Com base nos resultados obtidos, o NDBP mostrou-se um potente e promissor doador de NO, podendo ser modulado pela presença de xantina oxidase. O tratamento agudo com NDBP também diminuiu agudamente a atividade da NADPH oxidase em tecidos de animais normotensos.
Adicionalmente, a partir dos estudos in vivo, podemos concluir que o tratamento crônico com NDBP promoveu importantes efeitos benéficos frente ao processo hipertensivo, tais como, prevenção no aumento da pressão arterial em animais com hipertensão induzida por ANG II; reversão de alterações histopatológicas causadas pela ANG II, como fibrose renal e cardíaca; modulação parcial na atividade e expressão da NADPH oxidase; diminuição do estresse oxidativo em animais hipertensos, via redução na produção de ânion superóxido; aumento dos níveis plasmáticos de nitrato/nitrito.
Em conjunto, esses resultados sugerem um importante efeito cardioprotetor do NDBP, que em geral parece estar envolvido nos mecanismos responsáveis pela modulação da atividade da NADPH oxidase.
96
REFERÊNCIAS
ABUDUXIKE, G.; ALJUNID, S. M. Development of health biotechnology in developing countries: Can private-sector players be the prime movers? Biotechnology advances, v. 30, n. 6, p. 1589–1601, 2012.
ADENIYI, A. O.; OLUBOLADE, A. O.; OWIRA, P. M. Naringin mitigates cardiac hypertrophy by reducing oxidative stress and inactivating c-Jun Nuclear Kinase (JNK- 1) protein in type I diabetes. J Cardiovasc Pharmacol. , v. 28, 2015.
AFANASEV, I. Detection of superoxide in cells, tissues and whole organisms. Front Biosci (Elite Ed). , v. 1, n. 1, p. 153-60., 2009.
AGO, T. et al. Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase.. Circulation , v. 109, n. 2, p. 227-33, 2004.
AL GHOULEH, I. et al. Oxidases and peroxidases in cardiovascular and lung
disease: new concepts in reactive oxygen species signaling.. Free Radic Biol Med, v. 51, n. 7, p. 1271-88, 2011.
AL-SA'DONI, H.; FERRO, A. S-Nitrosothiols: a class of nitric oxide-donor drugs.. Clin Sci (Lond). , v. 98, n. 5, p. 507-20, 2000.
ANDRADE, J. P. E. A. Sociedade Brasileira de Cardiologia / Sociedade Brasileira de Hipertensão / Sociedade Brasileira de Nefrologia. VI Diretrizes Brasileiras de
Hipertensão. Arq Bras Cardiol, v. 95, n. (1 supl.1), p. 1-51, 2010.
ARAÚJO CS, W. M. Oxidative stress in hypertension: role of the kidney. Antioxid Redox Signal., v. 20, p. 74-101, 2014.
AZARMI, Y. et al. Allopurinol prevents nitroglycerin-induced tolerance in rat thoracic aorta. J Cardiovasc Pharmacol., v. 63, n. 2, p. 113-9, 2014.
BABIOR, B. M. NADPH oxidase: an update.. ; 93,5:1. Blood, v. 93, n. 5, p. 1464–76, 1999.
BABIOR, B. M.; LAMBETH, J. D.; NAUSEEF, W. The neutrophil NADPH oxidase., v. 397, n. 2, p. 342-4, 2002.
BACHETTI, T. et al. Co-expression and modulation of neuronal and endothelial nitric oxide synthase in human endothelial cells. J Mol Cell Cardiol. , v. 37, n. 5, p. 939- 45, 2004.
BAEHNER, R. L.; NATHAN, D. G. Leukocyte oxidase: defective activity in chronic granulomatous disease. Science, v. 155, n. 3764, p. 835–36, 1967.
BATLOUNI, M. Endotélio e hipertensão arterial. Rev Bras Hipertens, v. 8, n. 3, 2001.
BAUER, V.; SOTNÍKOV, R. Nitric oxideethe endothelium-derived relaxing factor and its role in endothelial functions.. General Physiology Biophysics., v. 29, n. 4, p. 319-40, 2010.
