Med. Klinik IV, Univ. Klinik Benjamin Franklin, Freie Universität Berlin, Germany
Correspondence and offprint requests to: Dr Martin Tepel, Med. Klinik IV, Univ.-Klinik Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. Email: tepel{at}zedat.fu-berlin.de
Keywords: essential hypertension; hypertension; oxidative stress; uraemia
Reactive oxygen species: general aspects
Reactive oxygen species, including superoxide radicals, hydrogen peroxide, nitric oxide, peroxynitrite, hydroxyl radicals and hypochlorous acid are by-products of normal metabolic processes in cells. Reactive oxygen species can be found in several cells including macrophages and vascular smooth muscle cells. At low concentrations reactive oxygen species can act as physiological mediators of cellular responses whereas higher concentrations may cause cell damage [1,2]. The major sources of reactive oxygen species are leakages from the electron transport chains of mitochondria and endoplasmic reticulum. Cellular energy metabolism is based on the production of ATP through the electron transport reaction in which O2 accepts electrons and H+ and then is eventually reduced to water. Only 12% of the electrons are leaked to generate superoxide radicals in reactions mediated by coenzyme Q and ubiquinone and its complexes. During ageing (and probably in patients with hypertension and/or atherosclerosis) respiratory function declines and results in enhanced production of reactive oxygen species in mitochondria whereas the activities of free radical scavenging enzymes are reduced. In turn, reactive oxygen species induce stress responses by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell [3]. Neutrophils and macrophages produce reactive oxygen species during phagocytosis (oxygen burst) or stimulation with several agents through the activation of nicotinamide adenine dinucleotide phosphate reduced [NAD(P)H] oxidase that is assembled at the plasma membrane from resident plasma membrane components and cytosolic protein components [4]. The NAD(P)H oxidase is also the major source of vascular superoxide production. Vascular NAD(P)H oxidase contains the plasma membrane components gp91phox-homologues (nox1, nox4 or gp91phox) and p22phox, and the cytosolic protein components p47phox and p67phox [5]. It should be noted that the activation of vascular NAD(P)H oxidase by angiotensin II stimulates both superoxide production and NO production, thereby increasing peroxynitrite formation [6]. Endothelial nitric oxide synthase [7], inducible nitric oxide synthase [8] and xanthine oxidase [9] are other sources of superoxide radicals. After activation of vascular NAD(P)H oxidase (for example, by angiotensin II, thrombin, platelet-derived growth factor and others) the production of reactive oxygen species depends on activation of several intracellular signalling pathways including protein kinase C, the upstream activator of epidermal growth factor receptor, c-src, epidermal growth factor receptor transactivation, phosphatidylinositol-3-kinase and rac, a small molecular weight G protein. Several cellular signalling molecules such as protein tyrosine kinases, serine/threonine kinases, phospholipase C or cytosolic calcium are modified by reactive oxygen species. Reactive oxygen species activate protein tyrosine kinase pathways including epidermal growth factor receptor, insulin receptor, and platelet-derived-growth-factor receptor [10,11]. Reactive oxygen species activate extracellular signal-regulated kinases through c-src and ras [12]. Reactive oxygen species activate serine/threonine kinases including mitogen-activated protein kinase, p39 mitogen-activated protein kinase, Akt and protein kinase C [13,14].
