Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension

The present review examines the clinical and experimental data to support the view that homocysteine and oxidative stress, two alternative risk factors of vascular disease, may play a role in the pathogenesis of primary or essential hypertension. Although the precise mechanism of this disease has not been elucidated, it may be related to impairment of vascular endothelial and smooth muscle cell function. Thus, the occurrence of endothelial dysfunction could contribute to alterations of the endothelium-dependent vasomotor regulation. Hyperhomocysteinemia limits the bioavailability of nitric oxide, increases oxidative stress, stimulates the proliferation of vascular smooth muscle cells, and alters the elastic properties of the vascular wall. The link between oxidative stress and hyperhomocysteinemia is also biologically plausible, because homocysteine promotes oxidant injury to the endothelium. Cumulated evidence suggests that the diminution of oxidative stress with antioxidants or the correction of hyperhomocysteinemia with vitamins-B plus folic acid, could be useful as an adjuvant therapy for essential hypertension. Further studies involving long-term trials could help to assess the tolerability and efficacy of the use of these therapeutic agents.     

原发性高血压患者血浆同型半胱氨酸与血管内皮功能的关系

目的研究原发性高血压患者血浆同型半胱氨酸(Hcy)与肱动脉血流介导的内皮依赖性血管舒张功能(FMD)的关系。方法选择单纯高血压患者62例、高血压合并高同型半胱氨酸血症(H型高血压)患者61例及健康体检者30名,采用无创性高分辨超声技术检测3组休息、反应性充血后肱动脉内径的变化。采用循环酶法检测血浆Hcy水平。结果单纯高血压组、H型高血压组FMD均低于对照组(P<0.05),H型高血压组FMD最低(P<0.05);直线相关分析显示,Hcy与FMD呈负相关(r=-0.607,P<0.01);校正年龄、性别、Hcy、收缩压(SBP)、舒张压(DBP)、体质量指数(BMI)、空腹血糖(FPG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)等因素后,Logistic回归分析发现Hcy、SBP、DBP为FMD的影响因素(均P<0.05)。结论原发性高血压患者血浆Hcy与FMD呈负相关,Hcy可能参与了原发性高血压患者内皮功能障碍的发生与发展。     

Homocysteine and cerebral stroke in developing countries

Two-thirds of stroke deaths worldwide occur in developing countries. The higher prevalence of undernutritional states and parasitic infestations in many of these countries could lead to vitamin B(12) and folate deficiencies. Hyperhomocysteinemia, a proxy measure for the nutritional status of B vitamins, has been reported in many developing countries and is found to be associated with nutrition-related low plasma folate and vitamin B(12). Several epidemiological observations have linked hyperhomocysteinemia to increased risk for stroke. The exact molecular mechanism by which homocysteine promotes atherothrombosis is not clear, although several possible roles have been suggested. Homocysteine is believed to cause atherogenesis and thrombogenesis via endothelial damage, focal vascular smooth muscle proliferation probably causing irregular vascular contraction, and coagulation abnormalities. Supplementation with the nutrient cofactors required for optimal functioning of the homocysteine metabolic pathways significantly impacts plasma homocysteine levels, and offers a new integrated possibility for prevention of stroke in the underdeveloped and rapidly developing countries.     

The vasoactive role of nitric oxide: physiological and morphological aspects

Nitric oxide (NO) participates in the control of the cardiovascular system where two constitutive isoforms of NO-synthase were discovered: endothelial and neuronal. Both isoforms were observed in various cells, however, endothelial NO-synthase is predominantly present in the endothelium. Injury of the endothelium disturbs the balance between vasodilation and vasoconstriction and triggers different pathological alterations. In addition, whereas the intact endothelium protects vascular smooth muscle from oxidative attack, intervention in the vascular wall integrity increases the concentration of vascular superoxides, thus disturbing the effects of NO. To preserve NO-mediated vasorelaxation, different reserve mechanisms have developed. In case of damage of some endothelial receptor type, vasodilation could be ensured by activation of some other type of the present receptors. Moreover, morphological evidence demonstrated that both isoforms of NO-synthase were expressed also in smooth muscle cells and functional studies revealed that different pathological interventions in endothelial function (such as oxidative stress or hypertension) were associated with NO generation in the vascular media. In this case, the generation of NO by vascular smooth muscle may represent a physiologically relevant compensation of endothelial NO deficiency. Whereas long-term inhibition of endothelial NO-synthase resulted in an unequivocal pattern of cardiovascular changes, inhibition of neuronal NO-synthase led to opposite effects, suggesting a specific position of neuronal NO-synthase in the regulation of cardiovascular tone. The specificity of endothelial or neuronal NO function seems to be related to a particular circulatory area and it is presumably determined by mutual interactions with other regulatory systems (sympathoadrenergic, renin-angiotensin, etc.).     

