|Year : 2013 | Volume
| Issue : 2 | Page : 131-134
L-arginine improves vascular function in patients with systemic lupus erythematosus
Hima Bindu Gujjarlamudi1, Liza Rajasekhar2, MUR Naidu3
1 Department of Pharmacology, Rajiv Gandhi Institute of Medical Sciences, Ongole, Andhra Pradesh, India
2 Department of Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India
3 Department of Clinical Pharmacology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India
|Date of Submission||24-Mar-2012|
|Date of Acceptance||21-Apr-2012|
|Date of Web Publication||3-Jun-2013|
Hima Bindu Gujjarlamudi
Department of Pharmacology, Rajiv Gandhi Institute of Medical Sciences, Ongole, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: Systemic lupus erythematosus (SLE) is a chronic, inflammatory disorder, experiencing an excess of cardiovascular morbidity and mortality. Arterial stiffness (AS) and Endothelial dysfunction are key events in the initiation, progression, and rupture of atheromatous plaque. L-arginine corrects derangements in the vascular endothelial nitric oxide dependent signaling pathway. Thus, the aim of our study was to evaluate the effect of L-Arginine on AS and endothelial function in patients with SLE. Materials and Methods: Twenty-Five (22F, 3M) SLE patients, demographic data, associated risk factors, disease activity, and treatment regimen were collected. Pulse Wave Velocity (PWV) and Reflection index (RI) was determined non-invasively by PeriScope and Autodicrowin, respectively. PWV reflects large artery stiffness, whereas RI represents small artery tone. Patients were randomized to receive either placebo or L-arginine (3 g t.i.d) for 2 weeks. Paired Student 't' Test and percentage change was used for statistical comparison. Results: L-arginine treatment improved Carotid femoral PWV (P < 0.002) and excellent improvement in change in RI (P < 0.0001). There was significant change in hemodynamic parameters. In placebo group, neither there was statistical change in carotid femoral PWV nor change in RI. Conclusion: L-arginine supplementation has been shown to restore vascular function and to improve the clinical symptoms in SLE patients with vascular dysfunction.
Keywords: Arterial stiffness, endothelial function, L-arginine
|How to cite this article:|
Gujjarlamudi HB, Rajasekhar L, Naidu M. L-arginine improves vascular function in patients with systemic lupus erythematosus. Int J Nutr Pharmacol Neurol Dis 2013;3:131-4
|How to cite this URL:|
Gujjarlamudi HB, Rajasekhar L, Naidu M. L-arginine improves vascular function in patients with systemic lupus erythematosus. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2020 Jan 27];3:131-4. Available from: http://www.ijnpnd.com/text.asp?2013/3/2/131/112838
| Introduction|| |
Systemic Lupus Erythematosus (SLE) is a systemic inflammatory disease that mainly affects women. It has been increasingly recognized that patients with SLE have a high cardiovascular morbidity and mortality.  Urowitz et al., showed a bimodal mortality pattern in SLE, early death is mainly due to active disease and inflammation and later death is due to cardiovascular disease.  Atherosclerosis is one of the pathophysiological bases for cardiovascular and cerebrovascular diseases, which occurs prematurely in patients with SLE and is independent of traditional risk factors for cardiovascular disease  . The mechanism is likely to be due to a combination of factors encountered in this patient population and could be related to the disease itself, to the effects of therapy with corticosteroids and/or to conventional risk factors.
Atherosclerosis is characterized by a reduction in the bioavailability of vasodilating factors in particular nitric oxide (NO). Endothelial injury, oxidative modification of lipids, and inflammation, all contribute to the development of atherosclerosis. An increased arterial stiffness (AS) and signs of premature vascular ageing in the SLE patients were reported  and the increased vascular stiffness increases cardiovascular mortality.  Both Endothelial dysfunction (ED) and increased AS commonly coexist in patients at increased risk of cardiovascular disease.
