[en] We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive adults. Thirty-six adults (aged 58 [55;63] years) with or without primary hypertension participated in a three-way, randomized, double-blind, crossover study in which [placebo] and [febuxostat] and [febuxostat and rasburicase] were administered. Febuxostat and rasburicase reduce the uric acid concentration by xanthine oxidoreductase inhibition and uric acid degradation into allantoin, respectively. Endothelial function was assessed in response to acetylcholine, sodium nitroprusside, heating (with and without nitric oxide synthase inhibition) using a laser Doppler imager. Arterial stiffness was determined by applanation tonometry, together with blood pressure, renin-angiotensin system activity, oxidative stress, and inflammation. Uric acid concentration was 5.1 [4.1;5.9], 1.9 [1.2;2.2] and 0.2 [0.2;0.3] mg/dL with [placebo], [febuxostat] and [febuxostat-rasburicase] treatments, respectively (p < 0.0001). Febuxostat improved endothelial response to heat particularly when nitric oxide synthase was inhibited (p < 0.05) and reduced diastolic and mean arterial pressure (p = 0.008 and 0.02, respectively). The augmentation index decreased with febuxostat (ANOVA p < 0.04). Myeloperoxidase activity profoundly decreased with febuxostat combined with rasburicase (p < 0.0001). When uric acid dropped, plasmatic antioxidant capacity markedly decreased, while superoxide dismutase activity increased (p < 0.0001). Other inflammatory and oxidant markers did not differ. Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness. Clinical Trial Registration: NCT03395977, https://clinicaltrials.gov/ct2/show/NCT03395977.
Disciplines :
General & internal medicine
Author, co-author :
De Becker, Benjamin ; Department of Cardiology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Hupkens, Emeline; Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
Dewachter, Laurence; Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
Coremans, Catherine; RD3 - Pharmacognosy, Bioanalysis and Drug Discovery & Analytical Platform of the Faculty of Pharmacy (APFP), Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
Delporte, Cédric; RD3 - Pharmacognosy, Bioanalysis and Drug Discovery & Analytical Platform of the Faculty of Pharmacy (APFP), Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
van Antwerpen, Pierre; RD3 - Pharmacognosy, Bioanalysis and Drug Discovery & Analytical Platform of the Faculty of Pharmacy (APFP), Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
Franck, Thierry ; Université de Liège - ULiège > Centres généraux > Centre de l'oxygène : Recherche et développement (C.O.R.D.)
Zouaoui Boudjeltia, Karim; Laboratory of Experimental Medicine (ULB 222), Medicine Faculty, Université Libre de Bruxelles, CHU de Charleroi, Hopital Vesale, Montigny-le-Tilleul, Belgium
Cullus, Pierre; Biostatistics department, Medicine Faculty, Université Libre de Bruxelles, Brussels, Belgium
van de Borne, Philippe; Department of Cardiology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Language :
English
Title :
Acute effects of hypouricemia on endothelium, oxidative stress, and arterial stiffness: A randomized, double-blind, crossover study.
Erasme University Hospital KBS - Koning Boudewijnstichting F.R.S.-FNRS - Fonds de la Recherche Scientifique
Funding text :
DE BECKER Benjamin is a Research Fellow – Fonds National de la Recherche Scientifique (FNRS, Belgium). This work was supported by Grants from the “Fonds National de la Recherche Scientifique” (30309647, 34735921 to B.D.B and 31292322 to Ph.v.d.B.); “Docteur et Madame René Tagnon” fund; the “Fonds pour la Chirurgie Cardiaque”; and the “Fonds Erasme” from the Erasme Hospital-ULB, Brussels, Belgium. The Analytical Platform of the Faculty of Pharmacy (ULB) is supported by Fonds National de la Recherche Scientifique (FNRS, Belgium) and ULB Platform. The authors express their gratitude to the “Fonds National de la Recherche Scientifique” (Belgium), the “Docteur et Madame René Tagnon” Fund (Belgium), the “Fonds pour la Chirurgie Cardiaque” (Belgium) and the “Fonds Erasme,” Erasme Hospital-ULB, Brussels (Belgium). The authors thank all the participants for their participation and Mrs VANDESMAL Estel for the management of pharmaceutical products. Editorial assistance, in the form of language editing and correction, was provided by XpertScientific Editing and Consulting.DE BECKER Benjamin is a Research Fellow – Fonds National de la Recherche Scientifique (FNRS, Belgium). This work was supported by Grants from the “Fonds National de la Recherche Scientifique” (30309647, 34735921 to B.D.B and 31292322 to Ph.v.d.B.); “Docteur et Madame René Tagnon” fund; the “Fonds pour la Chirurgie Cardiaque”; and the “Fonds Erasme” from the Erasme Hospital‐ULB, Brussels, Belgium. The Analytical Platform of the Faculty of Pharmacy (ULB) is supported by Fonds National de la Recherche Scientifique (FNRS, Belgium) and ULB Platform.