BAYRAKTUTAN, U.; BLAYNEY, L.; SHAH, A. M. Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in
endothelial cells.. Arterioscler. Thromb. Vasc. Biol., v. 20, n. 8, p. 1903–11, 2000. BEDARD, K.; KRAUSE, K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.. Physiol. Rev., v. 87, n. 1, p. 245–313., 2007. BEDNOV, A. et al. l-arginine prevents hypoxia-induced vasoconstriction in dual- perfused human placental cotyledons. Placenta. , v. 4004, n. 15, p. 30039-4, 2015. BENDALL, J. K. et al. Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice.. Circulation , v. 105, n. 3, p. 293-6, 2002.
BERENDES, H.; BRIDGES, R. A.; GOOD, R. A. A fatal granulomatosus of childhood: the clinical study of a new syndrome. Minn Med., v. 40, n. 5, p. 309–12, 1957.
BERETTA, M. et al. Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2. Circ Res. , v. 110, n. 3, p. 385-93, 2012.
98
BERRY, C. et al. Investigation into the sources of superoxide in human blood
vessels: angiotensin II increases superoxide production in human internal mammary arteries.. Circulation, v. 101, n. 18, p. 2206-12, 2000.
BILAL, M. et al. Knowledge, Awareness and Self-Care Practices of Hypertension Among Cardiac Hypertensive Patients. Jun 1;8(2):46709. do. Glob J Health Sci., v. 8, n. 2, p. 467-09, 2015.
BODEN, W. E. et al. Nitrates as an integral part of optimal medical therapy and cardiac rehabilitation for stable angina: review of current concepts and therapeutics. Clin Cardiol. , v. 35, n. 5, p. 263-71, 2012.
BODEN, W. E. et al. Role of short-acting nitroglycerin in the management of ischemic heart disease. Drug Des Devel Ther., v. 9, p. 4793-805, 2015.
BÖGER, R. H. The pharmacodynamics of L-arginine. Altern Ther Health Med. , v. 20, n. 3, p. 48-54, 2014.
BRAGA, V. A. Dietary salt enhances angiotensin-II-induced superoxide formation in the rostral ventrolateral medulla. Auton Neurosci. , v. 155, n. 1-2, p. 14-8, 2010. BRAGA, V. A. et al. Angiotensin-II-induced reactive oxygen species along the SFO- PVN-RVLM pathway: implications in neurogenic hypertension.. Braz J Med Biol Res., v. 44, n. 9, p. 871-6, 2011.
BYRNE, J. A. et al. Contrasting roles of NADPH oxidase isoforms in pressure-
overload versus angiotensin II-induced cardiac hypertrophy.. Circ. Res. , v. 93, n. 9, p. 802–5., 2003.
CAMPESE, V. M.; MITRA, D.; SANDEE, D. Hypertension in renal parenchymal disease: why is it so resistant to treatment? Kidney Int 2006;, v. 69, n. 6, p. 967-973, 2006.
CAMPOS, R. R.; BERGAMASCHI, C. T. Neurotransmission alterations in central cardiovascular control in experimental hypertension. lCurr Hypertens Rev, v. 22, p. 193-198, 2006.
CANTU-MEDELLIN, N.; KELLEY, E. E. Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: insights regarding where, when and how. Nitric Oxide. , v. 34, p. 19-26, 2013.
CARLSTRÖM M, P. A. Important role of NAD(P)H oxidase 2 in the regulation of the tubuloglomerular feedback.. Hypertension, v. 53, p. 456 - 457, 2009.
CARLSTROM, M. et al. Role of nox2 in the regulation of afferent arteriole
responsiveness.. Am J Physiol Regul Integr Comp Physiol., v. 296, n. 1, p. R72- 79, 2009.
CARLSTRÖM, M. et al. Dietary inorganic nitrate reverses features of metabolic
syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci U S A. , v. 107, n. 41, p. 17716-20, 2010.
