Maintenance Of Arterial Hypertension Research Articles

Особливості артеріальної гіпертензії при ожирінні

Hypertension in obesity is a fairly common problem, and it has its own characteristics. Obesity promotes inflammation in the body, which can damage blood vessels and lead to atherosclerosis, which also contributes to increased blood pressure. Obesity can lead to increased resistance to blood flow in vessels through various mechanisms, including atherosclerosis, inflammation, and other physiological changes. The main direct physiological mechanism of the development and maintenance of arterial hypertension is endothelial dysfunction, which leads to an increase in vascular tone and further remodeling of the vascular wall, and this is a general result of the influence of known external factors.

Effects of maternal protein restriction on central and peripheral renin-angiotensin systems in male rat offspring

AimsWe investigated the involvement of the renin angiotensin system (RAS) on the cardiorespiratory control in rats from dams fed with a low-protein diet. Main methodsMale offspring were obtained from dams fed a normoprotein diet (NP, 17% casein) and low-protein diet (LP, 8% casein) during pregnancy and lactation. Direct measurements of arterial pressure (AP), heart rate (HR) and respiratory frequency (RF) were recorded in awake 90-day-old at resting and after losartan potassium through either intracerebroventricular (ICV) microinjections or intravenous (IV) administration. Cardiovascular variability was evaluated by spectral analysis. Peripheral chemoreflex sensitivity was assessed through the potassium cyanide (KCN; 40 μg/0.1 ml/rat, IV). Gene expression was evaluated by qPCR, and MAPK (Mitogen Activated Protein Kinase) expression was evaluated by western blot. Key findingsThe LP offspring had higher mean AP (MAP) and RF than NP offspring. In the spectral analysis, the LP rats also showed higher low frequency of systolic AP (NP: 2.7 ± 0.3 vs. LP: 5.0 ± 1.0 mmHg). After ICV losartan, MAP and RF in LP rats remained higher than those in NP rats, but without changes in HR. The peripheral chemoreflex was similar between the groups. LP group had lower gene expression of Rac1 (Ras-related C3 botulinum toxin substrate 1) (NP: 1.13 ± 0.06 vs. LP: 0.88 ± 0.08). Peripherally, LP rats had larger delta of MAP after IV losartan (NP: −9.8 ± 2 vs. LP: −23 ± 6 mmHg), without changes in HR and RF. SignificanceIn rats, the RAS participates peripherally, but not centrally, in the maintenance of arterial hypertension in male offspring induced by maternal protein restriction.

P4554Central-acting aminopeptidase a inhibitors for new treatment of hypertension: from discovery to clinical trial

Abstract The hyperactivity of the brain renin–angiotensin system (RAS) has been implicated in the development and maintenance of arterial hypertension (HTA). Our aim was to demonstrate that normalizing brain RAS hyperactivity could constitute a new therapeutic approach for HTA treatment We first demonstrated in the brain that aminopeptidase A (APA) is the enzyme generating angiotensin III (AngIII) from AngII. Then, using the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), we showed that AngIII is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in hypertensive rats. This suggests that brain APA may be a potential therapeutic target for HTA treatment. We then designed RB150 {4,4-dithio[bis(3-aminobutyl sulfonic acid)]}, an orally active prodrug of EC33. RB150, given orally in conscious deoxycorticosterone acetate-salt (DOCA-salt) rats or spontaneously hypertensive rats, crosses the intestinal, hepatic and blood-brain barriers, enters the brain, where it is cleaved by brain reductases, generating two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and induce a marked and sustained decrease in BP. The RB150-induced BP decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances and the improvement of the baroreflex function (Figure below). RB150 was renamed firibastat by OMS. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well-tolerated in healthy volunteers. Firibastat could constitute the first drug candidate of a new class of antihypertensive agents targeting the brain RAS, the clinical efficacy of which (Phase IIa and Phase IIb) in hypertensive patients was achieved. Acknowledgement/Funding INSERM, College de France, ANR LabCom, Quantum Genomics

Neuroimmune crosstalk in the pathophysiology of hypertension.