Adamopoulos, D., Argacha, J.-F., Gujic, M., Preumont, N., Degaute, J.-P., & van de Borne, P. (2009). Acute effects of nicotine on arterial stiffness and wave reflection in healthy young non-smokers. Clinical and Experimental Pharmacology and Physiology, 36(8), 784–789. https://doi.org/10.1111/j.1440-1681.2009.05141.x
Agarwal, V., Hans, N., & Messerli, F. H. (2013). Effect of allopurinol on blood pressure: a systematic review and meta-analysis. The Journal of Clinical Hypertension, 15(6), 435–442. https://doi.org/10.1111/j.1751-7176.2012.00701.x
Alem, M. (2018). Allopurinol and endothelial function: A systematic review with meta-analysis of randomized controlled trials. Cardiovascular Therapeutics, 36(4):e12432.
Alshahawey, M., Mahmoud Shahin, S., Wahid Elsaid, T., & Ali, S. N. (2017). Effect of Febuxostat on the endothelial dysfunction in hemodialysis patients: A randomized, placebo-controlled, double-blinded study. American Journal of Nephrology, 45, 452–459.
Borghi, C., Tykarski, A., Widecka, K., Filipiak, K. J., Domienik-Karłowicz, J., Kostka-Jeziorny, K., Varga, A., Jaguszewski, M., Narkiewicz, K., & Mancia, G. (2018). Expert consensus for the diagnosis and treatment of patient with hyperuricemia and high cardiovascular risk. Cardiology Journal, 25(5), 545–564. https://doi.org/10.5603/CJ.2018.0116
Bruning, R. S., Santhanam, L., Stanhewicz, A. E., Smith, C. J., Berkowitz, D. E., Kenney, W. L., & Holowatz, L. A. (2012). Endothelial nitric oxide synthase mediates cutaneous vasodilation during local heating and is attenuated in middle-aged human skin. Journal of Applied Physiology, 112, 2019–2026.
Cicalese, S., Scalia, R., & Eguchi, S. (2019). Xanthine oxidase inhibition as a potential treatment for aortic stiffness in hypertension. American Journal of Hypertension, 32(3), 234–236.
Cicero, A. F. G., Pirro, M., Watts, G. F., & Mikhailidis, D. P. (2017). Effects of allopurinol on endothelial function: A systematic review and meta-analysis of randomized placebo-controlled trials. Drugs, 78(1), 99–109.
De Becker, B., Borghi, C., Burnier, M., & van de Borne, P. (2019). Uric acid and hypertension: a focused review and practical recommendations. Journal of Hypertension, 37(5), 878–883. https://doi.org/10.1097/HJH.0000000000001980.
De Becker, B., Coremans, C., Chaumont, M., Delporte, C., Van Antwerpen, P., Franck, T., Rousseau, A., Zouaoui Boudjeltia, K., Cullus, P., & van de Borne, P. (2019). Severe hypouricemia impairs endothelium-dependent vasodilatation and reduces blood pressure in healthy young men: A randomized, placebo-controlled, and crossover study. Journal of the American Heart Association, 8(23), e013130.