CARLSTRÖM, M. et al. Superoxide dismutase 1 limits renal microvascular
remodeling and attenuates arteriole and blood pressure responses to angiotensin II via modulation of nitric of nitric oxide bioavailability. Hypertension, v. 56, n. 5, p. 907-13, 2010.
CARLSTROM, M. et al. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension..
Cardiovasc Res. , v. 89, n. 3, p. 574-85, 2011.
CARLSTRÖM, M.; PERSSON, A. E. Important role of NAD(P)H oxidase 2 in the regulation of the tubuloglomerular feedback. Hypertension. , v. 53, n. 3, p. 456-7, 2009.
CARPENTER, A. W.; SCHOENFISCH, M. H. Nitric oxide release: part II. Therapeutic applications. Chem Soc Rev. , v. 41, n. 10, p. 3742-52., 2012.
CARVAJAL, J. A. et al. Molecular mechanism of cGMP-mediated smooth muscle relaxation.. J Cell Physiol., v. 184, n. 3, p. 409-20., 2000.
CASTELLO, P. R. et al. Oxygen-regulated isoforms of cytochrome c oxidase have differential effects on its nitric oxide production and on hypoxic signaling. Proc Natl Acad Sci U S A., v. 105, n. 24, p. 8203-8, 2008.
100
CASTIGLIONE, N. et al. Nitrite and nitrite reductases: From molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. , v. 17, n. 4, p. 684-716, 2012.
CHABRASHVILI, T. et al. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol , v. 285, n. 1, p. R117–24, 2003.
CHAMBLISS, K. L.; SHAUL, P. W. Rapid activation of endothelial NO synthase by estrogen: evidence for a steroid receptor fast-action complex (SRFC) in caveolae. Steroids. , v. 67, n. 6, p. 413-9, 2002.
CHAN, S. H.; CHAN, J. Y. Angiotensin-generated reactive oxygen species in brain and pathogenesis of cardiovascular diseases.. Antioxid Redox Signal., v. 19, n. 10, p. 1074-84, 2013.
CHANG, H. R. et al. Reduction of ventricular hypertrophy and fibrosis in
spontaneously hypertensive rats by L-arginine. Chin J Physiol. , v. 48, n. 1, p. 15- 22, 2005.
CHEN, F. et al. Enzymatic regulation and functional relevance of NOX5.. Curr Pharm Des. , v. 29, 2015.
CHEN, K.; PITTMAN, R. N.; POPEL, A. S. Nitric oxide in the vasculature: where does it come from and where does it go? A quantitative perspective. Antioxid Redox Signal. , v. 10, n. 7, p. 1185-98, 2008.
CHEN, Z.; ZHANG, J.; STAMLER, J. S. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A, v. 99, n. 12, p. 8306-11, 2002. CHENG, Q. et al. Combination of the dipeptidyl peptidase IV inhibitor LAF237 [(S)-1- [(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the angiotensin II type 1 receptor antagonist valsartan [N-(1-oxopentyl)-N-[[2‘-(1H-tetrazol-5-yl)-[1,1‘-
biphenyl]-4-yl]methyl]. J. Pharmacol. Exp. Ther., v. 327, n. 683–691, 2008.
CHIN, K.Y.; MICHEL, L.; QIN, C.X.; CAO, N.; WOODMAN, O.L.; RITCHIE, R.H. The HNO donor Angeli's salt offers potential haemodynamic advantages over NO or
dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo. Pharmacol Res. v. 30, n. 104, p. 165-75, 2015.
CHISTÉ, R. C. et al. Superoxide anion radical: generation and detection in cellular and non-cellular systems. Curr Med Chem. , v. 28, 2015.
CHIUVE, S. E. et al. Lifestyle-based prediction model for the prevention of CVD: the Healthy Heart Score. Journal of the American Heart Association, v. 13, n. 6, p. 1- 12, 2014.
CONESKI, P. N.; SCHOENFISCH, M. H. Nitric oxide release: part III. Measurement and reporting. Chem Soc Rev. , v. 41, n. 10, p. 3753-8, 2012.
