Oxidative Stress And Hypertension Pdf
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- Oxidative stress and hypertension: Possibility of hypertension therapy with antioxidants
- Oxidative Stress and Essential Hypertension
- Oxidative Stress and Essential Hypertension
Quynh N. Dinh, Grant R. Drummond, Christopher G. Hypertension is a complex condition and is the most common cardiovascular risk factor, contributing to widespread morbidity and mortality. Hypertension is associated with inflammation; however, whether inflammation is a cause or effect of hypertension is not well understood.
Oxidative stress and hypertension: Possibility of hypertension therapy with antioxidants
Experimental evidence supports a pathogenic role of free radicals or reactive oxygen species ROS in the mechanism of hypertension. However, oxidative stress can be involved in the occurrence of endothelial dysfunction and related vascular injury.
Thus, ROS activity could trigger pathophysiological cascades leading to inflammation, monocyte migration, lipid peroxidation, and increased deposition of extracellular matrix in the vascular wall, among other events. In addition, impairment of the antioxidant capacity associates with blood pressure elevation, indicating potential role of antioxidants as therapeutic antihypertensive agents. Nevertheless, although increased ROS biomarkers have been reported in patients with essential hypertension, the involvement of oxidative stress as a causative factor of human essential hypertension remains to be established.
The aim of this chapter is to provide a novel insight into the mechanism of essential hypertension, including a paradigm based on the role played by oxidative stress. Update on Essential Hypertension. Hypertension is a major risk factor for cardiovascular disease [ 1 ]. Recently, a growing body of evidence has involved oxidative stress in the mechanism of development of hypertension.
Indeed, reactive oxygen species ROS contribute to regulating the biological processes occurring in the vascular wall, both in normal physiological conditions, as well as in the occurrence of hypertension [ 2 — 4 ].
Available evidence of the contribution of oxidative stress in the pathogenesis of human hypertension includes enhancement of ROS production, together with decreased bioavailability of both nitric oxide NO and antioxidants.
Furthermore, mechanical stimuli known to occur in blood pressure elevation further contribute to increased ROS production. The regulation of vasomotor tone depends upon a delicate balance between vasoconstrictor and vasodilator forces, the latter being likely to be modulated by oxidative stress.
The present study was aimed to present an update of the available studies related to the role of oxidative stress in the mechanism of development of blood pressure elevation, as well as the role of antioxidants in the prevention or treatment of this derangement. The response to cardiovascular risk factors is expressed in alterations of endothelial function, a chronic inflammatory process characterized by loss of antithrombotic factors and an increase in vasoconstrictor and prothrombotic products, thus elevating the risk of cardiovascular events.
Consequently, an impairment of the ability of endothelium to induce vasodilation leads to hypertension. Recently, it has been argued that ROS play a key role in this pathological process. The occurrence of oxidative stress is due to an imbalance between ROS generation and the antioxidant potential in the body, the latter being overwhelmed by the increased ROS concentration in the steady state.
It should be noted that although ROS are mediators of normal biological effects related to vascular function at the cell level, the increased levels of these species can give rise to pathological changes, as those observed in cardiovascular disease. Accordingly, increased ROS concentration has been demonstrated both in patients with essential hypertension and in various animal models of hypertension [ 8 — 12 ].
In addition, this derangement is accompanied by a decreased antioxidant potential [ 13 ]. Therefore, these data provide evidence of the involvement of vascular oxidative stress in the mechanism of development of essential hypertension [ 2 , 3 , 14 ].
In the vascular wall, as well as in the kidney, superoxide anion is mainly produced enzymatically through NOX activity; consequently, the upregulation of this enzyme exerts an important pathogenic role in the development of renal dysfunction and vascular damage [ 12 , 21 ].
The latter induces downregulation of prostacyclin synthase, further allowing the development of hypertension. Finally, oxidative stress leads to eNOS uncoupling [ 16 , 22 ]. Therefore, several effects contribute to the impairment of endothelial function related to oxidative stress. Thus, NOX activation in the vascular wall results in several effects contributing to the mechanism of development of hypertension [ 23 ]. Deficiency or oxidation of either of these two factors will result in decreased NO production.
Furthermore, peroxynitrite is formed through the reaction between NO and superoxide [ 24 ]. The activity and function of eNOS are changed due to the peroxidant ability generated by peroxynitrite, and this enzyme produces more superoxide instead of NO [ 22 , 25 ].
This enzyme system provides an important endothelial source of superoxide in the vascular wall [ 23 , 26 ]. It has been reported that spontaneously hypertensive rats demonstrate increased levels of both endothelial XO activity and ROS production, together with increased arteriolar tone [ 21 ]. The mitochondrion could behave as both a ROS source and target.
Superoxide is produced in the intermembrane space, but it is rapidly carried to the cytoplasm [ 28 ]. Either ubiquinol or coenzyme Q could be a source of superoxide when these mitochondrial components are partially reduced; but these molecules behave as antioxidants when they are fully reduced [ 29 ].
