Methylglyoxal, oxidative stress, and hypertension

Pathogenic mechanisms for essential hypertension are unclear despite striking efforts from numerous research teams over several decades. Increased production of reactive oxygen species (ROS) has been associated with the development of hypertension and the role of ROS in hypertension has been well documented in recent years. In this context, it is important to better understand pathways and triggering factors for increased ROS production in hypertension. This review draws a causative linkage between elevated methylglyoxal level, methylglyoxal-induced production of ROS, and advanced glycation end products in the development of hypertension. It is proposed that elevated methylglyoxal level and resulting protein glycation and ROS production may be the upstream links in the chain reaction leading to the development of hypertension.     

肠道菌群与高血压病主要危险因素的相关性及 中药干预研究现状

近年来国内、外文献报道高血压病的发生可能与肠道菌群失调相关。肠道菌群与高血压病主要危险因素(肥胖、高血脂、糖尿病、代谢综合征、动脉粥样硬化)具有一定的相关性,某些益生菌或其发酵产品可能通过改善肠道菌群的方式为高血压病的治疗提供新的思路和途径。近年来研究显示中药具有较长的肠道停留时间,从而有利于其发挥调节肠道菌群的作用,提示某些中药具有调节肠道菌群的作用。但目前国内、外尚无关于中药直接通过肠道菌群作用而干预高血压病的文献报道,而近年来国内有研究显示肠道菌群可能是中药干预高血压病主要危险因素的作用机制之一。     

Genetics of hypertension: From experimental animals to humans

Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.     

维生素D与高血压关系的研究进展

众所周知维生素D(VitD)在钙、磷代谢及骨重建中具有重要的作用。而近年来许多研究发现VitD与高血压、心力衰竭、缺血性心脏病和脑卒中等心血管事件的发生呈负相关,其具体机制尚不完全清楚,经过补充VitD可以预防或治疗高血压,VitD缺乏参与了高血压的形成,成了最近争论的焦点。故本文将对VitD和高血压相互关系的研究进展做一综述,为高血压的防治提供新的理论依据。     

Neurohumoral mechanisms of sodium-dependent hypertension

The contribution of neurohumoral factors to arterial pressure has been studied in several models of sodium-dependent hypertension including the deoxycorticosterone-saline, Dahl salt-sensitive rats, and reduced renal mass-saline. Observations from these animals have largely pointed to the sympathetic nervous system and arginine vasopressin (AVP) as the critical factors responsible for mediating the increased arterial pressure. Our work has indicated that the one-kidney, figure-8 renal wrap model of experimental hypertension is also sodium dependent. In these rats, prior sodium depletion prevented the development of hypertension whereas high sodium intake exacerbated the increase in arterial pressure. An activation of the sympathetic nervous system and increased AVP activity appeared to be responsible for the hypertension in rats maintained on normal and high sodium intake. Stimulation of the AVP and sympathetic nervous systems in sodium-dependent hypertension may be associated with a suppression of cardiovascular gamma-aminobutyric acid (GABA)-ergic function in the central nervous system. The inhibitory neurotransmitter, GABA, and an inhibitor of GABA uptake, nipecotic acid, lowered arterial pressure in a sodium-stimulated model of hypertension.     

Mechanisms of obesity-related hypertension.

Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension and cardiovascular disease. Although the importance of obesity as a cause of hypertension is well established, the molecular basis of the relationship between obesity and increased blood pressure remains poorly understood. This brief review examines the association between obesity and hypertension along with the mechanisms proposed to explain this association, while presenting evidence of a direct causal effect of adipose tissue in the development of hypertension through the involvement of the adrenal cortex.     

DOCA-salt hypertension in cats

The possibility of reproducing DOCA-salt hypertension in cats has been explored. It has been shown that administration of DOCA and sodium chloride may result in the development of a hypertensive condition in some of cats. Unilateral nephrectomy increases the probability of hypertension occurrence. To attain a steady and noticeable (up to 190 +/- 8/146 +/- 7 mm Hg) elevation of arterial pressure, it is necessary that appreciable amounts of DOCA and sodium chloride be administered for a long time (during 6 months) in the presence of unilateral nephrectomy. The hypertension thus induced is marked by the increased (71%) overall peripheral resistance and by the decreased cardiac output, which rises for a short period in the course of hypertension development.     