CRANE, M. S. et al. Novel role for low molecular weight plasma thiols in nitric oxide- mediated control of platelet function.. J Biol Chem., v. 277, n. 49, p. 46858-63, 2002. CROSS, A. The participation of the hemes of flavocytochrome b245 in the electron transfer process in NADPH oxidase. Blood, v. 93, n. 12, p. 4449, 1999.
CROWLEY, S. D. et al. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system.. J Clin Invest. , v. 115, n. 4, 2005.
CROWLEY, S. D. et al. Angiotensin ii causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci U S A., v. 103, n. 47, p. 17985-90, 2006.
CSONT, T.; FERDINANDY, P. Cardioprotective effects of glyceryl trinitrate: beyond vascular nitrate tolerance. Pharmacology & Therapeutics, v. 105, p. 57-68, 2005. CSONT, T.; FERDINANDY, P. Cardioprotective effects of glyceryl trinitrate: beyond vascular nitrate tolerance. Pharmacol Ther., v. 105, n. 1, p. 57-68, 2005.
CUCORANU, I. et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1- induced differentiation of cardiac fibroblasts into myofibroblasts.. Circ. Res., v. 97, n. 9, p. 900-7, 2005.
102
DAIBER, A.; MÜNZEL, T. Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate- Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress. Antioxid Redox Signal. , v. 23, n. 11, p. 899-942., 2015.
DANSER, A. H. et al. Bradykinin-induced release of nitric oxide by the isolated
perfused rat heart: importance of preformed pools of nitric oxide-containing factors. J Hypertens., v. 16, n. 2, p. 239-44, 1998.
DATLA SR, G. K. Reactive oxygen species, NADPH oxidases, and hypertension. Hypertension, v. 56, p. 325-330, 2010.
DATLA, S. R.; GRIENDLING, K. K. Reactive oxygen species, NADPH oxidases, and hypertension. Hypertension, v. 56, n. 3, p. 325–30, 2010.
DATLA, S. R.; GRIENDLING, K. K. Reactive oxygen species, NADPH oxidases, and hypertension.. Hypertension, v. 56, p. 325-330, 2010.
DENNINGER, J. W.; MARLETTA, M. A. Guanylate cyclase and the, NO/cGMP signaling pathway.. Biochim Biophys Acta., v. 1411 , n. 2-3, p. 334-50, 1999. DERBYSHIRE, E. R.; MARLETTA, M. A. Structure and regulation of soluble guanylate cyclase.. Annu Rev Biochem., v. 81, n. 533-59, 2012.
DI ZHANG, A. et al. Cross-talk between mineralocorticoid and angiotensin II signaling for cardiac remodeling. Hypertension, v. 52, n. 6, p. 1060-7, 2008.
DIAS, A. T. et al. Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension. J Transl Med., v. 6, p. 12- 35, 2014.
DIKALOV, S. I.; UNGVARI, Z. Role of mitochondrial oxidative stress in hypertension. American Journal of Physiology. Heart and Circulatory Physiology., v. 305, n. 10, p. H1417–1427, 2013.
DONKO, A. et al. Dual oxidases.. Philos. Trans. R. Soc. Lond. B. Biol. Sci, v. 29, n. 360, p. 2301–08., 2005.
DU, Z. Y. et al. The nitric oxide donor, diethylamine NONOate, enhances
preservation of the donor rat heart.. J Heart Lung Transplant. , v. 17, n. 11, p. 1113- 20, 1998.
DWORAKOWSKI, R. et al. Redox signalling involving NADPH oxidase-derived reactive oxygen species. Biochem Soc Trans., v. 34, n. 5, p. 960-4, 2006.
ELMARAKBY, A. A. et al. Synergistic actions of enalapril and tempol during chronic angiotensin ii-induced hypertension.. Vascul Pharmacol. , v. 46, n. 2, p. 144-51, 2007.
ENGEL, H. et al. Enhancing Nitric Oxide Bioavailability via Exogen Nitric Oxide Synthase and L-Arginine Attenuates Ischemia-Reperfusion-Induced Microcirculatory Alterations. Ann Plast Surg. , v. 29, 2014.