Pulse wave velocity (PWV) is a simple, accurate, noninvasive, cost-effective, reproducible, and robust marker of AS.  Reflection index, (RI) (height of diastolic to systolic multiplied by 100) is used as a marker for small artery tone and the change in RI after salbutamol challenge test will define the endothelial function status.
L-Arginine is an essential amino acid, which yields NO and L-citrulline catalyzed by the action of NO synthase (NOS). Once synthesized, NO diffuses to the underlying vascular smooth muscle where it activates soluble guanylate cyclase, leading to an increase in guanosine-3,5 1 monophosphate and relaxation.  NOS may be inhibited by the endogenous l-arginine analog, asymmetric dimethyl l-arginine (ADMA) which is derived from the post-translational methylation of peptide-bound arginines in various proteins including histones and heat shock proteins. It inhibits NO production causing vasoconstriction and increases systemic vascular resistance and impairs renal function. Supplemental l-arginine is believed to be capable of competing with ADMA  and overcome this inhibitory effect restoring the vasodilatation in these conditions. Impaired vasodilation in response to normal physiological stimuli is a hallmark of atherosclerosis. Administration of l-arginine to experimental animals and human beings has been shown to reverse the vasomotor dysfunction and the beneficial effect is associated with an increase in overall NO synthesis. When l-arginine 9 g/day orally for 6 months was given to patients with angina associated with coronary artery disease, there was an improvement in acetylcholine-induced coronary vascular relaxation with a decrease in anginal episodes.  There was 150% improvement in walking distance in patients with peripheral arterial disease with 8 g bid of l-arginine for 14 days. 
Therefore, the aim of the present study is to evaluate the effect of L-Arginine on AS and endothelial function in patients with SLE.
| Materials and Methods|| |
Twenty-Five (22F, 3M) SLE patients above 18 years of age, diagnosed as SLE according to ACR classification criteria,  were recruited after the study protocol duly approved by Institutional Ethics Committee, NIMS. Written Informed Consent was obtained before starting study- related procedure. Subjects were excluded if they were pregnant or lactating or if they had cardiovascular or metabolic disease like diabetes. Demographic data, associated risk factors, disease activity  and treatment regimen were collected.
Assessment of vascular function
The study was conducted in the Clinical Pharmacology unit, NIMS, Hyderabad. PWV and RI was determined non-invasively by PeriScope  and Autodicrowin, respectively (Ms. Genesis Medical Systems, Hyderabad). The patients rested in supine position for 10 minutes before the recordings. RI was recorded at baseline and 15 min after 400 μg of Salbutamol inhalation, the change in RI  was noted to assess the endothelial-dependent vasodilatory function.
During the first visit, AS and endothelial function was assessed as described. Patients were randomized in 2:1 ratio to receive either placebo (8 patients) or L-arginine (17 patients) 3g t.i.d for 2 weeks and asked to come for the second visit. At the second visit, the same procedure was repeated to determine the improvement in vascular function status.
The statistical analysis was performed using Sigma graph pad software, USA version-4. All the data were expressed as mean ± SD. Analysis was carried out by paired 't' test and the efficacy parameters were presented as percentage change from baseline. For statistical significance, the probability value of <0.05 was considered.
| Results|| |
Characteristic features related to patient were described in [Table 1]. Disease duration was 2.9 ± 1.8 years. SLE disease activity index (SLEDAI) and damage index were 4.5 ± 6.9 and 0.5 ± 0.9, respectively. Of 25 patients, 23 were positive to anti-nuclear antibodies (ANA), 21 positive to anti-DNA antibodies, and 10 positive to anti-cardiolipin antibodies. With regard to clinical features, six patients had a history of renal involvement and one had transient ischemic attack. All 25 patients were using prednisolone and hydroxychloroquine. Eleven patients had taken cyclophosphamide, five had methotrexate, eleven were using azathioprine, five were on antihypertensives, and four were on aspirin.