Delporte, C., Franck, T., Noyon, C. Dufour, D., Rousseau, A., Madhoun, P., Desmet, J-M., Serteyn, D., Raes, M., Nortier, J., Vanhaeverbeek, M., Moguilevsky, N., Nève, J., Vanhamme, L., Van Antwerpen, P., & Zouaoui Boudjeltia, K. (2012). Simultaneous measurement of protein-bound 3-chlorotyrosine and homocitrulline by LC-MS/MS after hydrolysis assisted by microwave: Application to the study of myeloperoxidase activity during hemodialysis. Talanta, 99, 603–609. https://doi.org/10.1016/j.talanta.2012.06.044.
Deng, G., Qiu, Z., Li, D., Fang, Y., & Zhang, S. (2016). Effects of allopurinol on arterial stiffness: A Meta-analysis of randomized controlled trials. Medical Science Monitor, 22, 1389–1397.
Dreyfuss, C., Wauters, A., Adamopoulos, D., Pochet, S., Azarkan, M., Berkenboom, G., van de Borne, P., & Argacha, J. F. (2013). L-NAME iontophoresis: A tool to assess NO-mediated vasoreactivity during thermal hyperemic vasodilation in humans. Journal of Cardiovascular Pharmacology, 61(5), 361–368. https://doi.org/10.1097/FJC.0b013e3182858f81.
Félétou, M. (2011). The endothelium part 2: EDHF-mediated Responses “The Classical Pathway”. Morgan & Claypool Life Sciences Publishers Series INTEGRATED.
Félétou, M., & Vanhoutte, P. M. (2006). Endothelium-derived hyperpolarizing factor where are we now? Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 1215–1225.
Franck, T., Minguet, G., Delporte, C., Derochette, S., Zouaoui Boudjeltia, K., Van Antwerpen, P., Gach, O., Deby-Dupont, G., Mouithys-Mickalad, A., & Serteyn, D. (2015). An immunological method to combine the measurement of active and total myeloperoxidase on the same biological fluid and its application in finding inhibitors which interact directly with the enzyme. Free Radical Research, 49(6), 790–799. https://doi.org/10.3109/10715762.2015.1027197
Gois, P., & Erdm, S. (2017). Pharmacotherapy for hyperuricemia in hypertensive patients (Review). Cochrane Database Systematic Review, 4(4), CD008652.
Grayson, P. C., Young Kim, S., Lavalley, M., & Choi, H. K. (2011). Hyperuricemia and incident hypertension: A systematic review and meta-analysis. Arthritis Care & Research, 63(1), 102–110. https://doi.org/10.1002/acr.20344.
Gunawardhana, L., McLean, L., Punzi, H. A., Hunt, B., Palmer, R. N., Whelton, A., & Feig, D. I. (2017). Effect of Febuxostat on ambulatory blood pressure in subjects with hyperuricemia and hypertension: A phase 2 randomized placebo-controlled study. Journal of the American Heart Association, 6(11), e006683.
Hays, A. G., Iantorno, M., Schär, M., Lai, S., Czarny, M., Breton, E., Palmer, R. N., Whelton, A., Weiss, R. G., & Gerstenblith, G. (2018). The influence of febuxostat on coronary artery endothelial dysfunction in patients with coronary artery disease: A phase. American Heart Journal, 197, 85–93.
Higgins, P., Dawson, J., Lees, K. R., Mcarthur, K., Quinn, T. J., & Walters, M. R. (2011). Xanthine oxidase inhibition for the treatment of cardiovascular disease: A systematic review and meta-analysis. Cardiovascular Therapeutics, 30(4), 217–226.
Johnson, J. M., & Kellogg, D. L. (2010). Local thermal control of the human cutaneous circulation. Journal of Applied Physiology, 109(4), 1229–1238. https://doi.org/10.1152/japplphysiol.00407.2010
Johnson, R. J., Choi, H. K., Yeo, A. E., Lipsky, P. E., & Commentary, S. E. (2019). Uric acid pegloticase treatment significantly decreases blood pressure in patients with chronic gout. Hypertension, 74, 95–101.