FAN, H.; ROBETORYE, R. S. Real-time quantitative reverse transcriptase polymerase chain reaction. Methods Mol Biol. , v. 630, p. 199-213, 2010. FÉLÉTOU, M.; HUANG, Y.; VANHOUTTE, P. M. Vasoconstrictor prostanoids.. Pflugers Arch., v. 459, n. 6, p. 941-50, 2010.
FERRER, M. et al. The scientific muscle of Brazil's health biotechnology, v. 22, p. 8- 12, 2004.
FINK, B.; BASSENGE, E. Association between vascular tolerance and platelet upregulation: comparison of nonintermittent administration of
pentaerithrityltetranitrate and glyceryltrinitrate. J Cardiovasc Pharmacol. , v. 40, n. 6, p. 890-7., 2002.
FÖRSTERMANN, U.; LI, H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol., v. 164, n. 2, p. 213-23., 2011.
FÖRSTERMANN, U.; MÜNZEL, T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. , v. 113, n. 13, p. 1708-14., 2006.
104
FÖRSTERMANN, U.; SESSA, W. C. Nitric oxide synthases: regulation and function. Eur Heart J. , v. 33, n. 7, p. 829-37, 2012.
FRANÇA-SILVA, M.-S. et al. The 2-nitrate-1,3-
dibuthoxypropan,anewnitricoxidedonor, induces vasorelaxation in mesenteric arteries of the rat. European JournalofPharmacology, v. 690, p. 170-175, 2012A.
FRANÇA-SILVA, M. S. et al. The new nitric oxide donor 2-nitrate-1,3-
dibuthoxypropan alters autonomic function in spontaneously hypertensive rats. Autonomic Neuroscience: Basic and Clinical, v. 171, p. 28 - 35, 2012B.
FURCHGOTT, R. F. Studies on Relaxation of Rabbit Aorta by Sodium Nitrite: The Basis for the Proposal that Acid-activable Inhibitory Factor from Bovine Retractor Penis Is Inorganic Nitrite and the Endothelium-derived Relaxing Factor Is Nitric Oxide. Vasodilatation. Raven Press, p. 401-14, 1988.
FURCHGOTT, R. F.; VANHOUTTE, P. M. Endothelium-derived relaxing and contracting factors. FASEB J., v. 3, n. 9, p. 2007-18, 1989.
FURCHGOTT, R. F.; ZAWADZKI, J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature , v. 288, n. 5789, p. 373-6, 1980.
GAO, X. et al. Adenosine a(1)-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment. Am J Physiol Regul Integr Comp Physiol, v. 301, p. 1699-1681, 2011.
GAO, X. et al. NADPH oxidase in the renal microvasculature is a primary target for blood pressure-lowering effects by inorganic nitrate and nitrite.. Hypertension, v. 65, n. 1, p. 161-70, 2015.
GHOFRANI, H.; WEAVER, F. A.; NADIM, M. K. Resistant hypertension: medical management and alternative therapies. Cardiol Clin., v. 33, n. 1, p. 75-87, 2015.
GHOULEH, I. A. L. et al. Oxidases and Peroxidases in Cardiovascular and Lung Disease: New Concepts in Reactive Oxygen Species Signaling. Free Radic Biol Med., v. 51, n. 7, p. 1271–88, 2011.
GOLDENBAUM, G.; DICKERSON, R. Nitric oxide production by lightning discharges.. J Geophys Res Atmos, v. 98, p. 18333-38., 1993.
GOLWALA, N. H. et al. Vascular responses to nitrite are mediated by xanthine
oxidoreductase and mitochondrial aldehyde dehydrogenase in the rat. Can J Physiol Pharmacol. , v. 87, n. 12, p. 1095-101, 2009.
GRASSI, G. et al. Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia, v. 48, p. 1359-1365, 2005.