There was a significant change in hemodynamic parameters after treatment with L-arginine. CFPWV was changed from 801 ± 128 to 754 ± 113 (P = 0.002) [Figure 1]. The change in RI was significantly (P < 0.0001) improved from 0.6 ± 7.8 to -12.5 ± 6.4 after the treatment suggesting an improvement in endothelial function [Figure 2] [Table 2]. There was neither statistical change in carotid femoral PWV [9.01 ± 1.76 to 8.88 ± 1.36 m/sec] nor change in RI [-0.9 ± 6.7 to -5.5 ± 3.1] [Table 3] in placebo group. Even there was no change in hemodynamic parameters after the use of placebo.
|Table 2: Hemodynamic characteristics of Systemic lupus erythematosus patients before and after l- arginine treatment|
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|Table 3: Hemodynamic characteristics of Systemic lupus erythematosus patients before and after placebo treatment|
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| Discussion|| |
SLE is complicated by premature atherosclerosis, with higher rates of MI ranging from 9 to 50 times greater than expected. , The pathogenesis of vascular disease in SLE is not clear. It may include the interactions between chronic inflammation, corticosteroid use, augmented traditional risk factors, kidney dysfunction, and hypertension.  They contribute to alterations of the vasculature and the development of vascular stiffness and atherosclerosis. The rise in vascular stiffness leads to several aberrations such as an increase in ventricular afterload and myocardial oxygen demand, impairment of ventricular relaxation, and subendocardial ischemia.
PWV, a noninvasive method, is widely used as an index of large artery elasticity and stiffness.  Higher the velocity, higher the rigidity of the vascular wall and lower the distensibility.  ED is believed to represent a widespread phenomenon that occurs at an early stage in the atherogenic process.  The inflammatory process due to SLE as well as vascular thrombosis induced by antiphospholipid antibodies may contribute to ED.  In our previous study, the change in RI from pre Salbutamol to post Salbutamol in SLE patients was significantly less from that of healthy controls, indicating impaired endothelial-dependent vasodilatation  in SLE patients.
Elevated blood pressure affects between 39% and 64% of SLE patients in United States,  which is much greater than the general population.  The cause of raised blood pressure includes corticosteroid use, weight gain, kidney disease, and potentially inflammation-induced vascular injury.
In patients who received placebo for 2 weeks, there was no significant difference in PWV, RI, and hemodynamic parameters.
L-arginine is an essential amino acid, required by the constitutive enzyme endothelial NOS to produce NO. Supplementation with L-arginine restores vascular function and improves the clinical symptoms of various diseases associated with vascular dysfunction. It reduces blood pressure and also improves renal parameters. We observed a significant improvement in AS and the change in RI after salbutamol challenge test was also improved indicating improved endothelial function after 15 days of L-arginine therapy. Improvement of endothelial function will lead to improved vasodilatation and therefore increased blood flow. Even the hemodynamic parameters changed after L-arginine therapy. There was a significant reduction in blood pressure after 2 weeks of therapy. This suggests that L-arginine improves endothelial function and AS by increasing the bioavailability of NO as a nitric oxide donor and decreasing the inflammation acting as an antioxidant.
| Conclusion|| |
L-arginine supplementation has been shown to restore vascular function and to improve the clinical symptoms in SLE patients with vascular dysfunction.