Homocysteine and arterial disease. Experimental mechanisms

Hyperhomocysteinemia (hH(e)) in the general population is associated with incidence and progression of arterial occlusive disease, although the underlying mechanisms are not well defined. Current research supports a role for homocysteine (H(e))-mediated endothelial damage and endothelial dysfunction. This mechanism appears to be a key factor in subsequent impaired endothelial-dependent vasoreactivity and decreased endothelium thromboresistance. These consequences may predispose hyperhomocysteinemic vessels to the development of increased atherogenesis. Additional mechanisms of H(e)-mediated vascular pathology, including protein homocysteinylation and vascular smooth muscle cell proliferation may also play a role. Continued investigation into the mechanisms contributing to H(e) toxicity will provide further insight into the processes by which hH(e) may increase atherosclerosis.     

Venous function in hypertension

The results described in this review clearly demonstrate that venous extensibility, contractility and prostaglandin synthesis are altered in veins from hypertensive animals and man. Similarly, venous smooth muscle compliance seems to be impaired in human essential and experimental animal hypertension. Decreased venous compliance and enhanced venous contractility may account for the transient increase in cardiac output observed during the labile phase of hypertension. Alterations in venous contractility may reflect intrinsic changes in the vascular smooth muscle later in the hypertensive process. Alternatively, the veins may respond sooner to a circulating humoral stimulus which will subsequently modify arterial smooth muscle function, or to which the arteries are unresponsive. Therefore, the study of venous and arterial smooth muscle function during the development of the hypertensive process could well identify the site, and perhaps, stimulus for the initial changes that occur in hypertension. Similarly, a study of venous and arterial smooth muscle function in hypertension can adequately define those changes intrinsic to the high blood pressure and those secondary to the increased vascular pressure of the hypertension. Therefore, analysis of the type, mechanism and sequence of venous changes which occur in hypertension can provide insight into rational drug therapy to treat the cause, and not the symptoms, of hypertensive vascular disease.     

Glucocorticoids and vascular reactivity

Corticosteroid hormones play an important role in the control of vascular smooth muscle tone by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. Increased cortisol response has been associated with an increase in arterial contractile sensitivity to norepinephrine and vascular resistance. Glucocorticoids regulate vascular reactivity by acting on both endothelial and vascular smooth muscle cells. Both glucocorticoid receptor protein and mRNA have been identified in endothelial and vascular smooth muscle cells. In endothelial cells. glucocorticoids suppress the production of vasodilators. such as prostacyclin and nitric oxide. In vascular smooth muscle cells. glucocorticoids enhance agonist-mediated pharmacomechanical coupling at multiple levels. The effect of glucocorticoids on vascular reactivity is regulated by 11 beta-hydroxysteroid dehydrogenase (11beta-SD). The presence of 11beta-HSD in many tissues suggests that it modulates the access of corticosteroids to their receptors at both renal and extra-renal sites. The two 11beta-HSD isozymes catalyze the interconversion of cortisol and cortisone. Type 11beta-HSD has bidirectional activity, while the type 2 mainly converts cortisol into cortisone, the biologically inactive form. Both type 1 and type 2 11beta-HSD have been found in vascular endothelial and smooth muscle cells, suggesting that abnormal 11B-HSD expression may play a pathogenic role in the common forms of hypertension. In this article, we review possible mechanisms involved in the glucocorticoid-mediated potentiation of vascular reactivity, its regulation by 11beta-HSD, and their physiological and pathophysiological significance.     