Johnson, R. J., Feig, D. I., Herrera-Acosta, J., & Kang, D.-H. (2005). Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension, 45(1), 18–20. https://doi.org/10.1161/01.HYP.0000150785.39055.e8
Johnson, R. J., Sánchez-Lozada, L. G., Mazzali, M., Feig, D. I., Kanbay, M., & Sautin, Y. Y. (2013). What are the key arguments against uric acid as a true risk factor for hypertension? Hypertension, 61(5), 948–951.
Kamel, B., Graham, G. G., Williams, K. M., Pile, K. D., & Day, R. O. (2016). Clinical pharmacokinetics and pharmacodynamics of febuxostat. Clinical Pharmacokinetics, 56(5), 459–475.
Kanbay, M., Segal, M., Afsar, B., Kang, D.-H., Rodriguez-Iturbe, B., & Johnson, R. J. (2013). The role of uric acid in the pathogenesis of human cardiovascular disease. Heart, 99(11), 759–766. https://doi.org/10.1136/heartjnl-2012-302535.
Kanbay, M., Siriopol, D., Nistor, I. et al (2014). Effects of allopurinol on endothelial dysfunction: A meta-analysis. American Journal of Nephrology, 39(4), 348–356. https://doi.org/10.1159/000360609
Khosravan, R., Grabowski, B. A., Wu, J., Joseph-ridge, N., & Vernillet, L. (2006). Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clinical Pharmacokinetics, 45(8), 821–841. https://doi.org/10.2165/00003088-200645080-00005
Kubli, S., Waeber, B., Dalle-Ave, A., & Feihl, F. (2000). Reproducibility of laser doppler imaging of skin blood flow as a tool to assess endothelial function. Journal of Cardiovascular Pharmacology, 36(5), 640–648. https://doi.org/10.1097/00005344-200011000-00014
Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y., Castro, A. F., Feldman, H. I., Kusek, J. W., Eggers, P., Van Lente, F., Greene, T., & Coresh, J. (2009). A new equation to estimate glomerular filtration rate. Annals of Internal Medicine, 150(9), 604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006
Lytvyn, Y., Har, R., Locke, A., Lai, V., Fong, D., Advani, A., Perkins, B. A., & Cherney, D. Z. I. (2017). Renal and vascular effects of uric acid lowering in normouricemic patients with uncomplicated type 1 diabetes. Diabetes, 66(7), 1939–1949.
Mazzali, M., Kanbay, M., Segal, M. S., Shafiu, M., Jalal, D., Feig, D. I., & Johnson, R. J. (2010). Uric acid and hypertension: Cause or effect? Current Rheumatology Reports, 12(2), 108–117.
Meotti, F. C., Jameson, G. N. L., Turner, R. Harwood, D. T., Stockwell, S., Rees, M. D., Thomas, S. R., & Kettle, A. J. (2011). Urate as a physiological substrate for myeloperoxidase. Journal of Biological Chemistry, 286(15), 12901–12911. https://doi.org/10.1074/jbc.M110.172460
Minor, T., Isselhard, W., Yamamoto, Y., Obara, M., & Saad, S. (1993). The effects of allopurinol and SOD on lipid peroxidation and energy metabolism in the liver after ischemia in an aerobic/anaerobic persufflation. Surgery Today, 23, 728–732. https://doi.org/10.1007/BF00311713
Mitchell, G. F., Hwang, S., Vasan, R. S. Larson, M. G., Pencina, M. J., Hamburg, N. M., Vita, J. A., Levy, D., & Benjamin, E. J. (2010). Arterial stiffness and cardiovascular events the framingham heart study gary. Circulation, 121, 505–511. https://doi.org/10.1161/CIRCULATIONAHA.109.886655
Mitchell, G. F., Parise, H., Benjamin, E. J., Larson, M. G., Keyes, M. J., Vita, J. A., Vasan, R. S., & Levy, D. (2004). Changes in arterial stiffness and wave reflection with advancing age in healthy men and women the framingham heart study. Hypertension, 43, 1239–1245. https://doi.org/10.1161/01.HYP.0000128420.01881.aa
Ohta, Y., Ishizuka, A., Arima, H. Hayashi, S., Iwashima, Y., Kishida, M., Yoshihara, F., Nakamura, S., & Kawano, Y. (2017). Effective uric acid-lowering treatment for hypertensive patients with hyperuricemia. Hypertension Research, 40(3), 259–263. https://doi.org/10.1038/hr.2016.139
Perez-Gomez, M. V., Bartsch, L., Castillo-Rodriguez, E., Fernandez-Prado, R., Kanbay, M., & Ortiz, A. (2019). Potential dangers of serum urate-lowering therapy. American Journal of Medicine, 132(4), 457–467. https://doi.org/10.1016/j.amjmed.2018.12.010
Qu, L., Jiang, H., & Chen, J. (2016). Effect of uric acid-lowering therapy on blood pressure: systematic review and meta-analysis Li-hui. Annals of Medicine, 49(2), 142–156.
