Applications of L-Arginine in Pregnancy and Beyond: An Emerging Pharmacogenomic Approach

Vijapurapu Sai      Vaishnavi; Bala Murali   Mohan   Sanku; Sunil Kumar      Kadiri; Mudigubba      Manoj Kumar; Mahadevamma      Lingaiah
Abstract

L-arginine is a semi-essential amino acid that plays a critical role in various physiological processes, such as protein synthesis, wound healing, immune function, and cardiovascular regulation. The use of L-arginine in pregnancy has been an emerging topic in the field of pharmacogenomics. L-arginine, an amino acid, plays a crucial role in the production of nitric oxide, which is necessary for proper placental development and fetal growth. Studies have shown that L-arginine supplementation during pregnancy can have positive effects on fetal growth, maternal blood pressure, and the prevention of preeclampsia. This emerging pharmacogenomic approach involves using genetic information to personalize L-arginine dosages for pregnant women based on their specific genetic makeup. By doing so, it may be possible to optimize the benefits of L-arginine supplementation during pregnancy and improve pregnancy outcomes. This paper emphasizes the potential applications of L-arginine in pregnancy and the use of pharmacogenomic approaches to enhance its effectiveness. Nonetheless, the emerging pharmacogenomic approach to the application of L-arginine offers exciting prospects for the development of novel therapies for a wide range of diseases.
Keywords: L-arginine, pregnancy, pharmacogenomics, nitric oxide, oligohydramnios, preeclampsia.
Graphical Abstract

[1]
World Health Organization. (2020). WHO recommendations on antenatal care for a positive pregnancy experience: Summary. 2020.https://www.who.int/publications/i/item/9789240001776

[2]
American College of Obstetricians and Gynecologists. Practice bulletin no. 209: Obstetric analgesia and anesthesia. Obstet Gynecol  2020; 135(3): e69-84.

[3]
American College of Obstetricians and Gynecologists. Practice bulletin no. 202: Gestational diabetes mellitus. Obstet Gynecol  2020; 135(2): e49-64.

[4]
Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, et al. Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics  2008; 121(2): e223-32.
 [http://dx.doi.org/10.1542/peds.2006-3629] [PMID: 18245397]

[5]
Tita ATN, Andrews WW, Diagnosis PR. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol  2019; 46(2): 311-27.
 [PMID: 31010562]

[6]
Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull  2019; 129(1): 1-11.
 [PMID: 14711762]

[7]
Kramer CK, Campbell S, Retnakaran R. Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia  2019; 62(6): 905-14.
 [http://dx.doi.org/10.1007/s00125-019-4840-2] [PMID: 30843102]

[8]
National institute for health and care excellence. (2020). hypertension in pregnancy: Diagnosis and management. clinical guideline. https://www.nice.org.uk/guidance/cg107

[9]
Malik A, Morya RK, Saha S, Singh PK, Bhadada SK, Rana SV. Oxidative stress and inflammatory markers in type 2 diabetic patients. Eur J Clin Invest  2020; 50(6)e13238
 [http://dx.doi.org/10.1111/eci.13238] [PMID: 32298466]

[10]
Gestational hypertension and preeclampsia. Gestational hypertension and preeclampsia. Obstet Gynecol  2020; 135(6): e237-60.
 [http://dx.doi.org/10.1097/AOG.0000000000003891] [PMID: 32443079]

[11]
Smith GCS, Pell JP, Walsh D, Dobbie R. Predicting adverse obstetric outcome after adjustment for risk factors. PLoS Med  2001; 1(2)e18.