Serotonin and the vascular system. Role in health and disease, and implications for therapy

Serotonin released from aggregating platelets can reach sufficient concentrations to affect local vascular function in a number of ways. The monoamine can cause contraction of blood vessels by its direct action on smooth muscle or by potentiating the effect of other vasoconstrictor agents. It can also induce vasodilatation by a direct relaxing effect on smooth muscle, by inhibition of adrenergic nerves, and by release of an uncharacterized relaxing factor from endothelial cells. One of its most likely physiological roles is to aid in haemostasis by promoting platelet aggregation and by causing local vasoconstriction at sites of injury. It probably has a role in some forms of vascular pathology as well: it may contribute to vasospasm of cerebral, coronary, and digital arteries, particularly if there is endothelial dysfunction or damage. Much evidence has implicated serotonin (5-hydroxytryptamine) in the pathogenesis of migraine. Serotonergic agonists, such as ergotamine, and antagonists, such as methysergide and pizotifen, are both used in therapy of migraine. Promising but conflicting early results have not yet defined a place for serotonergic antagonists in other vasospastic disorders. The antihypertensive efficacy of one serotonergic antagonist, ketanserin, raises questions about the possible involvement of serotonin in either the initiation or the maintenance of the elevated peripheral vascular resistance in several forms of hypertension, including essential hypertension.     

Glucocorticoids induce endothelin release from vascular smooth muscle cells but not endothelial cells

Vascular smooth muscle cells in culture are capable of secreting endothelin which is a vasoconstrictor and mitogenic peptide. The effect of glucocorticoids on endothelin release from vascular smooth muscle cells of the rat and rabbit aortas was investigated. Micromolar concentrations of dexamethasone and cortisol caused a 2 to 5-fold increase in endothelin release from the two smooth muscle cell types but no such response was observed in endothelial cells of the bovine aorta. Glucocorticoids appear to selectively induce endothelin release from vascular smooth muscle cells and this may be relevant to glucocorticoid-induced hypertension.     

EVIDENCE FOR A ROLE FOR THE CARDIOVASCULAR AMPLIFIERS IN HUMAN PRIMARY HYPERTENSION

1. Hypertrophy of vascular and cardiac smooth muscle is present in human primary hypertension. The amplifier properties associated with hypertrophy play a major role in maintaining hypertension. 2. Long-term antihypertensive drug therapy causes substantial regression of the structural changes, assessed by the non-autonomic component of vascular resistance, and by left ventricular mass. The latter occurs more slowly. 3. The more complete the reversal of left ventricular hypertrophy, the more slowly hypertension redevelops if long-term antihypertensive therapy is discontinued. 4. Subjects who redevelop hypertension more rapidly tend to have higher cardiac output, suggesting that the cardiac amplifier may play a role in the pathogenesis. 5. Studies of small arteries and of veins from patients with primary hypertension suggest that there may be a general disturbance of vascular smooth muscle function, independent of the mechanical effects of elevated systemic blood pressure.     

Calcium antagonists. Clinical use in the treatment of systemic hypertension

Increased peripheral vascular resistance is the cause of elevated systemic blood pressure in most patients with long standing hypertension. The desired haemodynamic effect in antihypertensive therapy is dilation of the constricted arterioles by a drug that acts directly on the vascular smooth muscle while not affecting the heart or the venous return. Hydralazine, diazoxide and minoxidil act directly on vascular smooth muscle to produce vasodilatation and have been used with variable degrees of success in the long term treatment of hypertension. Their cellular mechanism of dilation is not understood fully, but the ability to chelate certain trace metals required for smooth muscle contraction has been proposed as a possible mechanism of action for these drugs. The calcium antagonists (calcium entry blocking drugs) are a distinct group of compounds that interfere with the normal transmembrane flux of extracellular calcium ions on which vascular tissue depends for contraction or impulse generation. Thus, calcium anti-agonists can reduce the contractile activity of the heart, and promote coronary and systemic vasodilatation. These effects provide the clinical rationale for the use of calcium antagonists in the management of ischaemic heart disease and hypertrophic cardiomyopathy. Since systemic vasodilatation can be expected to reduce elevated arterial blood pressure, interest has focused recently on calcium antagonists in the medical management of systemic hypertension. All the calcium antagonists are able, in low concentrations, to relax the smooth muscle vasculature from coronary, cerebral, mesenteric, and renal arteries. The effects on the myocardium, cardiac impulse tissue, and vascular smooth muscle are different in magnitude, however, depending on the individual agent that is used. Clinical experience in the treatment of hypertension with this class of agents is confined to verapamil, nifedipine, and diltiazem. In this article, the scientific rationale for using calcium antagonists in the treatment of arterial hypertension is explored and the clinical experiences with the different calcium antagonists used in hypertension are reviewed.     

