Abstract
In spite of a wide range of drugs being available in the market, treatment of arterial hypertension still remains a challenge, and new therapeutic strategies could be developed in order to improve the rate of success in controlling this disease. Since oxidative stress has gained importance in the last few years as one of the mechanisms involved in the origin and development of hypertension, and considering that L-carnitine (LC) is a useful compound in different pathologies characterized by increased oxidative status, the aim of the present study was to investigate the systemic antioxidant effect of LC and its correlation to blood pressure in two experimental models of hypertension: (1) spontaneously hypertensive rats (SHR) and (2) rats with hypertension induced by Nω-nitro-L-arginine methyl ester (L-NAME). Treatment with captopril was also performed in SHR in order to compare the antioxidant and antihypertensive effects of LC and captopril. The antioxidant defense capacity, in terms of antioxidant enzyme activity, glutathione system availability and plasma total antioxidant capacity, was measured in both animal models with or without an oral, chronic treatment with LC. All the antioxidant parameters studied were diminished in SHR and in L-NAME-treated animals, an alteration that was in general reversed after treatments with LC and captopril. In addition, LC produced a significant but not complete reduction of systolic and diastolic blood pressure levels in these two models of hypertension, whereas captopril was able to normalize blood pressure. Both LC and captopril prevented the reduction in nitric oxide (NO) levels observed in hypertensive animals. This suggests a decrease in the systemic oxidative stress and a higher availability of NO induced by LC in a similar way to captopril’s effects, which could be relevant in the management of arterial hypertension eventually.
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Arthur JR, Boyne R (1985) Superoxide dismutase and glutathione peroxidase activities in neutrophils from selenium deficient and copper deficient cattle. Life Sci 36:1569–1575
Berry C, Brosnan MJ, Fennell J, Hamilton CA, Dominiczak AF (2001) Oxidative stress and vascular damage in hypertension. Curr Opin Nephrol Hypertens 10:247–255
Bolterman RJ, Manriquez MC, Ortiz Ruiz MC, Juncos LA, Romero JC (2005) Effects of captopril on the renin angiotensin system, oxidative stress, and endothelin in normal and hypertensive rats. Hypertension 46:943–947
Bravo Y, Quiroz Y, Ferrebuz A, Vaziri ND, Rodriguez-Iturbe B (2007) Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension. Am J Physiol Ren Physiol 293:F616–F623
Cao G, Prior RL (1999) Measurement of oxygen radical absorbance capacity in biological samples. Meth Enzymol 299:50–62
Carlberg I, Mannervik B (1975) Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 250:5475–5480
Cediel E, Sanz-Rosa D, Oubina MP, Heras N de las, Gonzalez Pacheco FR, Vegazo O, Jimenez J, Cachofeiro V, Lahera V (2003) Effect of AT1 receptor blockade on hepatic redox status in SHR: possible relevance for endothelial function? Am J Physiol Regul Integr Comp Physiol 285:R674–R681
Dayanandan A, Kumar P, Panneerselvam C (2001) Protective role of L-carnitine on liver and heart lipid peroxidation in atherosclerotic rats. J Nutr Biochem 12:254–257
de Cavanagh EM, Inserra F, Ferder L, Fraga CG (2000) Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues. Am J Physiol Regul Integr Comp Physiol 278:R572–R577
Dincer Y, Sekercioglu N, Pekpak M, Gunes KN, Akcay T (2008) Assessment of DNA oxidation and antioxidant activity in hypertensive patients with chronic kidney disease. Ren Fail 30:1006–1011
Duarte J, Jimenez R, O'Valle F, Galisteo M, Perez-Palencia R, Vargas F, Perez-Vizcaino F, Zarzuelo A, Tamargo J (2002) Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. J Hypertens 20:1843–1854