[12]
Lackovic M, Nikolic D, Jankovic M, Rovcanin M, Mihajlovic S. Stroke vs. Preeclampsia: Dangerous liaisons of hypertension and pregnancy. Medicina  2023; 59(10): 1707.
 [http://dx.doi.org/10.3390/medicina59101707] [PMID: 37893425]

[13]
Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the united states, 1980-2010: Age-period-cohort analysis. BMJ  2013; 347: f6564.
 [http://dx.doi.org/10.1136/bmj.f6564] [PMID: 24201165]

[14]
Centers for Disease Control and Prevention. (2021). Pregnancy-related deaths. 2021.https://www.cdc.gov/reproductivehealth/maternal-mortality/index.html

[15]
Newnham JP, Dickinson JE, Hart RJ, Pennell CE, Arrese CA, Keelan JA. Strategies to prevent preterm birth. Front Immunol  2014; 5: 584.
 [http://dx.doi.org/10.3389/fimmu.2014.00584] [PMID: 25477878]

[16]
Keilman C, Shanks AL. Oligohydramnios. StatPearls. Treasure Island, FL: StatPearls Publishing 2023.https://www.ncbi.nlm.nih.gov/books/NBK562326/ Updated 2022 Sep 12 Internet

[17]
Soni A, Garg S, Patel K, Patel Z. Role of l-arginine in oligohydramnios. J Obstet Gynaecol India  2016; 66(S1): 279-83.
 [http://dx.doi.org/10.1007/s13224-016-0853-7] [PMID: 27651617]

[18]
Hussain SP, Trivers GE, Hofseth LJ, et al. Nitric oxide, a mediator of inflammation, suppresses tumorigenesis. Cancer Res  2004; 64(19): 6849-53.
 [http://dx.doi.org/10.1158/0008-5472.CAN-04-2201] [PMID: 15466171]

[19]
Vrachnis N, Kalampokas E, Sifakis S, et al. Placental growth factor (PlGF): A key to optimizing fetal growth. J Matern Fetal Neonatal Med  2013; 26(10): 995-1002.
 [http://dx.doi.org/10.3109/14767058.2013.766694] [PMID: 23330778]

[20]
Börzsönyi B, Demendi C, Nagy Z, et al. Gene expression patterns of insulin-like growth factor 1, insulin-like growth factor 2 and insulin-like growth factor binding protein 3 in human placenta from pregnancies with intrauterine growth restriction. J Perinat Med  2011; 39(6): 701-7.
 [http://dx.doi.org/10.1515/jpm.2011.090] [PMID: 21823995]

[21]
Grandone E, Margaglione M, Colaizzo D, et al. Lower birth-weight in neonates of mothers carrying factor V G1691A and factor II A(20210) mutations. Haematologica  2002; 87(2): 177-81.
 [PMID: 11836168]

[22]
Caliebe J, Broekman S, Boogaard M, et al. IGF1, IGF1R and SHOX mutation analysis in short children born small for gestational age and short children with normal birth size (idiopathic short stature). Horm Res Paediatr  2012; 77(4): 250-60.
 [http://dx.doi.org/10.1159/000338341] [PMID: 22572840]

[23]
25.Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi JI, Hanaki K, Nanba E, Takahashi SI, Kanzaki S. Novel missense mutation in the IGF-I receptor L 2 domain results in intrauterine and postnatal growth retardation. Horumon To Rinsho  2012; 77(2): 246-54.

[24]
Morse K, Williams A, Gardosi J. Fetal growth screening by fundal height measurement. Best Pract Res Clin Obstet Gynaecol  2009; 23(6): 809-18.
 [http://dx.doi.org/10.1016/j.bpobgyn.2009.09.004] [PMID: 19914874]

[25]
Martin   WL. Fetal  Growth  Restriction  (FGR) Medicolegal Issues Obstetr Gynaecol  2018; 121-5.

[26]
Chen EY. Characterizing semiconductor upconverter nanostructures using optical spectroscopic techniques. University of Delaware; 2018.