Sezai, A., Soma, M., Nakata, K., Nakata, K-i., Osaka, S., Ishii, Y., Yaoita, H., Hata, H., & Shiono, M. (2015). Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD). Journal of Cardiology, 66(4), 298–303. https://doi.org/10.1016/j.jjcc.2014.12.017
Tani, S., Nagao, K., & Hirayama, A. (2015). Effect of febuxostat, a xanthine oxidase inhibitor, on cardiovascular risk in hyperuricemic patients with hypertension: A prospective, open-label, pilot study. Clinical Drug Investigation, 35(12), 823–831. https://doi.org/10.1007/s40261-015-0349-8
Tausche, A. K., Christoph, M., Forkmann, M., Richter, U., Kopprasch, S., Bielitz, C., Aringer, M., & Wunderlich, C. (2014). As compared to allopurinol, urate-lowering therapy with febuxostat has superior effects on oxidative stress and pulse wave velocity in patients with severe chronic tophaceous gout. Rheumatology International, 34(1), 101–109. https://doi.org/10.1007/s00296-013-2857-2
Ueng, S. (2005). Rasburicase (Elitek): a novel agent for tumor lysis syndrome. Baylor University Medical Center Proceedings, 18, 275–279. https://doi.org/10.1080/08998280.2005.11928082
Verdecchia, P., Schillaci, G., Reboldi, G., Santeusanio, F., Porcellati, C., & Brunetti, P. (2000). Relation between serum uric acid and risk of cardiovascular disease in essential hypertension: The PIUMA study. Hypertension, 36(6), 1072–1078. https://doi.org/10.1161/01.HYP.36.6.1072
Waring, W. S., McKnight, J. A., Webb, D. J., & Maxwell, S. R. J. (2007). Lowering serum urate does not improve endothelial function in patients with type 2 diabetes. Diabetologia, 50(12), 2572–2579. https://doi.org/10.1007/s00125-007-0817-7
Wauters, A., Dreyfuss, C., Pochet, S. Hendrick, P., Berkenboom, G., van de Borne, P., & Argacha, J-F. (2013). Acute exposure to diesel exhaust impairs nitric oxide-mediated endothelial vasomotor function by increasing endothelial oxidative stress. Hypertension, 62(2), 352–358. https://doi.org/10.1161/HYPERTENSIONAHA.111.00991
Yasmin, B. M. J. (1999). Similarities and differences between augmentation index and pulse wave velocity in the assessment of arterial stiffness. QJM, 92(10), 595–600. https://doi.org/10.1093/qjmed/92.10.595
Yiginer, O., Ozcelik, F., Inanc, T., Aparci, M., Ozmen, N., Cingozbay, B. Y., Kardesoglu, E., Suleymanoglu, S., Sener, G., & Cebeci, B. S. (2008). Allopurinol improves endothelial function and reduces oxidant-inflammatory enzyme of myeloperoxidase in metabolic syndrome. Clinical Research in Cardiology, 97(5), 334–340. https://doi.org/10.1007/s00392-007-0636-3
Zhou, Y., Zhao, M., Pu, Z., Xu, G., & Li, X. (2018). Relationship between oxidative stress and inflammation in hyperuricemia. Medicine, 97(49), e13108.