Relationships between the endothelin and nitric oxide pathways

1. In the normal blood vessel, the vascular endothelium regulates the tone of the underlying smooth muscle and the reactivity of blood elements, such as platelets and neutrophils, by the release of mediators, in particular nitric oxide (NO) and endothelin-1 (ET-1). 2. Nitric oxide is a potent vasodilator that also inhibits platelet and neutrophil aggregation and adhesion; ET-1 is the most potent mammalian vasoconstrictor peptide yet found. Recently, much research effort has focused on examining the interactions between these two important mediators. At a simple level, ET-1 acts on specific receptors on the endothelium to increase the release of NO, while NO depresses the production and/or release of ET-1 from endothelial cells. 3. While ET-1 appears to have a relatively small influence on the basal regulation of blood pressure, NO appears central. For example, inhibition of NO production in normotensive animals produces a marked elevation in blood pressure. 4. Conversely, numerous vascular disease states have been associated with elevations in the production and/or release of ET-1 and it has been implicated in the deleterious changes associated with ischaemia-reperfusion injury, subarachnoid haemorrhage and hypertension. In these conditions, NO production may also be increased by the induction of NO synthetic pathways within the vascular smooth muscle. Endothelin-1 may also be produced by the vascular smooth muscle under similar circumstances. 5. Therefore, in pathological states, a new balance between NO and ET-1 production may be central to changes in blood vessel reactivity, smooth muscle proliferation and blood coagulability.     

血管平滑肌细胞的内皮依赖性超极化(英文)

In response to various neurohumoral substances en-dothelial cells release nitric oxide (NO) and prostacy-clin, and produce hyperpolarization of the underlying vascular smooth muscle cells, possibly by releasing another factor termed endothelium-derived hyperpolarizing factor (EDHF). NO and prostacyclin stimulate smooth muscle soluble guanylate and adenylate cyclase respectively and can activate, depending on the vascular tissue studied, ATP-sensitive potassium ( KATP) and large conductance calcium-activated potassium channels (BKca). Furthermore, NO directly activates BKca. In contrast to NO and prostacyclin, EDHF-mediated responses are sensitive to the combination of charybdotox-in plus apamin but do not involve KATP or BKca. As hyperpolarization of the endothelial cells is required to observe endothelium-dependent hyperpolarization, an electric coupling through myoendothelial gap junctions may explain the phenomenon. An alternative explanation is that the hyperpolarization of the endothelial cells cau     

Recent advances in the study of endothelium-dependent hyperpolarizing factor (EDHF)

Recent advances in the properties and physiological functions of endothelium-dependent hyperpolarizing factor (EDHF) in vascular tissues were reviewed briefly. The EDHF-induced hyperpolarization is inhibited by charybdotoxin, indicating that the potential is produced mainly by activation of intermediate conductance Ca-sensitive K-channels. During generation of EDHF responses, endothelial Ca2+ concentration was elevated, suggesting that the activated K-channels were distributed on the endothelial membrane. This was confirmed by direct recording of membrane potentials from endothelial and smooth muscle cells using double patch electrodes. Measurement of the propagation of potentials applied to endothelial or smooth muscle cells to surrounding cells revealed that there were tight electrical connections between endothelial cells much more than between endothelial and smooth muscle cells or between smooth muscle cells, and these observations yielded a possible spread of electrical signal along the endothelial layer first, and then the signals would be conducted to smooth muscle cell layers. These properties of vascular tissues allow speculating that EDHF is an electrical signal propagated from endothelial cells electrotonically through myoendothelial gap junctions. Several candidates have been proposed as EDHF, and possibilities of individual substances for EDHF were discussed. The cellular mechanism of the hyperpolarization-induced vasodilatation remains unclear, and this should be clarified in the future for further understanding of the EDHF-induced vasodilatation.     

Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells.