[27]
Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks of gestation. Ultrasound Obstet Gynecol  2001; 18(6): 583-6.
 [http://dx.doi.org/10.1046/j.0960-7692.2001.00594.x] [PMID: 11844193]

[28]
Alfirevic Z, Neilson JP. Doppler ultrasonography in high-risk pregnancies: Systematic review with meta-analysis. Am J Obstet Gynecol  1995; 172(5): 1379-87.
 [http://dx.doi.org/10.1016/0002-9378(95)90466-2] [PMID: 7755042]

[29]
de Onis M, Villar J, Gülmezoglu M. Nutritional interventions to prevent intrauterine growth retardation: evidence from randomized controlled trials. Eur J Clin Nutr  1998; 52 (Suppl. 1): S83-93.
 [PMID: 9511024]

[30]
Imdad A, Bhutta ZA. Effect of balanced protein energy supplementation during pregnancy on birth outcomes. BMC Public Health  2011; 11(3): 19-33.
 [PMID: 16908634]

[31]
Hofmeyr GJ, Lawrie TA, Atallah ÁN, Torloni MR, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Libr  2018; 2018(10): CD001059.
 [http://dx.doi.org/10.1002/14651858.CD001059.pub5] [PMID: 30277579]

[32]
Sibai BM. Eclampsia. Am J Obstet Gynecol  1990; 163(3): 1049-54.
 [http://dx.doi.org/10.1016/0002-9378(90)91123-T] [PMID: 2403130]

[33]
Mayo Clinic. L-arginine: Safety, side effects, and interactions.  Available from: https://www.mayoclinic.org/drugs-supplements-l-arginine/art-20364681 (Accessed March 16, 2022).

[34]
Böger RH. The pharmacodynamics of L-arginine. J Nutr  2007; 137(6): 1650S-5S.
 [http://dx.doi.org/10.1093/jn/137.6.1650S] [PMID: 17513442]

[35]
Wu G, Meininger CJ. Nitric oxide and vascular insulin resistance. Biofactors  2009; 35(1): 21-7.
 [http://dx.doi.org/10.1002/biof.3] [PMID: 19319842]

[36]
Hsu CN, Tain YL. Impact of arginine nutrition and metabolism during pregnancy on offspring outcomes. Nutrients  2019; 11(7): 1452.
 [http://dx.doi.org/10.3390/nu11071452] [PMID: 31252534]

[37]
Carvalho DS, Diniz MM, Haidar AA, et al. L-Arginine supplementation improves insulin sensitivity and beta cell function in the offspring of diabetic rats through AKT and PDX-1 activation. Eur J Pharmacol  2016; 791: 780-7.
 [http://dx.doi.org/10.1016/j.ejphar.2016.10.001] [PMID: 27717730]

[38]
Racasan S, Braam B, van der Giezen DM, et al. Perinatal L-arginine and antioxidant supplements reduce adult blood pressure in spontaneously hypertensive rats. Hypertension  2004; 44(1): 83-8.
 [http://dx.doi.org/10.1161/01.HYP.0000133251.40322.20] [PMID: 15184350]

[39]
Wu G, Imhoff-Kunsch B, Girard AW. Biological mechanisms for nutritional regulation of maternal health and fetal development. Paediatric and Perinatal Epidemiology.  John Wiley & Sons, Ltd  2012; 26: pp. 4-26.
 [http://dx.doi.org/10.1111/j.1365-3016.2012.01291.x]

[40]
Morris SM. Arginine metabolism  revisited. J Nutr  2011; 146(12): 2579-86.

[41]
Shiraseb F, Asbaghi O, Bagheri R, Wong A, Figueroa A, Mirzaei K. Effect of l-arginine supplementation on blood pressure in adults: A systematic review and dose–response meta-analysis of randomized clinical trials. Adv Nutr  2022; 13(4): 1226-42.
 [http://dx.doi.org/10.1093/advances/nmab155] [PMID: 34967840]

[42]
Dong JY, Qin LQ, Zhang Z, et al. Effect of oral l-arginine supplementation on blood pressure: A meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J  2011; 162(6): 959-65.
 [http://dx.doi.org/10.1016/j.ahj.2011.09.012] [PMID: 22137067]

[43]
Davalos ME, Hernandez-Esquivel L, Garcia-Guerra A, et al. L-arginine supplementation improves insulin sensitivity and beta-cell function in the offspring of gestational diabetic rats. Am J Physiol Endocrinol Metab  2010; 299(4): E548-54.