GRAY, S. P.; JANDELEIT-DAHM, K. A. The role of NADPH Oxidase in Vascular Disease - Hypertension, Atherosclerosis & Stroke. Curr Pharm Des. , v. 29, 2015. GRENDELMEIER, I. Renal hypertension--the role of the kidneys in blood pressure regulation and the kidneys as end organ. Ther Umsch., v. 72, n. 6, p. 369-74, 2015. GRIENDLING, K. K. et al. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and
pathophysiology. Arterioscler. Thromb. Vasc. Biol., v. 20, n. 10, p. 2175-83, 2000. GRIENDLING, K. K.; SORESCU, D.; USHIO-FUKAI, M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. , v. 86, n. 5, p. 494-501., 2000. GRIEVE, D. J. et al. Involvement of the nicotinamide adenosine dinucleotide phosphate oxidase isoform Nox2 in cardiac contractile dysfunction occurring in response to pressure overload.. J Am Coll Cardiol., v. 47, n. 4, p. 817-26, 2006. GROEMPING, Y.; RITTINGER, K. Activation and assembly of the NADPH oxidase: a structural perspective.. Biochem J., v. 15, n. 386, p. 401-16, 2005.
GROHA , P. et al. New ESH/ESC guidelines on arterial hypertension : what is new and what indications remain for renal denervation? Herz, v. 39, n. 8, p. 952-6, 2014.
106
GROSSI, L.; D'ANGELO, S. Sodium nitroprusside: mechanism of NO release mediated by sulfhydryl-containing molecules. J Med Chem. , v. 48, n. 7, p. 2622-6, 2005.
GU, Q. et al. Antihypertensive medication use among US adults with hypertension. Circulation, v. 113, n. 2, 2006.
GUIDO, G.; SERAVALLE, G.; FOSCA, Q. T. The ‗neuroadrenergic hypothesis‘ in hypertension: current evidence. Exp Physiol., v. 1, n. 95, p. 581–6, 2010.
GUYENET, P. G. The sympathetic control of blood pressure. Nat Rev Neurosci, v. 7, p. 335-346, 2006.
HALBACH, M. et al. Baroreflex activation therapy : A novel interventional approach to treat heart failure with reduced ejection fraction. Herz, v. 40, n. 7, p. 959-65, 2015. HEZEL, M. P. et al. Effects of long-term dietary nitrate supplementation in mice. Redox Biol. , v. 29, n. 5, p. 234-42, 2015.
HUANG, B.; CHEN, S. C.; WANG, D. L. Shear flow increases S-nitrosylation of proteins in endothelial cells. Cardiovasc Res. 2009 Aug 1;83(3):536-46., v. 83, n. 3, p. 536-46, 2009.
HUANG, Z. et al. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest. , v. 115, n. 8, p. 2099-107., 2005.
HUSAIN, K. et al. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem August ; 6(3): 209-217, v. 6, n. 3, p. 209-17, 2015.
HUYNH, Q. L. et al. Prediction of Cardiovascular and All-Cause Mortality at 10 Years in the Hypertensive Aged Population. American journal of hypertension, v. 14, 2014.
IGNARRO, L. J. After 130 years, the molecular mechanism of action of nitroglycerin is revealed. Proc Natl Acad Sci U S A., v. 99, n. 12, p. 7816-17, 2002.
IGNARRO, L. J. et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.. Proc Natl Acad Sci U S A., v. 84, n. 24, p. 9265- 69, 1987.
IRVINE, J.C.; RAVI, R.M.; KEMP-HARPER, B.K.; WIDDOP, R.E. Nitroxyl donors retain their depressor effects in hypertension. Am J Physiol Heart Circ Physiol. v. 305, n. 6, p. H939-45, 2013.
JANUSZKO-GIERGIELEWICZ, B.; KUBIAK, M.; GROMADZIńSKI, L. The role of combination therapy in the management of hypertension in patients with chronic kidney disease. Przegl Lek. , v. 70, n. 4, p. 199-204, 2013.
JAY, D. B. et al. Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells.. Free Radic Biol Med. , v. 45, n. 3, p. 329-35, 2008.
JERÓNIMO M, D. T. G. C. F. N. J. Renovascular hypertension: a case with atypical neurological signs.. BMJ Case Rep, v. 8, 2015.