Hypertension is an important risk factor for cardiovascular morbidity and mortality andfor events such as myocardial infarction, stroke, heart failure and chronic kidney disease and is a major determinant of disability-adjusted life-years. Despite the importance of hypertension, the pathogenesis of essential hypertension, which involves the complex interaction of several mechanisms, is still poorly understood. Evidence suggests that interplay between bone marrow, microglia and immune mediators underlies the development of arterial hypertension, in particular through mechanisms involving cytokines and peptides, such as neuropeptide Y, substance P, angiotensin II and angiotensin-(1-7). Chronic psychological stress also seems to have a role in increasing the risk of hypertension, probably through the activation of neuroimmune pathways. In this Review, we summarize the available data on the possible role of neuroimmune crosstalk in the origin and maintenance of arterial hypertension and discuss the implications of this crosstalk for recovery and rehabilitation after cardiac and cerebral injuries.

Immunohistochemical evidence of tissue hypoxia and astrogliosis in the rostral ventrolateral medulla of spontaneously hypertensive rats

Increased activity of the sympathetic nervous system has been highlighted as a key factor that contributes to the development and maintenance of arterial hypertension. However, the factors that precipitate sustained increases in sympathetic activity remain poorly understood. Resting tissue oxygen partial pressure (PtO2) in the brainstem of anesthetized spontaneously hypertensive rats (SHRs) has been shown to be lower than in normotensive rats despite normal levels of arterial PO2. A hypoxic environment in the brainstem has been postulated to activate astroglial signalling mechanisms in the rostral ventrolateral medulla (RVLM) which in turn increase the excitability of presympathetic neuronal networks. In this study, we assessed the expression of indirect markers of tissue hypoxia and astroglial cell activation in the RVLM of SHRs and age-matched normotensive Wistar rats. Immunohistochemical labelling for hypoxia-induced factor-1α (HIF-1α) and bound pimonidazole adducts revealed the presence of tissue hypoxia in the RVLM of SHRs. Double immunostaining showed co-localization of bound pimonidazole labelling in putative presympathetic C1 neurons and in astroglial cells. Quantification of glial fibrillary acidic protein (GFAP) immunofluorescence showed relatively higher number of astrocytes and increased GFAP mean grey value density, whilst semi-quantitative analysis of skeletonized GFAP-immunoreactive processes revealed greater % area covered by astrocytic processes in the RVLM of adult SHRs. In conclusion, the morphological findings of tissue hypoxia and astrogliosis within brainstem presympathetic neuronal networks in the SHR support previous observations, showing that low brainstem PtO2 and increased astroglial signalling in the RVLM play an important role in pathological sympathoexcitation associated with the development of arterial hypertension.

OP.8C.06] CENTRAL ANTIHYPERTENSIVE EFFECTS OF CHRONIC TREATMENT WITH RB150/QGC001, AN ORALLY ACTIVE AMINOPEPTIDASE A INHIBITOR PRODRUG IN DOCA-SALT HYPERTENSIVE RATS