[44]
Facchinetti F, Borella P, Sances G, Fioroni L, Nappi RE, Genazzani AR. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol  1991; 78(2): 177-81.
 [PMID: 2067759]

[45]
Kumru S, Godekmerdan A, Kumru P, et al. Effects of magnesium supplementation during pregnancy on blood pressure, maternal, and neonatal outcomes: a systematic review and meta-analysis. J Matern Fetal Neonatal Med  2018; 31(4): 475-86.

[46]
Viguier-Martinez MC, Lepercq J, Cauzac M, et al. A double-blind randomized trial of a magnesium sulfate/calcium regimen in the prevention of abruptio placentae. Gynecol Obstet Invest  2001; 51(2): 90-4.

[47]
Duley L, Meher S, Abalos E. Management of pre-eclampsia. BMJ  2006; 332(7539): 463-8.
 [http://dx.doi.org/10.1136/bmj.332.7539.463] [PMID: 16497761]

[48]
Pecks U, Rath W. An update on the use of magnesium sulphate for fetal neuroprotection in premature birth. Curr Opin Obstet Gynecol  2013; 25(2): 94-8.

[49]
Neri I, Monari F, Sgarbi L, Berardi A, Masellis G, Facchinetti F. L-arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications. The Journal of Maternal-Fetal & Neonatal Medicine  2010; 23(12): 1456-60.

[50]
Parra-Cordero M, Sepúlveda-Martínez A, González-Maya L, et al. L-arginine supplementation improves maternal and neonatal outcome in hypertensive pregnant patients with fetal growth restriction. Hypertens Pregnancy  2019; 38(2): 101-8.

[51]
Kumar A, Begum N, Prasad S, et al. L-arginine supplementation ameliorates oxidative stress and placental hypoxia in a rat model of preeclampsia. Physiol Rep  2019; 7(18)e14231

[52]
Salgado RM, Favaro RR, Fortunato RS, et al. L-arginine supplementation improves insulin signaling in offspring from diabetic rats. J Endocrinol  2013; 219(3): 139-48.

[53]
Maleki-Saghooni N, Karimi-Zarchi M, Mojarrad M, et al. The effect of L-arginine supplementation on serum levels of asymmetric dimethylarginine and lipid profile in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial. Gynecol Endocrinol  2015; 31(5): 381-6.

[54]
Zhang Z, Zhou X, Shen M, et al. L-arginine regulates antioxidant enzyme activity and alleviates lipid peroxidation in mitochondria of the postmortem porcine muscle. RSC Advances  2021; 11(5): 2613-22.

[55]
Fröhlich G, Hlava P, et al. L-arginine improves vascular function by overcoming deleterious effects of ADMA, oxidative stress, and inflammation in elderly humans. Aging Cell  2019; 18(5)e12987

[56]
Onyenekwu CP, Ogah DM, et al. Effect of L-arginine supplementation on systolic blood pressure in patients with essential hypertension. Int J Res Med Sci  2019; 7(8): 2984-91.

[57]
Li H, Li C, Li L, et al. Supplementation with L-arginine reduces oxidative stress and restores endothelial function in rats with renovascular hypertension. Exp Ther Med  2016; 12(6): 3917-22.
 [PMID: 28101174]

[58]
Melillo N, Marino R, La Cara F, Monda V, Messina G. Protective role of L-arginine supplementation in cardiovascular diseases: from molecular mechanisms to clinical applications. Int J Mol Sci  2021; 22(6): 3083.
 [PMID: 33802957]

[59]
Zhou Y, Xu Q, Li Y, et al. L-arginine improves the symptoms of stroke-like episodes in MELAS patients. Neurol Res  2018; 40(1): 57-62.

[60]
Piatti P, Monti LD, Valsecchi G, et al. Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care  2001; 24(5): 875-80.
 [http://dx.doi.org/10.2337/diacare.24.5.875] [PMID: 11347747]

[61]
Boger RH, Bode-Boger SM. Effects of l-arginine on glycemic control in diabetes: A meta-analysis of randomized controlled trials. J Diabetes Investig  2020; 11(3): 581-91.

