kakuuchi H, Okamoto M. Differential reactivity of two homogeneous LDL-cholesterol methods to LDL and VLDL subfractions, as demonstrated by ultracentrifugation and HPLC. Clin Chem 2002;48:1946–54. Greg Miller W, Parvin P, Waymack F, et al. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem 2002;48:489–98. Warnick GR, Knopp RH, Fitzpat rick V, Bronson L. Estimating lowdensity lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. Clin Chem 1990;36:15–9. Bachorik PS. Measurement of low-density lipoprotein cholesterol. In: Rifai N, Warnick GR, Dominiczak MH, editors. Handbook of lipoprotein testing. Washington, DC: AACC Press; 1997. p. 145–60.
107
[12] Okada M, Matsui H, Ito Y, et al. Low-density lipoprotein cholesterol can be chemically measured: a new superior method. J Lab Clin Med 1998:132. [13] Esteban-Salán M, Guimón-Berdesi A, Viuda-Unzueta JM, et al. Analytical and clinical evaluation of two homogeneous assays for LDL-cholesterol in hyperlipidemic patients. Clin Chem 2000;46:1121–31. [14] Scharnagl H, Nauck M, Wieland H, Marz W. The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin Chem Lab Med 2001;39:426–31. [15] Onat A, Yıldı rım B, Uslu N, Gürbüz N, Kelefl I, Çetinkaya A. Investigations plasma lipoproteins and apolipoproteins in Turkish adults: overall levels, associations with other risk parameters and HDL's role as a marker of coronary risk in women. Türk Kardiyol Dern Aras 1999;27:72–9. [16] Onat A. Risk factors and cardiovascular disease in Turkey. Atherosclerosis 2001;156:1–10. [17] Yuksel HK, Coskun A, Duran S, Yavuz O. Preliminary results of HDL levels in the Duzce region (Turkey): normal rather than low. Anadolu Kardiyol Derg 2006;6(2):174–5. [18] Bijtster P. A multi-cent re evaluation of the measurement of high density lipoprotein cholesterol by the Reflotron assay. Eur J Clin Chem Clin Biochem 1993;31(3):173–8. [19] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.141
The beneficial effects of angiotensin-converting enzyme inhibitors on serum asymmetric dimethylarginine levels in the patients with cardiovascular disease Turgay Celik a,⁎, Atila Iyisoy a , Cagdas Yuksel b , Bekim Jata a a
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, 06018 Etlik-Ankara, Turkey b Sarikamis Army District Hospital, Department of Cardiology, Sarikamis, Turkey Received 16 June 2008; accepted 26 November 2008 Available online 21 December 2008
Keywords: Asymmetric dimethylarginine; Angiotensin-converting enzyme inhibitors
We have read with great interest the study published in the recent issue of the Journal, by Kawata et al. [1]. In that study measurements of serum asymmetric dimethylarginine (ADMA) and coronary flow velocity reserve (CFVR) using
⁎ Corresponding author. Tel.: +90 312 3044268; fax: +90 312 3044250 E-mail address: [email protected] (T. Celik).
transthoracic Doppler echocardiography were performed at baseline and after 4 weeks of temocapril therapy in 18 patients with type 2 diabetes. Although blood pressure, fasting blood sugar and lipid profiles remained unchanged, serum ADMA concentrations decreased significantly and CFVR increased significantly after the treatment. Moreover, a strong correlation was observed between the difference of ADMA and that of CFVR. Temocapril reduced serum
108
Letters to the Editor
ADMA concentrations, improved CFVR beyond its blood pressure lowering effect. They conclude that their results suggest that decrease in ADMA by temocapril treatment is related to improvement of coronary circulation as determined by CFVR in patients with type 2 diabetes. There is abundant evidence that the endothelium plays a pivotal role in the maintenance of vascular tone and structure. Dysfunction of the endothelial L-arginine–nitric oxide pathway is a common mechanism by which several cardiovascular risk factors mediate their deleterious effects on the vascular wall [2]. There is a growing clinical evidence to support the hypothesis that ADMA, an endogenous inhibitor of nitric oxide synthase is a new independent cardiovascular risk factor [3]. Asymmetric dimethylarginine mediates endothelial dysfunction in coronary artery disease, lipid disorders, chronic heart failure, diabetes mellitus and arterial hypertension [3]. Angiotensin-converting enzyme inhibitors (ACEI) improve endothelial function in hypertensive patients, proving that the activation of the renin–angiotensin– aldesterone system (RAAS) may contribute to the endothelial dysfunction in the patients with hypertension [4]. Ito et al. the mechanisms for the increased ADMA levels in hypertensive patients [5]. Patients with essential hypertension were randomized to an ACEI treatment group (perindopril, 4 mg/ day), an AT1 receptor antagonist treatment group (losartan, 50 mg/day) or a beta-blocker treatment group (bisoprolol, 5 mg/day) for 4 weeks. Before and after the treatment, blood pressure (BP), serum concentration of ADMA and plasma concentration of von Willebrand factor (vWF) were measured. Perindopril, losartan and bisoprolol decreased BP to a similar extent, and either perindopril or losartan, but not bisoprolol, significantly decreased serum ADMA and plasma