Objective: Hyperactivity of the brain renin-angiotensin system (RAS) is implicated in the development and maintenance of arterial hypertension (HTA). We previously showed that angiotensin III (AngIII) is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in alert hypertensive rats. Therefore, aminopeptidase A (APA) the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of HTA. This led to the development of RB150 (also known as QGC001), a prodrug of the specific and selective APA inhibitor, EC33. When given orally, RB150 is able to cross the blood-brain-barrier, to inhibit brain APA activity and to decrease BP in two experimental models of HTA. We investigate here the effects of repeated oral administrations of RB150 (50 mg/kg/day) over 10 days on BP in conscious DOCA-salt rats to assess if a tolerance to the antihypertensive RB150 effect occurs after chronic treatment. Design and method: For this purpose, 5 hours after RB150 administration, we measured daily variations in systolic BP (sBP) by the tail-cuff method, plasma arginine-vasopressin (AVP) levels by radioimmunoassay and metabolic parameters Results: Chronic oral treatment with RB150 significantly decreased sBP compared with saline over the 10 days treatment period, without significantly altering heart rate. The maximal decrease in sBP (−29.6 ± 6 mmHg) was observed on the second day and the average RB150-induced decrease in sBP over 10 days was not significantly changed (−21 ± 5 mmHg), showing no tolerance to the antihypertensive effect of RB150 after repeated administrations. Chronic oral treatment with RB150 reduced by 59% the increase in plasma AVP levels observed in DOCA-salt rats compared with normotensive rats receiving saline. The administration of RB150 increased significantly diuresis by 39% and natriuresis by 34% without modification of plasma sodium and potassium levels when compared to DOCA-salt rats receiving saline over a 10 days analysis. This may participate to the blood pressure decrease by reducing the size of fluid compartment. Conclusions: Our results further confirm the interest of developing RB150 as a novel centrally-acting agent for the treatment of HTA.

Renin and Aldosterone Measurements in the Management of Arterial Hypertension

Renin-angiotensin-aldosterone system (RAAS) is recognized as the main regulatory system of hemodynamics in man, and its derangements have a key role in the development and maintenance of arterial hypertension. Classification of the hypertensive states according to different patterns of renin and aldosterone levels ("RAAS profiling") allows the diagnosis of specific forms of secondary hypertension and may identify distinct hemodynamic subsets in essential hypertension. In this review, we summarize the application of RAAS profiling for the diagnostic assessment of hypertensive patients and discuss how the pathophysiological framework provided by RAAS profiling may guide therapeutic decision-making, especially in the context of uncontrolled hypertension not responding to multi-therapy.

Hypertension and Obesity: Correlates With Renin‐Angiotensin‐Aldosterone System and Uric Acid

Arterial hypertension, obesity, the renin-angiotensinaldosterone system (RAAS), and uric acid are all independently ligated to an increased cardiovascular (CV) risk. Arterial hypertension and obesity are among the 20 leading risk factors that increase the mortality of the general population with hypertension, which is number one. In turn, obesity is one of the most common factors responsible for the development of arterial hypertension. On the other hand, the RAAS and uric acid have been shown to participate independently in the development and maintenance of arterial hypertension, as well as in the mechanisms leading to the development of hypertension in obesity. Furthermore, RAAS as well as uric acid have been shown to be related to an increase in CV morbidity and mortality in hypertension and obesity. In fact, uric acid could play a role in the epidemic of obesity-related metabolic syndrome and cardiorenal disease. In this issue of The Journal of Clinical Hypertension, Zhang and colleagues expand the knowledge of the participation of the RAAS and uric acid in the pathogenesis of hypertension in obesity. The authors describe that serum uric acid is strongly related to angiotensinogen in an obesity-dependent manner in untreated hypertensive patients. They also describe that serum uric acid seems to contribute to the enhancement of plasma angiotensinogen and could be involved in the pathophysiology of obesity-related hypertension where an increase in activity of RAAS is one of the mechanisms underlying the development and maintenance of arterial hypertension. The pathophysiological scene of hypertension in obesity is a vicious circle in which specific mechanisms can contribute at the same time to trigger others, leading to the progressive deterioration of the cardiorenal system. This crosstalk between hypertension and obesity is represented in the Figure where it is shown how these mechanisms are interconnected. In this context, hyperuricemia is strongly related to arterial hypertension. At the same time, increased sympathetic activity and increased RAAS are also mechanisms underlying hypertension and obesity, where the results of Zhang and colleagues also point to angiotensinogen as an important player in the pathogenesis of obesity hypertension. The high level of circulating angiotensinogen observed in untreated hypertensive obese patients is also likely

What are the benefits of renal denervation in patients with resistant hypertension?