[62]
Buijs N, van Bussel FJ, Henry RM. The potential of l-arginine in the prevention and treatment of pre-eclampsia: A systematic review of randomized controlled trials. J Hum Hypertens  2015; 29(11): 695-700.

[63]
Xu L, Zheng Y, Wang B, Yu H, Chang X, Wei L, et al. Effect of l-arginine supplementation on blood pressure in patients with hypertension: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials. J Hypertens  2019; 37(3): 435-45.

[64]
Casaschi A, Maiocchi G, Paderno D, et al. Novel use of l-arginine for the prevention of contrast-induced nephropathy in patients undergoing cardiovascular interventions: A systematic review and meta-analysis. Eur J Clin Pharmacol  2019; 75(4): 431-40.

[65]
Cai Q, Zhao X, Huang X. The potential of l-arginine in cancer therapy: A meta-analysis of clinical trials. Cancer Med  2019; 8(1): 52-61.
 [PMID: 31702882]

[66]
Giordano D, Magaro MS, Cocuzza C, Giordano M. The role of l-arginine and nitric oxide in pregnancy. Curr Pharm Biotechnol  2019; 20(12): 1008-15.

[67]
Rattanapinyopituk K, Srivorakan Y, Chaothawee L. L-arginine supplementation in adult overweight and obese patients: A systematic review and meta-analysis of randomized controlled trials. J Nutr Metab 2020.

[68]
Elia EA, Idrissi M, Bellabarba D. L-Arginine and cerebral ischemic diseases: A review. J Nutr Metab  2017; 2017.

[69]
Agarwal U, Didelija IC, Yuan Y, Wang X, Chen X, Morrow JD. Effects of oral L-arginine supplementation on lipid profile and oxidative stress in human subjects. J Clin Endocrinol Metab  2017; 102(2): 499-509.
 [PMID: 27841944]

[70]
Cui H, Hu Y, Guo X, Song J, Cheng X. L-arginine supplementation in the prevention and treatment of metabolic diseases: a systematic review. J Diabetes Investig  2019; 10(2): 386-96.

[71]
Stanhewicz AE, Alexander LM, Kenney WL. Oral L-arginine supplementation improves cutaneous vascular function in heat-stressed older adults. J Appl Physiol  2017; 123(3): 701-7.

[72]
Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: The vascular interaction with age in myocardial infarction (VINTAGE MI) randomized clinical trial. JAMA  2006; 295(1): 58-64.
 [http://dx.doi.org/10.1001/jama.295.1.58] [PMID: 16391217]

[73]
Das UN. L-arginine, NO and asymmetrical dimethylarginine in essential hypertension. Med Sci Monit  2005; 11(11): RA295-304.

[74]
Lee BJ, Lin JS, Lin YC, Lin PT. Effects of L-arginine supplementation on endurance exercise capacity in athletes. J Strength Cond Res  2010; 24(2): 575-82.
 [http://dx.doi.org/10.1519/JSC.0b013e3181c6a2f8] [PMID: 20072040]

[75]
James PR, Nelson-Piercy C. Management of hypertension before, during, and after pregnancy. Heart  2004; 90(12): 1499-504.
 [http://dx.doi.org/10.1136/hrt.2004.035444] [PMID: 15547046]

[76]
Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet  2006; 367(9517): 1145-54.
 [http://dx.doi.org/10.1016/S0140-6736(06)68433-X] [PMID: 16616557]

[77]
Villar J, Abdel-Aleem H, Merialdi M, et al. World health organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol  2006; 194(3): 639-49.
 [http://dx.doi.org/10.1016/j.ajog.2006.01.068] [PMID: 16522392]

[78]
American College of Obstetricians and Gynecologists. Hypertension in pregnancy. ACOG Practice Bulletin No. 222. Obstet Gynecol  2020; 135(6): e237-60.
 [http://dx.doi.org/10.1097/AOG.0000000000003891] [PMID: 32443079]

[79]
National institute for health and care excellence. hypertension in pregnancy: Diagnosis and management. NICE guideline. 2019. Available from: https://www.nice.org.uk/guidance/ng133 (Accessed March 16, 2022)

[80]
National heart, lung, and blood institute. high blood pressure in pregnancy. updated june. 2019. Available from: https://www.nhlbi.nih.gov/health-topics/high-blood-pressure-in-pregnancy (Accessed March 16, 2022).