Superoxide produced by mammalian mitochondria in vitro mostly comes from complex I. In addition, it was found that patients with hypertension show reduced activity of antioxidant enzymes [ 30 ]. In response to mechanical and hormonal stimuli, the endothelium releases agents participating in the regulation of vasomotor tone.
Particularly relevant is the ability of endothelium to exert a protective role through the generation of vasorelaxing factors.
It is of interest considering that the adventitia can also participate in the development of hypertension, which is achieved through ROS contribution in either reduction of NO bioavailability or vascular remodeling.
NO plays a key role as a paracrine regulator of vascular tone. The effect of decreased NO bioavailability is particularly relevant, leading to reduction of vasodilatory capacity in the vasculature, thereby providing a mechanism of hypertension.
It is of interest to mention that NO diffuses easily to the adjacent VSMC, thus binding to receptors such as soluble guanylyl cyclase. It should be remarked that reduced NO levels can be the result of its combination with superoxide to form peroxynitrite, a compound capable of enhancing oxidative stress by oxidizing BH4, destabilizing eNOS, and producing more superoxide [ 22 , 24 , 25 ].
Consequently, ROS levels and oxidative stress biomarkers may appear normal despite the occurrence of an oxidative challenge. However, the consequences of oxidative stress will be apparent when ROS production becomes overwhelming and the compensatory mechanisms are inadequate, thus explaining the pathophysiological consequences [ 38 ]. Pharmacological inhibition of ACE by captopril and enalapril prevented blood pressure rise in young spontaneously hypertensive rats. The hypotensive effect of captopril is higher than that of enalapril, which could be due to the antioxidant role of its thiol group [ 39 ].
Vascular endothelium, among others vascular tissues, produces potent vasoconstrictor isopeptides known as endothelins. ETB induces relaxation on endothelial cells [ 42 ].
It acts through the activation of NOX. UT receptors have been identified in several other organs besides vascular bed, suggesting that vasoconstriction is not its only effect [ 44 , 45 ]. VSMC proliferation is stimulated by norepinephrine. PGI2 is considered one of the most important vasodilators depending on the endothelium and relaxes the vascular musculature. A large amount of substances that generate an increase in PGI2 release have been described, such as thrombin, arachidonic acid, histamine, and serotonin.
Prostaglandin H2 is formed by the prostaglandin H2 synthase, which uses arachidonic acid as a substrate. Then, prostaglandin H2 is converted to PGI2, a vasoactive molecule. It has been demonstrated that peroxynitrite inhibits the enzymatic activity of prostacyclin synthase.
It has been proposed that homocysteine plays an important role in the pathophysiology of primary hypertension [ 3 ]. An increase in homocysteinemia augments the proliferation of VSCM, thus altering the elasticity of vascular wall; it generates an oxidative stress state and diminishes NO bioavailability, thus impairing vasodilation. All the mechanisms exposed contribute to elevated blood pressure [ 47 ].
Homocysteine could also lead to endothelium oxidative damage [ 3 ]. The administration of vitamins B6, B12, and folic acid has been proposed as a potential adjuvant treatment in hypertension, probably by correcting the increased homocysteinemia [ 3 , 48 ].
Despite the above mentioned, further randomized controlled trials are required to establish the efficacy of these therapeutic agents in the treatment of hypertension.
Schematic summary of the role of vascular oxidative stress in the pathogenesis of hypertension. It has been described that this antioxidant could act as an enzyme modulator on the vascular wall, upregulating eNOS and downregulating NOX [ 51 ]. An inverse relationship between vitamin C plasma levels and arterial pressure in both healthy and hypertensive population has been demonstrated in several studies [ 15 ].
Antioxidant supplementation improves vascular function and reduces blood pressure in both experimental models [ 52 , 53 ] and in patients [ 54 , 55 ]. Ascorbate may improve vasodilation, probably by increasing NO bioavailability [ 56 — 58 ]. The absence of antihypertensive effect observed in trials using the administration of ascorbate could be due to the lack of consideration of its pharmacological characteristics, mainly pharmacokinetics.
It was determined in experimental conditions that the antihypertensive effect of ascorbate is reachable at a plasma concentration of 10 mM [ 57 ]. This concentration allows ascorbate to efficiently compete against the reaction between NO and superoxide, which is increased in oxidative stress—related conditions such as hypertension. The plasma level mentioned earlier is not reachable through oral administration of vitamin C. Daily oral doses of vitamin C between 60 and mg are sufficient for the renal ascorbate threshold to occur.
An epidemiological association between high dietary vitamin E intake and a lower incidence of cardiovascular disease has been established [ 58 ].
Interestingly, some studies fail to demonstrate the beneficial effects of vitamin E in cardiovascular disease patients [ 66 — 69 ]. Moreover, one trial proving vitamin E supplementation showed an increase in blood pressure and cardiac frequency in type 2 diabetes patients [ 70 ]. Probably, vitamin E by itself is unlikely to achieve enough levels to counteract all components of oxidative stress acting in primary hypertension [ 71 ]. In fact, both antioxidants may act synergistically to generate appropriate conditions for NO synthesis in endothelium [ 73 ].