KALININA, N. et al. Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions.. Arterioscler. Thromb. Vasc. Biol., v. 22, n. 12, p. 2037-43, 2002.
KATSUMI, H.; NISHIKAWA, M.; HASHIDA, M. Development of nitric oxide donors for the treatment of cardiovascular diseases. Cardiovasc Hematol Agents Med Chem. , v. 5, n. 3, p. 204-8, 2007.
KAWADA, N. et al. A mouse model of angiotensin ii slow pressor response: Role of oxidative stress. J Am Soc Nephrol. , v. 13, n. 12, p. 2860-68, 2002.
KEARNEY, P. M. et al. Global burden of hypertension: analysis of worldwide data. Lancet, v. 365, n. 9455, p. 217-223, 2005.
KELLOGG, D. L. J. et al. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol, v. 98, n. 2, p. 629-32, 2005.
KIM, M.; HAN, C. H.; LEE, M. Y. NADPH oxidase and the cardiovascular toxicity associated with smoking.. Toxicol Res., v. 30, n. 3, p. 149-57, 2014.
108
KNORR, M.; HAUSDING, M.; PFEFFER, A.; JURK, K.; JANSEN, T.; SCHWIERCZEK, K.; OELZE, M.; KRÖLLER-SCHÖN, S.; SCHULZ, E.; WENZEL, P.; GORI, T.; BURGIN, K.; SARTOR, D.; SCHERHAG, A.; MÜNZEL, T.; DAIBER, A. In vitro and in vivo characterization of a new organic nitrate hybrid drug covalently bound to pioglitazone. Pharmacology. v. 93, n. 5-6, p. 203-15, 2014.
KOBORI, H.; NANGAKU, M. N. L. G.; NISHIYAMA, A. The intra-renal renin-
angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev, v. 59, n. 3, p. 251-87, 2007.
KOKIWAR, P. R.; GUPTA, S. S.; DURGE, P. M. Prevalence of hypertension in a rural community of central India. The Journal of the Association of Physicians of India., v. 60, p. 26-9, 2012.
KOLLAU, A. et al. Contribution of aldehyde dehydrogenase to mitochondrial
bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide. Biochem J. , v. 385, n. 3, p. 769-77, 2005.
KONE, B. C. Nitric oxide synthesis in the kidney: isoforms, biosynthesis, and functions in health. Semin Nephrol., v. 24, n. 4, p. 299-315, 2004.
KONIOR, A. et al. NADPH oxidases in vascular pathology. Antioxid Redox Signal, v. 20, n. 17, p. 2794-814, 2014.
KOPKAN, L.; MAJID, D. S. Superoxide contributes to development of salt sensitivity and hypertension induced by nitric oxide deficiency. Hypertension., v. 46, n. 4, p. 1026-31., 2005.
KOROSHETZ, W. Perspective: Time to tackle blood pressure. Nature [0028-0836] yr:2014 vol:510 iss:7506 pg:S4, v. 510, p. S4, 2014.
KUMAR, S. et al. Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase C delta. Am J Physiol Lung Cell Mol Physiol. , v. 298, n. 1, p. L105-16, 2010.
KURODA, J. et al. NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc. Natl. Acad. Sci., v. 107, p. 15565-15570, 2010.
LAI, E. Y. et al. P47phox is required for afferent arteriolar contractile responses to angiotensin ii and perfusion pressure in mice. Hypertension, v. 59, n. 2, p. 415-20, 2012.
LAMBETH, J. K. T.; DIEBOLD, B. Regulation of Nox and Duox enzymatic activity and expression.. Free Radic Biol Med., v. 43, n. 3, p. 319-31, 2007.
LANDMESSER, U. et al. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension, v. 40, n. 4, p. 511-5, 2002. LANTELME, P.; HARBAOUI, B.; COURAND, P. Y. Resistant hypertension and carotid baroreceptors stimulation. Presse Med., v. 44, n. 7-8, p. 730-6, 2015. LANTOINE F1, I. L. et al. Nitric oxide production in human endothelial cells stimulated by histamine requires Ca2+ influx. Biochem J. , v. 330, n. 2, p. 695-9, 1998.