Famularo G, De SC, Trinchieri V, Mosca L (2004) Carnitines and its congeners: a metabolic pathway to the regulation of immune response and inflammation. Ann N Y Acad Sci 1033:132–138
Ferrari R, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C (2004) Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad Sci 1033:79–91
Gomez-Amores L, Mate A, Miguel-Carrasco JL, Jimenez L, Jos A, Camean AM, Revilla E, Santa-Maria C, Vazquez CM (2007) L-carnitine attenuates oxidative stress in hypertensive rats. J Nutr Biochem 18:533–540
Gomez-Amores L, Mate A, Revilla E, Santa-Maria C, Vazquez CM (2006) Antioxidant activity of propionyl-L-carnitine in liver and heart of spontaneously hypertensive rats. Life Sci 78:1945–1952
Gonzalez W, Fontaine V, Pueyo ME, Laquay N, Messika-Zeitoun D, Philippe M, Arnal JF, Jacob MP, Michel JB (2000) Molecular plasticity of vascular wall during N(G)-nitro-L-arginine methyl ester-induced hypertension: modulation of proinflammatory signals. Hypertension 36:103–109
Hamilton CA (2004) Strategies to reduce oxidative stress in cardiovascular disease. Clin Sci (Lond) 106:219–234
Irat AM, Aktan F, Ozansoy G (2003) Effects of L-carnitine treatment on oxidant/antioxidant state and vascular reactivity of streptozotocin-diabetic rat aorta. J Pharm Pharmacol 55:1389–1395
Ito H, Torii M, Suzuki T (1992) A comparative study on defense systems for lipid peroxidation by free radicals in spontaneously hypertensive and normotensive rat myocardium. Comp Biochem Physiol B 103:37–40
Izgut-Uysal VN, Agac A, Derin N (2003) Effect of L-carnitine on carrageenan-induced inflammation in aged rats. Gerontology 49:287–292
Kalaiselvi T, Panneerselvam C (1998) Effect of L-carnitine on the status of lipid peroxidation and antioxidants in aging rats. J Nutr Biochem 9:575–581
Kataoka C, Egashira K, Ishibashi M, Inoue S, Ni W, Hiasa K, Kitamoto S, Usui M, Takeshita A (2004) Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis. Am J Physiol Heart Circ Physiol 286:H768–H774
Kitamoto S, Egashira K, Kataoka C, Usui M, Koyanagi M, Takemoto M, Takeshita A (2000) Chronic inhibition of nitric oxide synthesis in rats increases aortic superoxide anion production via the action of angiotensin II. J Hypertens 18:1795–1800
Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201–1209
Lassegue B, Griendling KK (2004) Reactive oxygen species in hypertension; an update. Am J Hypertens 17:852–860
Llorens S, Salazar FJ, Nava E (2005) Assessment of the nitric oxide system in the heart, aorta and kidney of aged Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens 23:1507–1514
Mancia G et al (2007) 2007 Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European society of hypertension (ESH) and of the european society of cardiology (ESC). J Hypertens 25:1105–1187
Marzinzig M, Nussler AK, Stadler J, Marzinzig E, Barthlen W, Nussler NC, Beger HG, Morris SM Jr, Bruckner UB (1997) Improved methods to measure end products of nitric oxide in biological fluids: nitrite, nitrate, and S-nitrosothiols. Nitric Oxide 1:177–189
Miguel-Carrasco JL, Mate A, Monserrat MT, Arias JL, Aramburu O, Vazquez CM (2008) The role of inflammatory markers in the cardioprotective effect of L-carnitine in L-NAME-induced hypertension. Am J Hypertens 21:1231–1237
Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169
Paravicini TM (2008) NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diab Care 31(Suppl 2):S170–S180
Pauly DF, Pepine CJ (2003) The role of carnitine in myocardial dysfunction. Am J Kidney Dis 41:S35–S43
Rajasekar P, Palanisamy N, Anuradha CV (2007) Increase in nitric oxide and reductions in blood pressure, protein kinase C beta II and oxidative stress by L-carnitine: a study in the fructose-fed hypertensive rat. Clin Exp Hypertens 29:517–530