Systemic arterial hypertension is one of the most important public health issues, affecting more than one-quarter of the adult population in industrialized countries [1]. It is a major risk factor for cardiovascular disease morbidity and mortality [2,3]. In most patients, hypertension can be effectively managed by a combination of lifestyle interventions and medication [4]. However, a significant portion of patients treated for hypertension are resistant to therapy. Conventionally, resistant hypertension is defined as persistent elevation of blood pressure above goal levels despite the use of at least three hypertensive agents from different classes, including a diuretic, in optimal doses [5]. Current prevalence estimates suggest that 10–30% of patients with hypertension may be resistant to drug therapy [6]. Renal sympathetic overactivity seems to play a crucial role in the development of arterial hypertension and resistance to treatment. Activation of efferent renal sympathetic nerve fibers results in an increased renin secretion rate, increased renal vasoconstriction and enhanced sodium and water retention [7]. In addition, afferent sympathetic activation from the kidneys to the CNS, seems to enhance sympathetic nerve discharge itself again, leading to a vicious circle in the development of arterial hypertension and cardiovascular morbidity [8]. Both effects, the activation of efferent renal sympathetic nerve fibers as well as the afferent ‘feedback’ from the kidneys seem to play a crucial role in the pathogenesis and maintenance of arterial hypertension. The idea of treating arterial hypertension by targeting the autonomic nervous system is decades old. In the predrug era, treatment of malignant hypertension was limited to surgical approaches, such as nephrectomy and surgical lysis of the autonomic nerves. Nonselective surgical sympathectomy (thoracolumbar splanchnicectomy), the so-called Smithwick intervention,

Navike i znanja pacijenata i zdravstvenih radnika u pogledu unosa soli ishranom

Available data clearly indicate that high sodium and table salt intake are very important factors in the development and maintenance of arterial hypertension, but also some other chronic non-communicable diseases. The aim of this paper was assessment of respondents’ habits regarding salt intake and knowledge the influence of salt intake on arterial hypertension. The research was performed in form of questionnaire. The subjects were divided into groups of patients and medical staff. Four hundred and thirty nine properly filled questionnaires were taken for processing. More than half of respondents believe that they are sufficiently informed about the impact of salt on high blood pressure. Self-estimated daily salt intake was about 10g. Over 70% of subjects add salt to food during the meal. Over two thirds of subjects would choose lower sodium (salt) product. The vast majority of subjects (83.6%) expressed willingness to continue reducing salt intake with food. The majority of respondents know that increased salt intake affects blood pressure. CONCLUSIONS: Self-estimated daily intake of salt is high. Habit of adding salt to food was significantly represented. Respondents showed a good average level of knowledge regarding some facts about the impact of salt on high blood pressure.

Hypertensive effects of the iv administration of picomoles of ouabain

Ouabain, an endogenous digitalis compound, has been detected in nanomolar concentrations in the plasma of several mammals and is associated with the development of hypertension. In addition, plasma ouabain is increased in several hypertension models, and the acute or chronic administration of ouabain increases blood pressure in rodents. These results suggest a possible association between ouabain and the genesis or development and maintenance of arterial hypertension. One explanation for this association is that ouabain binds to the α-subunit of the Na(+) pump, inhibiting its activity. Inhibition of this pump increases intracellular Na(+), which reduces the activity of the sarcolemmal Na(+)/Ca(2+) exchanger and thereby reduces Ca(2+) extrusion. Consequently, intracellular Ca(2+) increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone. In fact, acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, increases the release of norepinephrine from the perivascular adrenergic nerve endings and promotes increases in the activity of endothelial angiotensin-converting enzyme and the local synthesis of angiotensin II in the tail vascular bed. Additionally, the hypertension induced by ouabain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin system. Thus, the association with peripheral mechanisms and central mechanisms, mainly involving the renin-angiotensin system, may contribute to the acute effects of ouabain-induced elevation of arterial blood pressure.