LASSEGUE, B.; CLEMPUS, R. E. Vascular NAD(P)H oxidases: specific features, expression, and regulation.. Am. J. Physiol. Regul. Integr. Comp. Physiol., v. 285, n. 2, p. R277–97, 2003.
LASSEGUE, B.; GRIENDLING, K. K. NADPH oxidases: Functions and pathologies in the vasculature.. Arterioscler Thromb Vasc Biol., v. 30, n. 4, p. 653–61, 2010. LASSÈGUE, B.; SAN MARTÍN, A.; GRIENDLING, K. K. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system.. Circ Res. , v. 110, n. 10, p. 1364-90, 2012.
LAU, K. S. et al. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol Genomics. , v. 2, n. 1, p. 21-7, 2000.
LAW MR, M. J. W. N. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ, v. 338, p. b1665, 2009.
110
LEDOUX, J. et al. Calcium-activated potassium channels and the regulation of vascular tone. Physiology., v. 21, p. 69-78, 2006.
LEVINE, A. B.; PUNIHAOLE, D.; LEVINE, T. B. Characterization of the role of nitric oxide and its clinical applications. Cardiology., v. 122, n. 1, p. 55-68, 2012.
LI, H. et al. Characterization of the mechanism of cytochrome P450 reductase- cytochrome P450-mediated nitric oxide and nitrosothiol generation from organic nitrates. J Biol Chem., v. 281, n. 18, p. 12546-54, 2006.
LI, J. M. et al. Opposing roles of p47phox in basal versus angiotensin II-stimulated alterations in vascular O2-production, vascular tone, and mitogen-activated protein kinase activation.. Circulation , v. 109, n. 10, p. 1307–131, 2004.
LI, Y. Q. et al. Apocynin attenuates oxidative stress and cardiac fibrosis in
angiotensin II-induced cardiac diastolic dysfunction in mice. Acta pharmacologica Sinica., v. 34, n. 3, p. 352-9, 2013.
LIM, S. S. et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Buden of Disease Study 2010. Lancet, v. 380, n. 9859, p. 2224-60, 2012.
LIN, S.; PAGE, N.A.; FUNG, S.M.; FUNG, H.L. In vitro organic nitrate bioactivation to nitric oxide by recombinant aldehyde dehydrogenase 3A1. Nitric Oxide. v. 30, n. 35, p. 137-43, 2013.
LIU, T. et al. Local and systemic vasodilatory effects of low molecular weight S- nitrosothiols. Free Radic Biol Med., v. 12, n. 91, p. 215-223, 2015.
LIVAK, K. J.; SCHMITTGEN, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔ Ct) method. Methods , v. 25, n. 4, p. 402– 08, 2001.
LORIN, J. et al. Arginine and nitric oxide synthase: regulatory mechanisms and cardiovascular aspects. Mol Nutr Food Res. 2014 Jan;58(1):101-16, v. 58, n. 1, p. 101-16, 2014.
LOSCALZO, J. The identification of nitric oxide as endothelium-derived relaxing factor.. Circulation Res., v. 113, n. 2, p. 100-3, 2013.
LUNDBERG, J. O. et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Bio, v. 5, n. 12, p. 865-9, 2009.
LUNDBERG, J. O.; GLADWIN, M. T.; WEITZBERG, E. Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov. , v. 14, n. 9, p. 623-641, 2015.
LURZ, P. et al. Renal sympathetic denervation in uncontrolled arterial hypertension after successful repair for aortic coarctation. Int J Cardiol, v. 21, n. 202, p. 322-327, 2015.
MA, S.; MA, C. C. Recent developments in the effects of nitric oxide-donating statins on cardiovascular disease through regulation of tetrahydrobiopterin and nitric oxide. Vascul Pharmacol. , v. 63, n. 2, p. 63-70, 2014.
MA, Y. et al. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress. Biochem Biophys Res Commun. , v. 291, n. 15, p. 30567-2, 2015.
MANCIA, G. et al. 2013 ES/ESC Guidelines for the management of arterial