vWF. These findings suggest that the RAAS may contribute to the mechanism of increased serum ADMA as well as to the endothelial injury observed in hypertensive patients. They conclude that the vasculoprotective actions of ACEI or AT1 receptor antagonists may be explained at least in part by amelioration of the endothelial injury through a decrease in the serum ADMA concentration. Angiotensin II increases reactive oxygen species (ROS) formation by vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [6]. Due to inactivation of dimethylarginine dimethylaminohydrolase (DDAH) by ROS, ACEI and AT1 receptor antagonist might improve ADMA metabolism by ameliorating oxidative stress. In fact, in some studies serum markers of oxidative stress have been reduced by these drugs [5,7]. In a nicely designed study, [8] Napoli et al. compared the effects of two ACE inhibitors: zofenopril containing reduced sulfhydryl groups and thus possesses direct radical-scavenging properties, and enalapril, which does not contain –SH groups and has no antioxidant activity. They demonstrated that zofenopril was much more effective in reducing ADMA concentration [8]. On the other hand, no change in serum lipid peroxidation products was observed in patients treated with ACEI in other studies [9]. One can claim
that RAAS blockade could decrease ADMA by lowering blood pressure since shear stress increases ADMA and symmetric dimethylarginine (SDMA) formation by endothelial cells. Simultaneous depression of both ADMA and SDMA [10] would be consistent with this possibility. However, it was reported that [9] ACEI or AT1 receptor antagonist decreased ADMA despite having no effect on blood pressure. Furthermore, it was found that only perindopril but not bisoprolol reduces ADMA in hypertensive patients despite similar decrease in blood pressure [5] suggesting that effect on blood pressure does not play an essential role. No changes in renal function were observed in most studies in which the patients treated with an ACEI or AT1 receptor antagonist. In fact, treatment with perindopril reduced plasma ADMA but had no effect on urinary ADMA in patients with type 2 diabetes [9]. In conclusion, ACEI and AT1 receptor antagonists are the drugs most consistently shown to reduce ADMA level in humans. Unfortunately, most of the human studies addressing the effect of pharmacotherapy on ADMA metabolism were accomplished on small patient subgroups and were relatively shortlasting. Besides, L-arginine was rarely measured in most studies, whereas L-arginine/ADMA ratio may be more important for NO synthase function than ADMA itself, and arginine concentration may be either increased [11] or decreased [12] by pharmacotherapy. We strongly believe that agents affecting ADMA more specifically (protein arginine methyltransferases inhibitors or dimethylarginine dimethylaminohydrolase inducers) deserve further investigation. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [13].
References [1] Kawata T, Daimon M, Hasegawa R, et al. Effect of angiotensinconverting enzyme inhibitor on serum asymmetric dimethylarginine and coronary circulation in patients with type 2 diabetes mellitus. Int J Cardiol 2009;132:286–8. [2] Böger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. J Nutr 2004;134(10 Suppl):2842S–7S. [3] Szuba A, Podgórski M. Asymmetric dimethylarginine (ADMA) a novel cardiovascular risk factor—evidence from epidemiological and prospective clinical trials. Pharmacol Rep 2006;58:16–20 Suppl. [4] Rizzoni D, Muiesan ML, Porteri E, et al. Effects of long-term therapy with lisinopril on resistance arteries of hypertensive patients with left ventricular hypertrophy. J Hypertens 1997;15:197–204. [5] Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Renin– angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Jpn Circ J 2001;65:775–8. [6] Kalinowski L, Malinski T. Endothelial NADH/NADPH dependent enzymatic sources of superoxide production: relationship to endothelial dysfunction. Acta Biochim Pol 2004;51:459–69. [7] Fu YF, Xiong Y, Guo Z. A reduction of endogenous asymmetric dimethylarginine contributes to the effect of captopril on endothelial dysfunction induced by homocysteine in rats. Eur J Pharmacol, 2005;508:167–75.
Letters to the Editor [8] Napoli C, Sica V, de Nigris F, Pignalosa O, Condorelli M, Ignarro LJ, et al. Sulfhydryl angiotensin converting enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension. Am Heart J 2004;148:e5. [9] Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. Circ J 2002;66:811–5. [10] Closs EI, Basha FZ, Habermeier A, Förstermann U. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1997;1:65–73.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.109
109
[11] Dierkes J, Westphal S, Martens-Lobenhoffer J, Luley C, Bode-Böger SM. Fenofibrate increases the L-arginine: ADMA ratio by increase of L-arginine concentration but has no effect on ADMA concentration. Atherosclerosis 2004;173:239–44. [12] Holven KB, Haugstad TS, Holm T, Aukrust P, Ose L, Nenseter MS. Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 2003;89:359–63. [13] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.