Therefore, the association between vitamins C and E provides a reinforcement of their biological properties in a synergistic manner and could lead to a significant antihypertensive effect; however, further studies are required [ 74 ]. However, most of these studies have some serious methodological bias, mainly lack of rigorous exclusion criteria [ 76 ]. XO has been proposed as an important enzymatic source of free radicals in the endothelium [ 24 ].
It produces uric acid by catalyzing the two final steps of purine metabolism. It has been demonstrated that XO activity is positively correlated with arteriolar tone and blood pressure [ 77 , 78 ]. Moreover, allopurinol, an XO inhibitor, is capable of improving endothelial function in some experimental models.
Despite the evidence supplied by small studies, a small number of randomized controlled trials have not demonstrated benefit using XO inhibitors [ 82 ].
Selenium is an essential trace element and a key part of several proteins. Several trials have proved the antioxidant properties of selenium [ 84 , 86 — 91 ]. In spontaneously hypertensive rats, selenium supplementation was associated with an increased antioxidant response and protection against cardiac oxidative injury, as well as a reduction in disease severity and mortality [ 92 ]. Therefore, it is plausible to propose that selenium deficiency could be an independent risk factor of cardiovascular disease, including hypertension [ 94 ].
NAC effectively prevents BH4 oxidation by the increased superoxide present in primary hypertension [ 97 ]. Besides this, NAC can protect against oxidative injury directly by scavenging ROS and inhibiting lipid peroxidation [ 98 , 99 ]. Polyphenols have been defined as the most abundant antioxidants in human diet.
They exert several protective mechanisms, including ROS scavenging, iron chelating and modulation of antioxidant enzymes [ , ]. In this regard, NO levels increase after the consumption of polyphenols by humans [ ].
Despite this, some studies using polyphenols and antioxidant vitamins have shown an increase in blood pressure [ ]. There is a growing amount of evidence supporting the view that oxidative stress is involved and plays a key role in the pathophysiology of primary hypertension.
In this regard, ROS act as mediators of the major physiological vasoconstrictors, increasing intracellular calcium concentration. In this review, we propose an integrative view of how oxidative stress is involved in the genesis of hypertension, mainly by reducing bioavailability of NO.
Oxidative Stress and Essential Hypertension
Experimental evidence supports a pathogenic role of free radicals or reactive oxygen species ROS in the mechanism of hypertension. However, oxidative stress can be involved in the occurrence of endothelial dysfunction and related vascular injury. Thus, ROS activity could trigger pathophysiological cascades leading to inflammation, monocyte migration, lipid peroxidation, and increased deposition of extracellular matrix in the vascular wall, among other events. In addition, impairment of the antioxidant capacity associates with blood pressure elevation, indicating potential role of antioxidants as therapeutic antihypertensive agents. Nevertheless, although increased ROS biomarkers have been reported in patients with essential hypertension, the involvement of oxidative stress as a causative factor of human essential hypertension remains to be established. The aim of this chapter is to provide a novel insight into the mechanism of essential hypertension, including a paradigm based on the role played by oxidative stress.
Hypertension is a major risk factor for myocardial infarction, heart failure, stroke, peripheral arterial disease, and aortic aneurysm, and is a cause of chronic kidney disease. Hypertension is often associated with metabolic abnormalities such as diabetes and dyslipidemia, and the rate of these diseases is increasing nowadays. Recently it has been hypothesized that oxidative stress is a key player in the pathogenesis of hypertension. A reduction in superoxide dismutase and glutathione peroxidase activity has been observed in newly diagnosed and untreated hypertensive subjects, which are inversely correlated with blood pressure. Hydrogen peroxide production is also higher in hypertensive subjects. Furthermore, hypertensive patients have higher lipid hydroperoxide production.
PDF | In the past 20 years, it has become clear that reactive oxygen species (ROS) contribute to the development of hypertension via myriad.
Oxidative Stress and Essential Hypertension
Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. Baradaran and H. Nasri and M. Baradaran , H.
Reactive oxygen species play a key role in the formation of endothelial dysfunction accompanying diabetes mellitus, hypertension, and other cardiovascular diseases. The combination of hypertension and diabetes is accompanied by higher oxidative stress than that seen with either disorder alone. The term oxidative stress refers to the state in which cells are exposed to excessive levels of molecular oxygen or reactive oxygen species ROS. Accumulating evidence suggests that oxidative stress alters many functions of the endothelium, including modulation of vasomotor tone.
Role of oxidative stress in cardiovascular diseases View all 7 Articles. Endothelial dysfunction is the hallmark of hypertension, which is a multifactorial disorder. In the cardiovascular system reactive oxygen species play a pivotal role in controlling the endothelial function and vascular tone.
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