Pharmacokinetics and Antihypertensive Effects of Candesartan Cilexetil in Patients Undergoing Haemodialysis

In patients with endstage renal failure (ERF), activation of the renin-angiotensin-aldosterone system plays an important role in the onset and maintenance of arterial hypertension. This study aimed to elucidate the antihypertensive effect, pharmacokinetics and safety of candesartan cilexetil in patients with ERF undergoing haemodialysis. In 14 anuric hypertensive patients undergoing haemodialysis (mean+/- SD 24-hour systolic [SBP]/diastolic [DBP] blood pressure [BP] 142.9 +/- 11.1/75.0 +/- 10.1 mmHg), 24-hour BP measurements on the second interdialysis day per week were performed at baseline and at weeks 4, 12 and 24. All patients started antihypertensive treatment with candesartan cilexetil 4 mg once daily immediately before the start of haemodialysis. Subsequently, the dose was titrated upward to 8 mg once daily until the patient's mean ambulatory BP measurement (ABPM) values were <130/80 mmHg. Plasma candesartan pharmacokinetics were investigated on days 7 and 14 after starting candesartan cilexetil treatment and after each titration step. After 6 months all patients demonstrated well controlled BP (ABPM mean +/- SD SBP 129.6 +/- 21.7/DBP 69.4 +/- 10.4 mmHg) and a significantly reduced pulse pressure (from a mean +/- SD 67.9 +/- 13.7 mmHg at baseline to a mean +/- SD 60.2 +/- 14.7 mmHg at 6 months), without any adverse events. Candesartan plasma concentrations increased over 3 hours followed by a continuous decline. Plasma concentrations remained stable after 7 and 14 days, independent of dosing. However, administration of candesartan cilexetil 8 mg (five patients) resulted in plasma concentrations about 1.4 times higher than those for candesartan cilexetil 4 mg. In this study with small number of patients with ERF undergoing haemodialysis, candesartan cilexetil was effective in lowering BP and pulse pressure without accumulation or associated adverse effects such as elevated potassium or symptomatic hypotension.

Parathyroid Hormone-Related Protein Overexpression Decreases Blood Pressure in Spontaneously Hypertensive Rats

We have recently demonstrated that arterial PTHrP expression and cardiovascular responses to this protein are altered in SHR compared with normotensive animals, Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats. To investigate whether the slightly, but significantly decreased, aortic PTHrP gene expression observed in SHR, compared to that of normotensive animals, may play a causative role in the maintenance of the elevated arterial blood pressure (ABP) of the SHR, we transfected a hepatic lobe with a PTHrP expression vector in a sense and antisense orientation. At 24 and 48 hours, sense pSV2neo-ECE induced a significant five-fold increase in PTHrP mRNA abundance with respect to antisense pSV2neo-ECE and vehicle. This increment in the PTHrP mRNA induced by the sense PTHrP expression vector was totally inhibited by the co-administration of the antisense PTHrP expression vector. At the same time, we observed a significant decrease of mean ABP (MABP) in SHR transfected with the sense pSV2neo-ECE to similar values as those obtained in the normotensive strain. Neither antisense PTHrP expression vector nor vehicle had any significant effect in any strain. Again, the effect of the sense PTHrP expression vector on MABP was blocked by the simultaneous treatment with the antisense PTHrP expression vector. At 48 hours, the hypotensive effect of the sense pSV2neo-ECE in SHR was reverted by the IV bolus injection of a specific competitive PTHrP receptor antagonist such as Nle8,18,Tyr34-bPTH(3–34)amide. We propose that a defect of this potent local vasodilator may contribute to the development and/or maintenance of arterial hypertension in SHR. This defect can be ameliorated by transfecting tissues with protein-exporting capabilities, such as the liver. Finally, our work adds additional data to a cumulative body of evidence suggesting that it might be possible to design an effective gene therapy to treat the common polygenic and multifactorial form of hypertension by increasing the activity of potent and physiological vasodilators.