Endothelins, nitric oxide, and oxygen-derived free radicals decisively regulate vascular tone. An imbalance in the biosynthesis of these substances in pathophysiologic conditions may trigger vasospasm and promote the development of atherosclerosis. Previous studies have shown that oxygen-derived free radicals can increase the synthesis of endothelin-1 in cultured endothelial cells. Interestingly, conditions of increased oxidative stress within smooth muscle cells as induced by angiotensin II infusion or hypercholesterolemia have been shown to be associated with increased autocrine synthesis of endothelin-1. Because endothelin-1 formed in smooth muscle cells can trigger hypersensitivity to vasoconstrictors, we tested whether oxidative stress per se may affect endothelin expression in vascular smooth muscle cells. Cultured human coronary artery smooth muscle cells were exposed to oxidative stress generated by the xanthine/xanthine oxidase reaction or by hydrogen peroxide. Preproendothelin-1 mRNA content was quantitated by means of quantitative polymerase chain reaction and endothelin-1 protein was measured by radioimmunoassay. Incubation with xanthine/xanthine oxidase significantly increased preproendothelin-1 mRNA synthesis, whereas GAPDH remained unchanged. Likewise, xanthine/xanthine oxidase also led to a dose-dependent increase of intracellular endothelin-1. The increase in ET-1 expression induced by xanthine/xanthine oxidase was significantly inhibited by superoxide dismutase but not by catalase. We conclude that oxygen-derived free radicals can stimulate the synthesis of endothelin-1 in endothelial and vascular smooth muscle cells by increasing preproendothelin-1 mRNA content and that this effect is mediated predominantly by superoxide anions. We therefore have identified a new mechanism in the interaction of oxidative stress and endothelin-1 expression in smooth muscle cells that may have important implications in diseases such as atherosclerosis and hypertension.     

Arginase: a critical regulator of nitric oxide synthesis and vascular function

1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.     

Cytochromes P450, vascular tone varicosis

Chronic venous insufficiency is a complex pathology that is characterised by various symptoms such as venous hypertension, endothelium dysfunction, vascular wall remodelling due to smooth muscle cell hypertrophy and inflammation resulting from the release of pro-inflammatory cytokines from invading leucocytes. Age, hormonal excess, multiparity, sedentariness and prolonged heat exposure represent the main risk factors among many others including hypoxia and shear stress which also influence varicose pathology. Some members of the large cytochrome P450 (CYP) family that are involved in the biotransformation of steroids and arachidonic acid have been shown to be expressed in various cell types (endothelial cells, smooth muscle cells, macrophages) of cardiovascular tissues. The vascular metabolites produced by CYPs are important factors in the regulation of the vascular tone. Most CYPs are markedly expressed in all the cell types of varicose veins in relation to the overall vascular remodelling associated with smooth muscle hypertrophy and periendothelial leucocyte infiltration. Because CYPs produce various vasoactive arachidonic acid metabolites, their increased expression could play a role in the impairement of the vascular tone which is characteristic of varicose veins. Furthermore, polymorphisms, particularly the CYP3A5 polymorphism, may promote changes in the level of expression of CYPs and thus may influence varicose vein formation or functions. This suggests that CYP modulators could be potentially active drugs to treat chronic venous insufficiency symptoms and control its evolution.     

Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction

Hyperhomocyst(e)inemia is associated with an increased risk for atherosclerotic disease and venous thromboembolism. The impact of elevated plasma homocysteine levels seems to be clinically relevant, since the total cardiovascular risk of hyperhomocyst(e)inemia is comparable to the risk associated with hyperlipidemia or smoking. There is substantial evidence for impairment of endothelial function in human and animal models of atherosclerosis, occurring even before development of overt plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of atherosclerotic lesion development and predicts future vascular events. NO is the most potent endogenous vasodilator known. It is released by the endothelium, and reduced NO bioavailability is responsible for impaired endothelium-dependent vasorelaxation in hyperhomocyst(e)inemia and other metabolic disorders associated with vascular disease. Substances leading to impaired endothelial function as a consequence of reduced NO generation are endogenous NO synthase inhibitors such as ADMA. Indeed there is accumulating evidence from animal and human studies that ADMA, endothelial function and homocyst(e)ine might be closely interrelated. Specifically elevations of ADMA associated with impaired endothelium-dependent relaxation were found in chronic hyperhomocyst(e)inemia, as well as after acute elevation of plasma homocyst(e)ine following oral methionine intake. The postulated mechanisms for ADMA accumulation are increased methylation of arginine residues within proteins, as well as reduced metabolism of ADMA by the enzyme DDAH, but they still need to be confirmed to be operative in vivo. Hyperhomocyst(e)inemia, as well as subsequent endothelial dysfunction can be successfully treated by application of folate and B vitamins. Since ADMA seems to play a central role in homocyst(e)ine-induced endothelial dysfunction, another way of preventing vascular disease in patients with elevated homocyst(e)ine concentrations could be supplementation with L-arginine to reverse the detrimental effects of ADMA.