| References|| |
|1.||Abu-Shakra M, Urowtiz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus: Results from a single center. I causes of death. J Rheumatol 1995;22:1259-64. |
|2.||Urowitz MB, Bookman AA, Kochler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. AM J Med 1976;60:221-5. |
|3.||Mary J, Roman MD, Shanker AB, Adrienne Davis AB, Michael D, et al. Prevalence and correlates of accelerated atherosclerosis in SLE. NEJM 2003;349:2399-406. |
|4.||Brodszki J, Bengtsson C, Lanne T, Nived O, Sturfelt G, Marsal K. Abnormal mechanical properties of larger arteries in post menopausal women with systemic lupus erythematosus. Lupus 2004;13:917-23. |
|5.||Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse wave velocity predicts cardiovascular mortality in subjects more than 70 yrs of age. Arterioscler Thromb Vasc Biol 2001;21:2046-50. |
|6.||van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman RS, et al. Association between arterial stiffness and atherosclerosis. The Rotterdam Study. Stroke 2001;32:454-60. |
|7.||Moncada S, Heggs A. The L-arginine - Nitric oxide pathway. NEJM 1993;329:2002-12. |
|8.||Boger RH, Ron ES. L-arginine improves vascular function by overcoming the deleterious effects of ADMA. Altern Med Rev 2005;10:14-23. |
|9.||Lerman A, Burnett JC JR, Higano ST, Mc Kinley LJ, Holmes DR Jr. long term L-arginine supplementation improves small vessel coronary endothelial function in humans. Circulation 1998;97:2123-8. |
|10.||Boger RH, Bode Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxide formation by L- arginine improves the symptoms of intermittent claudication in patients with PAOD. J Am Coll Cardiol 1998;32:1336-4. |
|11.||Hochberg MC. Updating the American College of Rheum. Revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. |
|12.||Bomberdier C, Gladmann DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients: The committee on prognosis studies in SLE. Arthritis Rheum 1992;35:630-40. |
|13.||Naidu MU, Reddy BM, Yashmaina S, Patnaik AN, Rani PU. Validity and reproducibility of arterial pulse wave velocity measurement using new device with oscillometric technic: A pilot study. Biomed Eng Online 2005;4:49. |
|14.||Naidu MU, Sridhar Y, Rani PU, Mateen AA. Comparison of two β2 adrenoceptor agonists by different routes of administration to assess human endothelial function. Indian J Pharmacol 2007;39:168-9. |
|15.||Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Janses-Mc Williams L, et al. Age specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus; comparison with the Framingham study. Am J Epidemiol 1997;145:408-15. |
|16.||Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:338-46. |
|17.||Selzer F, Sutton-Tyrell K, Fitzgerald S, Tracy R, Kuller L, Manzi S. Vascular stiffness in women with systemic lupus erythematosus. Hypertension 2001;37:1075-82. |
|18.||Asmar RG, Benetos A, Topuchian J, Laurent P, Pannier B, Brisac AM, et al. Assessment of arterial compliance by automatic PWV measurements. Validation and clinical application studies. Hypertension 1995;26:485-90. |
|19.||Nicholas WW, O'Rourke M. Mc Donald's blood flow in arteries. Theoretical, experimental and clinical principles. 4 th ed. London, Sydney, Auckland: Arnold E; 1998; 54-113; 201-222; 284-292; 347-401. |
|20.||El-Magadmi M, Bodill H, Ahmad Y, Durrington PN, Mackness M, Walker M, et al. Systemic lupus erythematosus. An independent risk factor for endothelial dysfunction in women. Circulation 2004;110:399-404. |
|21.||Lima DS, Sato EI, LimaVC, Miranda F Jr, Hatta FH. Brachial endothelial function is impaired in patients with systemic lupus erythematosus. J Rheumatol 2002;19:292-7. |
|22.||Chowienczyk RJ, Kelly RP, Mac Callum H, Millasseau SC, Andersson TL, Gosling RG et al. Photoplethysmographic assessment of pulse wave reflection: Blunted response to endothelial dependent β2 adrenergic vasodilation in type II diabetes mellitus. J Am Coll Cardiol. 1999;34:2007-14. |
|23.||Cornoni-Huntly J, LaCroix AZ, Havlik RJ. Race and sex differentials in the impact of hypertension in the United States: The National Health and Nutrition Examination Survey I epidemiological follow-up study. Arch Intern Med 1989;149:780-78. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]