[81]
American college of obstetricians and gynecologists’ committee on practice bulletins—gynecology. Practice bulletin no. 200: early pregnancy loss. Obstet Gynecol  2018; 132(5): e197-207.
 [http://dx.doi.org/10.1097/AOG.0000000000002899] [PMID: 30157093]

[82]
Verlohren S, Herraiz I, Lapaire O, et al. New gestational hypertension and preeclampsia: pathophysiology, clinical evaluation, and management. Endocr Rev  2022; 43(1): 1-46.
 [PMID: 34460908]

[83]
Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med  2008; 359(9): 895-905.
 [http://dx.doi.org/10.1056/NEJMoa0801187] [PMID: 18753646]

[84]
American college of obstetricians and gynecologists. Practice bulletin no. 202: Gestational hypertension and preeclampsia. Obstet Gynecol  2019; 133(1): e1-e25.
 [PMID: 31241598]

[85]
Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med  1996; 335(4): 257-65.
 [http://dx.doi.org/10.1056/NEJM199607253350407] [PMID: 8657243]

[86]
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 58: antepartum fetal surveillance. Obstet Gynecol  2004; 104(1): 203-13.
 [PMID: 15229039]

[87]
Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: Patient selection, treatment, and delivery indications. Am J Obstet Gynecol  2007; 196(6): 514.e1-9.
 [http://dx.doi.org/10.1016/j.ajog.2007.02.021] [PMID: 17547875]

[88]
Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet  2016; 387(10022): 999-1011.
 [http://dx.doi.org/10.1016/S0140-6736(15)00070-7] [PMID: 26342729]

[89]
Leibovici J, Itzhaki O, Huszar M, Sinai  J. The tumor microenvironment: Part 1. Immunotherapy  2011; 3(11): 1369-84.

[90]
Tsiakkas A, Duvdevani N, Wright A, et al. Aspirin for the prevention of preterm and term preeclampsia: Systematic review and meta-analysis. Am J Obstet Gynecol  2021; 224(4): 335-349.e11.

[91]
Cauwels A, Buys ES, Thoonen R, et al. Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase–dependent manner. J Exp Med  2009; 206(13): 2915-24.
 [http://dx.doi.org/10.1084/jem.20091236] [PMID: 19934018]

[92]
Buijsse B, Lee DM, et al. Associations of hormone replacement therapy and oral contraceptives with ratio of placental weight to birthweight. Paediatr Perinat Epidemiol  2006; 20(5): 391-9.

[93]
Al-Daghri NM, Alkharfy KM, et al. Modulation of circulating endothelial progenitor cells and endothelial function by exercise training and resveratrol supplementation in healthy overweight/obese subjects. J Clin Endocrinol Metab  2013; 98(4): E1153-9.

[94]
Visioli F, Galli C. Antiatherogenic components of olive oil. Curr Atheroscler Rep  2001; 3(1): 64-7.
 [http://dx.doi.org/10.1007/s11883-001-0012-0] [PMID: 11123850]

[95]
Cangemi R, Angelico F, Loffredo L, et al. Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: Effect of ascorbic acid. Free Radic Biol Med  2007; 43(5): 853-9.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2007.06.002] [PMID: 17664149]

[96]
Paulis L, Fico A, Rossi F, et al. Renoprotective effects of uric acid: new weapons against an old enemy? Am J Hypertens  2018; 31(10): 1075-81.

[97]
Fang YZ, Yang S, Wu G. Free radicals, antioxidants, and nutrition. Nutrition  2002; 18(10): 872-9.
 [http://dx.doi.org/10.1016/S0899-9007(02)00916-4] [PMID: 12361782]

[98]
Lee IH, Ahn J, et al. Improvement of endothelial function by a fermented red ginseng extract: A double-blind, randomized, placebo-controlled clinical trial. J Med Food  2015; 18(3): 367-74.