Hypertensive mechanisms: the role of altered smooth muscle and membrane function in the etiology of hypertension

The etiology of essential hypertension has been under intensive investigation for a number of years, and the availability of a number of rat models of this disease has aided our understanding of the relationship between abnormalities in cardiovascular regulatory function and hypertension. It is accepted that abnormalities at a number of levels of these regulatory processes could be the basis of the pathological process; however, the cause-effect relationship has not always been clearly established. This introduction addresses the potential relationship between a number of parameters and the control of blood pressure, and the Symposium attempts to relate altered smooth muscle and membrane function to hypertension.     

Undertreatment of hypertension and the risk of stroke in the oldest old

The benefit of pharmacological treatment of hypertension in the prevention of cardiovascular diseases has been established mainly in subjects younger than 80 years of age. The consequences of undertreatment of hypertension with regard to the occurrence of stroke was studied in the Netherlands. About 33% of the hypertensives younger than 80 years and 55% of the hypertensives older than 80 years were not pharmacologically treated, although they were 'candidates' for pharmacological treatment of hypertension. About 19% (n = 1350) of all strokes that occurred in the Netherlands in 1994 among hypertensives younger than 80 years may be attributable to untreated hypertension. Among hypertensives older than 80 years this percentage was 32% (n = 1345). Although the benefit of pharmacological treatment of hypertension in persons older than 80 years has not been established experimentally, the results suggest that a considerable proportion of the strokes among this group of hypertensives may be prevented.     

Role of endothelins in animal models of hypertension: focus on cardiovascular protection

Investigation of the regulation of vascular function by endothelium-derived factors has been a prominent topic of research in the field of hypertension during the last decade. Of the different endothelial factors, endothelins, which play an important role in vasodilatation-vasoconstriction balance, have been the subject of great interest and an impressive number of publications. This peptide, a very potent vasoconstrictor, triggers as well events involved in growth, proliferation, matrix production and local inflammation. In parallel, its role in hypertension has evolved from a simple vasoconstrictor to a central local regulator of vascular homeostasis contributing not only to the elevation of blood pressure, but also to the complications of hypertension. This review summarizes research on endothelins and its receptor antagonists in experimental hypertension, with special emphasis on vascular remodeling and target-organ protection.     

Hypertension developing in women using oral contraceptions]

Attention to the problem of hypertension in women using oral contraceptives has been increasing as the use of these preparations has increased. It is estimated that between 1-5% to 15-18% of those women using these preparations suffer from hypertension. Some sources have linked the occurrence of hypertension to a concentration of renin in the blood. It is not clear to this author, though, whether this is the result of some physiological disruption caused by the contraceptive, or caused by some other malfunction of this mechanism. The appearance of hypertension in the course of hormonal contraceptive use is considered to be an indication for the discontinuation of its use.     

Correction de l'hypertension intracranienne créée par compression mécanique directe du cerveau

An attempt has been made to correct cerebral hypertension induced by direct compression of the brain in a group of six dogs. The animals, which had been previously fitted with an inflatable subdural rubber balloon, were either kept eupneic (isolated mechanical hypertension) or deliberately hypoventilated (mixed mechanical and acidotic hypertension). In the first instance, administration of urea brought the intracranial pressure back to control values while, in the second case, injection of an amine buffer controlled only the acidotic component of intracranial hypertension.     

Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB

Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor κB (NF-κB) and its upstream activator IκB kinase-β (IKK-β, encoded by Ikbkb) in the mediobasal hypothalamus rapidly elevated blood pressure in mice independently of obesity. This form of hypothalamic inflammation-induced hypertension involved the sympathetic upregulation of hemodynamics and was reversed by sympathetic suppression. Loss-of-function studies further showed that NF-κB inhibition in the mediobasal hypothalamus counteracted obesity-related hypertension in a manner that was dissociable from changes in body weight. In addition, we found that pro-opiomelanocortin (POMC) neurons were crucial for the hypertensive effects of the activation of hypothalamic IKK-β and NF-κB, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-β and NF-κB in the mediobasal hypothalamus--particularly in the hypothalamic POMC neurons--is a primary pathogenic link between obesity and hypertension. Breaking this pathogenic link may represent an avenue for controlling obesity-related hypertension and CVD without requiring obesity control.     