Rauchova H, Dobesova Z, Drahota Z, Zicha J, Kunes J (1998) The effect of chronic L-carnitine treatment on blood pressure and plasma lipids in spontaneously hypertensive rats. Eur J Pharmacol 342:235–239
Redon J, Oliva MR, Tormos C, Giner V, Chaves J, Iradi A, Saez GT (2003) Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension 41:1096–1101
Rodriguez-Iturbe B, Zhan CD, Quiroz Y, Sindhu RK, Vaziri ND (2003) Antioxidant-rich diet relieves hypertension and reduces renal immune infiltration in spontaneously hypertensive rats. Hypertension 41:341–346
Samiec PS (1998) Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radic Biol Med 24:699–704
Sayed-Ahmed MM, Khattab MM, Gad MZ, Mostafa N (2001) L-carnitine prevents the progression of atherosclerotic lesions in hypercholesterolaemic rabbits. Pharmacol Res 44:235–242
Sener G, Paskaloglu K, Satiroglu H, Alican I, Kacmaz A, Sakarcan A (2004) L-carnitine ameliorates oxidative damage due to chronic renal failure in rats. J Cardiovasc Pharmacol 43:698–705
Simko F, Pechanova O, Pelouch V, Krajcirovicova K, Mullerova M, Bednarova K, Adamcova M, Paulis L (2009) Effect of melatonin, captopril, spironolactone and simvastatin on blood pressure and left ventricular remodelling in spontaneously hypertensive rats. J Hypertens 27(Suppl 6):S5-10–S5-10
Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A (1997) Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest 99:278–287
Torok J (2008) Participation of nitric oxide in different models of experimental hypertension. Physiol Res 57:813–825
Ulker S, McMaster D, McKeown PP, Bayraktutan U (2003) Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation. Cardiovasc Res 59:488–500
Vescovo G, Ravara B, Gobbo V, Sandri M, Angelini A, Della BM, Dona M, Peluso G, Calvani M, Mosconi L, Dalla LL (2002) L-Carnitine: a potential treatment for blocking apoptosis and preventing skeletal muscle myopathy in heart failure. Am J Physiol Cell Physiol 283:C802–C810
Vesela E, Racek J, Trefil L, Jankovy'ch V, Pojer M (2001) Effect of L-carnitine supplementation in hemodialysis patients. Nephron 88:218–223
Wilcox CS (2002) Reactive oxygen species: roles in blood pressure and kidney function. Curr Hypertens Rep 4:160–166
Yasunari K, Maeda K, Nakamura M, Yoshikawa J (2002) Oxidative stress in leukocytes is a possible link between blood pressure, blood glucose, and C-reacting protein. Hypertension 39:777–780
Yuan YV, Kitts DD (2002) Dietary fat source and cholesterol interactions alter plasma lipids and tissue susceptibility to oxidation in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Mol Cell Biochem 232:33–47
Yuan YV, Kitts DD, Godin DV (1998) Variations in dietary fat and cholesterol intakes modify antioxidant status of SHR and WKY rats. J Nutr 128:1620–1630
Zhan CD, Sindhu RK, Pang J, Ehdaie A, Vaziri ND (2004) Superoxide dismutase, catalase and glutathione peroxidase in the spontaneously hypertensive rat kidney: effect of antioxidant-rich diet. J Hypertens 22:2025–2033
Acknowledgments
This work was supported by grants from Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (PI051026), and Consejería de Salud, Junta de Andalucía (PI-0034). The group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), co-funded by the Spanish Ministerio de Educación y Ciencia and the European Regional Development Fund (ERDF; Grant BFU2007-30688-E/BFI). JL Miguel-Carrasco was supported by a research grant from Consejería de Salud, Junta de Andalucía (PI-0034).
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Mate, A., Miguel-Carrasco, J.L., Monserrat, M.T. et al. Systemic antioxidant properties of L-carnitine in two different models of arterial hypertension. J Physiol Biochem 66, 127–136 (2010). https://doi.org/10.1007/s13105-010-0017-7
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DOI: https://doi.org/10.1007/s13105-010-0017-7