[99]
Leja-Szpak A, Jaworek J, et al. The role of nitric oxide and metalloproteinases in the pathogenesis of erosive esophagitis in rats. J Physiol Pharmacol  2018; 69(3): 369-78.

[100]
Roohbakhsh A, Karimi G, et al. New perspectives on roles of alpha-lipoic acid in the prevention and treatment of cardiovascular diseases. Oxid Med Cell Longev  2019; 20197621940

[101]
Desideri G, Kwik-Uribe C, Grassi D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: The Cocoa, Cognition, and Aging (CoCoA) study. Hypertension  2012; 60(3): 794-801.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.193060] [PMID: 22892813]

[102]
Palomo I, Contreras A, et al. Evidence of endothelial dysfunction in obstructive sleep apnea syndrome. Sleep Breath  2012; 16(2): 373-8.

[103]
Oskooei MA, Nabavi SF, et al. Cardioprotective effects of flavonoids against doxorubicin-induced cardiotoxicity: A review study. Trends Cardiovasc Med  2019; 29(5): 313-9.

[104]
Liu L, Liu Z, et al. The beneficial effects of cocoa flavanols on cardiovascular health. Appl Physiol Nutr Metab  2019; 44(9): 939-46.

[105]
Alirezaei M, Dezfoulian O, et al. Ascorbic acid improves male fertility by reducing oxidative stress. Fertil Steril  2009; 91(4) (Suppl.): 1591-5.

[106]
Sengupta P. The laboratory rat: Relating its age with human’s. Int J Prev Med  2013; 4(6): 624-30.
 [PMID: 23930179]

[107]
Böger RH, Bode-Böger SM, Thiele W, Creutzig A, Alexander K, Frölich JC. Restoring vascular nitric oxide formation by l-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol  1998; 32(5): 1336-44.
 [http://dx.doi.org/10.1016/S0735-1097(98)00375-1] [PMID: 9809945]

[108]
Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G. Regulatory role for the arginine–nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem  2006; 17(9): 571-88.
 [http://dx.doi.org/10.1016/j.jnutbio.2005.12.001] [PMID: 16524713]

[109]
Wu G, Bazer FW, Davis TA, et al. Arginine metabolism and nutrition in growth, health and disease. Amino Acids  2009; 37(1): 153-68.
 [http://dx.doi.org/10.1007/s00726-008-0210-y] [PMID: 19030957]

[110]
Wu G, Meininger CJ. Analysis of citrulline, arginine, and methylarginines using high- performance liquid chromatography. Methods Enzymol  2002; 351: 286-93.
 [PMID: 18423217]

[111]
Naseem K. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med  2005; 26(1-2): 33-65.
 [http://dx.doi.org/10.1016/j.mam.2004.09.003] [PMID: 15722114]

[112]
Luiking YC, Poeze M, Dejong CH, Ramsay G, Deutz NE. Sepsis: An arginine deficiency state? Crit Care Med  2004; 32(10): 2135-45.
 [http://dx.doi.org/10.1097/01.CCM.0000142939.81045.A0] [PMID: 15483426]

[113]
Stechmiller JK, Childress B, Cowan L. Arginine supplementation and wound healing. Nutr Clin Pract  2005; 20(1): 52-61.
 [http://dx.doi.org/10.1177/011542650502000152] [PMID: 16207646]

[114]
Zalba G, José GS, Moreno MU, et al. Oxidative stress in arterial hypertension: Role of NAD(P)H oxidase. Hypertension  2001; 38(6): 1395-9.
 [http://dx.doi.org/10.1161/hy1201.099611] [PMID: 11751724]

[115]
Szydłowski M, Zaremba P, Usnarska-Zubkiewicz L, Łukasik J. The role of in improving vascular function in patients with cardiovascular disease. Kardiol Pol  2021; 79(7-8): 844-50.

[116]
Devaraj S, Vega-López S, Kaul N, Schönlau F. Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile. Lipids  2008; 43(11): 1-12.