Reactive oxygen species and hypertension in the absence of renal failure
There are several pieces of experimental evidence that increased oxidative stress contributes to the pathogenesis of hypertension. Hypertensive Dahl rats had significantly higher plasma hydrogen peroxide concentrations and superoxide radicals in microvessels of the mesentery compared to their normotensive counterparts [15]. Spontaneously hypertensive rats showed higher blood pressure and increased excretion of 8-isoprostaglandin F2alpha, which is thought to be formed nonenzymatically from the attack of superoxide radical on arachidonic acid. Long-term administration of superoxide scavenger tempol in the drinking water for 2 weeks reduced blood pressure and excretion of 8-isoprostaglandin F2alpha. These data indicate that superoxide radicals contribute to the development of hypertension in such rats [16]. The oral administration of buthionine sulfoxime, an inhibitor of glutathione synthase, to SpragueDawley rats increased blood pressure, reduced antioxidative tissue glutathione content, and increased tissue nitrotyrosine abundance, a marker of NO inactivation by reactive oxygen species. These data indicate that increased oxidative stress after glutathione depletion causes hypertension [17]. In the kidneys of spontaneously hypertensive rats an increase in p47phox and p67phox expression could be detected [18]. Angiotensin II infusion increased blood pressure and superoxide radical production in rats. The p22phox expression and NAD(P)H oxidase activity in rat aorta were increased in angiotensin II-induced hypertension [19]. Interestingly, the hydroxymethylglutaryl-coenzyme A reductase inhibitor, simvastatin, prevented the development of hypertension together with the inhibition of reactive oxygen species production in SpragueDawley rats infused with angiotensin II [20]. Angiotensin II infusion for 7 days increased systolic blood pressure in six wild-type mice from 105 ± 2 to 151 ± 6 mmHg and increased vascular superoxide radical production. On the other hand, angiotensin II infusion in six p47phox-deficient mice increased systolic blood pressure only from 96 ± 6 to 122 ± 4 mmHg without changing vascular superoxide radical production. These data indicate that angiotensin II-induced hypertension in mice depends at least partially on the presence of the p47phox subunit of NAD(P)H oxidase [21].
In humans, multiple regression analysis showed a significant correlation between mean blood pressure and oxidative stress in polymorphonuclear leucocytes [22]. In human internal mammary arteries and saphenous veins the administration of apocynin, an inhibitor of NAD(P)H oxidase that impedes assembly of the p47phox subunit with the membrane complex, reduced superoxide radical generation and caused vasorelaxation [23]. The endothelium-dependent acetylcholine-induced vasodilation was significantly reduced in patients with essential hypertension compared to normotensive control subjects. The administration of vitamin C enhanced the acetylcholine-induced vasodilation in hypertensive patients aged >30 years. These data point to the role of increased reactive oxygen species and vasoconstriction in patients with essential hypertension due to endothelial dysfunction and/or reduced vasodilator activity [24]. The response of forearm blood flow to acetylcholine, an endothelium-dependent vasodilator, was significantly improved after renal artery angioplasty in patients with renovascular hypertension. Angioplasty decreased systolic and diastolic blood pressure, plasma renin activity and plasma angiotensin II levels, serum malondialdehyde-modified low density lipoprotein, and urinary excretion of 8-hydroxy-2'-deoxyguanosine, indicating that oxidative stress is increased in patients with renovascular hypertension [25].
Reactive oxygen species and hypertension in uraemia
Several studies have revealed evidence of increased oxidative stress in chronic renal failure. Increased reactive oxygen species [26], elevated plasma lipid oxidation products, increased F2-isoprostanes, which are products of radical-induced peroxidation reactions of arachidonic acid, increased plasma protein 3-chlorotyrosine, a biomarker of myeloperoxidase-catalysed oxidation, depressed antioxidant capacity including impaired antioxidative enzyme systems have been reported in chronic renal failure [27]. Hypertension is a common complication of chronic renal failure. Renal hypertension may be caused by several factors including extracellular fluid volume expansion, increased sympathetic activity, elevated endothelin production, enhanced local or systemic reninangiotensin system activity, and accumulation of Na,K-ATPase inhibitors and Ca2+-ATPase inhibitors (Figure 1).
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In humans, acetylcholine-induced vasodilation has been shown to be reduced in resistance vessels of subcutaneous fat biopsies from patients with end-stage renal failure [31]. Measurements of blood flow using forearm plethysmography showed reduced vasodilation in response to carbachol (endothelium-dependent vasodilator) in both pre-dialysis patients and uraemic patients on continuous ambulatory peritoneal dialysis with a preserved response to sodium nitroprusside (endothelium-independent vasodilator) [32]. The endothelium-dependent vasodilation evaluated by forearm blood flow measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine was significantly reduced in patients with chronic renal failure compared to controls [33].
In conclusion, oxidative stress is an important pathogenic factor in patients with impaired renal function that at least partially causes uraemic hypertension.
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