Primary versus secondary structural changes of the blood vessels in hypertension

Various researchers have hypothesized that the thickening of the vascular wall plays an important role in the maintenance of hypertension. Such an alteration can increase the vascular resistance by exerting two effects. A thickened vascular wall could occlude the lumen of the blood vessel and (or) cause the artery to hyperreact to contractile stimuli. Until recently, it has been a general conclusion that such alterations were a secondary adaptation produced by the elevation of blood pressure. Consistent with this view, certain classes of larger arteries do exhibit a thickened vascular wall late during hypertension development and such changes can be prevented from occurring by antihypertensive treatment. However, recent studies involving the mesenteric and renal arteries of Wistar-Kyoto spontaneously hypertensive rats have shown that wall thickening of the vasculature occurs prior to hypertension development and is present even under conditions where the blood pressure has been normalized throughout the animal's life. These latter observations suggest that some structural alterations in the blood vessels observed in hypertension are pressure independent and could be of etiological importance in the initiation of hypertension.     

Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats

Background

CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood.

Methods

In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats.

Results

We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats.

Conclusions

The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment.     

Renal nerves and hypertension: an update

Increased efferent renal sympathetic nerve activity could facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the deoxycorticosterone acetate-salt-treated rat, which suggests that these responses result from, at least in part, loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in humans. The efferent renal sympathetic nerves play a diminishing role once hypertension is established in these models. Renal denervation in established one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not caused by changes in renin activity or sodium excretion but is associated with decreased sympathoadrenal activity. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. Interruption of afferent renal fibers also appears to be the mechanism by which renal denervation prevents or reverses the normal increase in arterial pressure seen after aortic baroreceptor deafferentation in the rat.     

单纯性收缩期高血压的特点和治疗

单纯性收缩期高血压常见于老年人,尤其是50岁以上的老年人。单纯性收缩期高血压也是老年人心脑血管疾病重要的危险因素,具有较高的致死、致残率。近年来在单纯性收缩期高血压研究方面取得许多新的进展。本文就单纯性收缩期高血压的临床特点以及治疗进行简要概述。     

Pharmacologic tools for assessment of adrenergic nerve activity in human hypertension

Measurement of plasma norepinephrine concentration (plasma NE) has not resolved the role of the adrenergic system in the pathogenesis or maintenance of hypertension. A better picture is gained if plasma NE measurement is combined with the assessment of sympathetic drive and reactivity by the use of specific sympathetic antagonists and agonists. In mild hypertension, the decrease in heart rate and cardiac output after beta-adrenoceptor blockade correlates with the level of plasma NE. In established hypertension, the fall in blood pressure or peripheral vascular resistance after alpha-adrenoceptor blockade is related to plasma NE levels. Similarly, changes in forearm vascular resistance induced by local alpha-adrenoceptor blockage correlates with plasma NE in hypertension. Cardiovascular responsiveness to adrenergic agonists is altered in hypertension. The response to cardiac beta-receptor stimulation decreases during the course of the disease. To the contrary, vascular responses to exogenous NE increase with the progression of the hypertensive disease. Results with total autonomic blockade indicate that in some patients with early or borderline hypertension, increased sympathetic tone is involved in the maintenance of blood pressure. In established hypertension, there is no definite indication of increased sympathetic tone, but the sympathetic nervous system may nevertheless play a prominent role in the maintenance of the blood pressure. A vascular hyperreactivity to adrenergic stimulation is characteristically associated with established hypertension. The nature of this hyperreactivity has not been fully elucidated, but it is very likely that it reflects structural vascular changes in hypertension.     

Plasma adenosine 3′,5′ -cyclic monophosphate in human hypertension

In a previous study we observed an increase in urinary cyclic AMP in labile hypertension in the upright position and during isoproterenol infusion, in contrast to a decrease in control subjects. In the present study we measured the plasma level of cyclic AMP in control subjects and patients with various types of hypertension. We obtained the following results: (1) plasma cyclic AMP increases in response to upright posture in control subjects and hypertensive patients; (2) values of cyclic AMP in the recumbent and upright positions are comparable in control subjects and patients with essential hypertension, but are significantly higher in those with true renovascular hypertension due to bilateral renal artery stenosis; (3) propranolol inhibits the increase of plasma cyclic AMP in response to posture in control subjects, but has an opposite effect in labile hypertension where there is a further increase; (4) the rise in blood pressure in pheochromocytoma is associated with a considerable increase in plasma cyclic AMP.Present and previous data suggest that kidney handling of cyclic AMP is abnormal in hypertension, and that the specific defect may be related to the type of hypertension.