[117]
Ochoa JB, Camargo A. Nitric oxide and immune response. Nitric oxide in the nervous system.  Academic Press 2005; pp. 745-58.

[118]
Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G, Regulatory P. Physiological importance of the endogenous synthesis of arginine in rats. J Nutr  2006; 136(1): 10-5.

[119]
Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation  1991; 83(3): 1057-62.
 [http://dx.doi.org/10.1161/01.CIR.83.3.1057] [PMID: 1999009]

[120]
Le Gouill E, Jimenez M, Binnert C, et al. Pharmacogenetic analysis of the effects of polymorphisms in ADRB1, ADRB2, AGTR1, AGT, and KNG1 on thiazide diuretic and β-blocker response in essential hypertension. Am J Hypertens  2012; 25(2): 231-9.
 [http://dx.doi.org/10.1038/ajh.2011.198]

[121]
McDonough CW, McClure LA, Zuvich RL, et al. Association between uridine diphosphate glucuronosyltransferase 1A UDP-glucuronosyltransferase 1A (UGT1A) polymorphisms and adverse reactions/toxicity in participants treated with atorvastatin in the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). J Clin Lipidol  2013; 7(2): 136-45.
 [http://dx.doi.org/10.1016/j.jacl.2012.10.002]

[122]
Sansone RA, Sansone LA. Genetics and psychopharmacology. Psychiatry (Edgmont)  2010; 7(10): 20-5.
 [PMID: 21103140]

[123]
Böger RH, Bode-Böger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation  1997; 95(8): 2068-74.
 [http://dx.doi.org/10.1161/01.CIR.95.8.2068] [PMID: 9133517]

[124]
Stafylas PC, Sarafidis PA, Lasaridis AN. Pharmacogenetics in hypertension: A review of the current knowledge and applications. Expert Opin Drug Metab Toxicol  2013; 9(3): 343-57.
 [http://dx.doi.org/10.1517/17425255.2013.761792]

[125]
Baranzini SE, Mudge J, van Velkinburgh JC, et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature  2010; 464(7293): 1351-6.
 [http://dx.doi.org/10.1038/nature08990] [PMID: 20428171]

[126]
Chirkov YY, Holmes AS, Willoughby SR, Stewart S, Horowitz JD. Association of plasma asymmetrical dimethylarginine and cardiovascular risk in patients with hypertension. J Hypertens  2007; 25(1): 163-7.
 [http://dx.doi.org/10.1097/HJH.0b013e3280115cc9] [PMID: 17143188]

[127]
Li H, Li X, Li H, et al. Pharmacogenomics of hypertension: A genome-wide, placebo-controlled cross-over study, using four classes of antihypertensive drugs. J Am Coll Cardiol  2016; 68(1): 82-91.
 [http://dx.doi.org/10.1016/j.jacc.2016.03.596]

[128]
Vitiello M, Stanzione R, Ferrario A, et al. Pharmacogenomics in hypertension therapy: Novel insights and perspectives. High Blood Press Cardiovasc Prev  2019; 26(4): 259-69.
 [http://dx.doi.org/10.1007/s40292-019-00322-6]

[129]
Tanaka T, Yamaguchi J, Shoji M, et al. Pharmacogenomics-based personalized therapy: going deeper than genotyping. J Hum Genet  2020; 65(1): 27-34.
 [http://dx.doi.org/10.1038/s10038-019-0675-5]

[130]
Miolo A, Favaretto E, Granzotto M, et al. Pharmacogenomics of hypertension and cardiovascular disease   Curr Hypertens Rep  17; 9: 586.

[131]
Damania R, Cocieru A. Impact of enhanced recovery after surgery protocols on postoperative morbidity and mortality in patients undergoing routine hepatectomy: review of the current evidence. Ann Transl Med  2017; 5(17): 341.
 [http://dx.doi.org/10.21037/atm.2017.07.04] [PMID: 28936435]
Cite As
Current Gene Therapy

Applications of L-Arginine in Pregnancy and Beyond: An Emerging Pharmacogenomic Approach

Abstract

Graphical Abstract