State of the sympathetico-adrenal system in patients with hypothalamic pubertal syndrome.

The role of the sympathetico-adrenal system in the pathogenesis of arterial hypertension in pubertal hypothalamic syndrome was studied in 29 males with pubertal hypothalamic syndrome and 13 healthy subjects, aged 15-23 years. The activity of the sympathetico-adrenal system was assessed in terms of the plasma dopamine, noradrenaline, and adrenaline concentrations as determined by HPLC using a high-sensitivity detector. Patients with stable arterial hypertension had significantly reduced levels of adrenaline, probably because of loss of phenylethanol methyltransferase activity, which may demonstrate that the sympathetico-adrenal system is not involved in the genesis and maintenance of arterial hypertension in pubertal hypothalamic syndrome. Patients with a body mass index of more than 35.0 kg/m2 had significant reductions in noradrenaline levels, evidently because of loss of tyrosine hydroxylase, whose activity is regulated by corticotrophin. Catecholamine levels were independent of the duration of illness, the duration of hypertension, or the stage of obesity.

Are renal hemodynamics a key factor in the development and maintenance of arterial hypertension in humans?

The kidney plays a key role in the control of body fluids and blood pressure. Evidence has shown that impairment of renal function can lead to the development of arterial hypertension. The regulation of renal blood flow appears to be a key element in the pathophysiology of the hypertensive process, because multiple evidence suggests the existence of a functional enhancement of renal vascular tone in this disorder. The existence of renal vasoconstriction and of an inherited defect in the regulation of renal blood flow has been proposed in the prehypertensive stage. The mechanisms responsible for this alteration include a lack of modulation of the renal vasculature to angiotensin II, increased sympathetic activity, or suppressed renal dopaminergic activity. Established hypertension is characterized by elevated renal vascular resistance, decreased renal blood flow, sustained glomerular filtration rate, and increased filtration fraction. The increase in renal vascular resistance is initially due to elevations in renal vascular tone and is reversible, whereas later it becomes irreversible because of structural changes involved in nephrosclerosis. Antihypertensive drugs are able to decrease blood pressure and to prevent the development of further renal vascular damage independently of variable effects on renal hemodynamics.

Sodium sensitivity in normotensive human subjects.

Compelling evidence implicates a high sodium intake in the development and maintenance of arterial hypertension. However, dietary sodium restriction reduces blood pressure in only a fraction of hypertensive patients. Studies in normotensive persons suggest that blacks and older persons excrete a sodium load less efficiently than persons of the same sex and race who are also matched for body weight and body surface area. Blacks show a greater natriuresis and decrease in blood pressure in response to volume contraction with furosemide administration than whites. These observations are consistent with an intrinsic renal abnormality in blacks and older persons, resulting in modest volume expansion. Such changes may contribute to sodium sensitivity and promote the development and maintenance of hypertension in persons with a high sodium intake.

Antihypertensive effect of spironolactone (SC-9420) on experimental renal hypertension.

Spironolactone was administered to rabbits with experimental renal hypertension. The blood pressure of these rabbits was decreased during spironolactone therapy. A marked increase in sodium and water excretion was noted on the third day, but potassium excretion did not change at that time. Treatment with spironolactone caused a rise of serum potassium in hypertensive rabbits. It is probable that spironolactone moves intracellular potassium out to extracellular space. Assuming from these results, water and electrolyte metabolism is not normal in the experimental renal hypertension, probably accompanied with excessive mineralocorticoid secretion. But the abnormal water and electrolyte metabolism, and hyperaldosteronism in experimental renal hypertension seem to play an independent different role in the development and maintenance of arterial hypertension. We are indebted to Prof. T. Torikai for his continuous leadership throughout this study.