Human Primary Hypertension Research Articles

Hypertension-induced cardiac pro-arrhythmic disorders of connexin-43 and extracellular matrix are attenuated in hairless versus wild-type of spontaneously hypertensive rats

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Development Agency under the contract no. 21-0410 VEGA grants no. 2/0002/20, 2/0006/23 Background Mechanical dysfunction and occurrence of malignant ventricular fibrillation (VF) are hallmarks of hypertensive heart disease and major health issue. Spontaneously hypertensive rats (SHR) that imitates human primary hypertension are prone to develop VF, mainly due to myocardial remodelling associated with disorders of electrical coupling protein connexin-43 (Cx43) and extracellular matrix (ECM) resulting in electrical instability. However, it is not known whether postnatal acclimation of hairless strain of SHR to surrounding temperature may induce cardio-protection. Therefore, we aimed to explore Cx43 and ECM alterations as well as susceptibility to inducible VF in hairless versus wild type SHR. Design and Methods Six-month-old wild type SHR males and females and hairless SHR housed at standard 22°C were examined. Biometric parameters, including electro- and echocardiography were registered. Left ventricular tissue was used for immunolabeling of Cx43 to reveal its topology and for western blotting to determine protein levels of Cx43 and its function modulating protein kinases, PKCε, PKCδ and PKCα as well as for ECM markers, TGF-β, SMAD2/3, MMP-2, collagen-1 and its histological deposition. Susceptibility of the heart to electrically-inducible VF was tested using isolated perfused heart technique. Key results Comparing to wild type males, hairless SHR exhibited less pronounced prolongation of QT and QRS interval as well as an increase of ejection fraction. Myocardial Cx43 and its variant phosphorylated at serine-368, which preserve electrical coupling, were increased and pro-arrhythmic cardiomyocyte Cx43 topology was attenuated in males and females hairless vs wild type SHR. Moreover, the level of β-catenin, which ensures mechano-electrical coupling, was also increased in hairless SHR. On the other hand, collagen-1 and hydroxyproline were lower and the TGF-β1 and SMAD2/3 proteins were suppressed in males hairless vs wild type SHR. Myocardial ECM remodelling was less pronounced in females regardless rat strain. Hairless SHR males were less susceptible to inducible VF compared to wild type SHR, while females were less prone to develop VF regardless the strain. In conclusion, our findings imply that postnatal acclimation of hairless SHR is accompanied by attenuation of hypertension-induced adverse down-regulation of Cx43 and up-regulation of extracellular matrix proteins. It may contribute, at least in part, to the protection from malignant cardiac arrhythmias and mechanical dysfunction.

DISPARATE IMPACT OF PRIMARY HYPERTENSION ON RIGHT VERSUS LEFT HEART VENTRICLES OF MALES AND FEMALES WILD TYPE AND HAIRLESS STRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Poor adherence to lifestyle changes and antihypertensive drugs contributes to increase a risk for malignant cardiac arrhythmias. Hypertension contributes to myocardial structural remodeling, abnormalities in connexin43 (Cx43) which promote electrical instability and mechanical dysfunction. However, it is not known whether changes are confined solely to left heart ventricle (LV) or there is response of right heart ventricle (RV). SHR mimic human primary hypertension and hairless SHR is model of temperature acclimation characterized by increase thermogenesis. Aim of the study was to explore key factors involved in development of malignant arrhythmias and progression to heart failure, in left and right heart ventricles, of males and females wild type (WT) and hairless SHR. Design and method: 6-month-old males and females WT and hairless SHR and normotensive WKY strain of rats were housed at standard 22°C. Biometric parameters, including electro- and echo-cardiographic were registered. LV and RV tissue was used for immuno-labelling of Cx43 to detect its topology and western blotting for determination protein levels of Cx43, PKA, PKC∊, PKCδ and markers of extracellular matrix (ECM) remodelling: TGFβ, SMAD2/3, MMP-2 and collagen-1. Susceptibility of the heart to electrically-inducible VF was tested using isolated perfused heart technique. Results: Comparing to WKY, QT and QRS intervals were prolonged in WT SHR with normalisation in hairless SHR. Hypertension resulted in decrease in Cx43 with its abnormal topology in LV of males and less in hairless SHR but not in females. Cx43 levels and its topology were preserved in RV regardless rat strain and sex. There were no differences in protein levels of ECM-markers when comparing LV and RV in all strains. PKC∊ and PKCδ were increased in RV versus LV in both SHR strains. Hairless SHR males and females were less prone to inducible VF compared to WT SHR. Conclusions: Findings point out that hypertension-induced pro-arrhythmic disorders of Cx43 are related to the left while not to right heart ventricle in both hypertensive strains. There is a benefit of cold acclimation in hypertension that may contribute, to the protection from malignant cardiac arrhythmias and mechanical dysfunction. Supported by Vega2/0002/20,2/0006/23 and APVV21-0410.

Cardiometabolic effects of DOCA-salt in male C57BL/6J mice are variably dependent on sodium and nonsodium components of diet.

Hypertension characterized by low circulating renin activity accounts for roughly 25%-30% of primary hypertension in humans and can be modeled experimentally via deoxycorticosterone acetate (DOCA)-salt treatment. In this model, phenotypes develop in progressive phases, although the timelines and relative contributions of various mechanisms to phenotype development can be distinct between laboratories. To explore interactions among environmental influences such as diet formulation and dietary sodium (Na) content on phenotype development in the DOCA-salt paradigm, we examined an array of cardiometabolic endpoints in young adult male C57BL/6J mice during sham or DOCA-salt treatments when mice were maintained on several common, commercially available laboratory rodent "chow" diets including PicoLab 5L0D (0.39% Na), Envigo 7913 (0.31% Na), Envigo 2920x (0.15% Na), or a customized version of Envigo 2920x (0.4% Na). Energy balance (weight gain, food intake, digestive efficiency, and energy efficiency), fluid and electrolyte homeostasis (fluid intake, Na intake, fecal Na content, hydration, and fluid compartmentalization), renal functions (urine production rate, glomerular filtration rate, urine Na excretion, renal expression of renin, vasopressin receptors, aquaporin-2 and relationships among markers of vasopressin release, aquaporin-2 shedding, and urine osmolality), and blood pressure, all exhibited changes that were subject to interactions between diet and DOCA-salt. Interestingly, some of these phenotypes, including blood pressure and hydration, were dependent on nonsodium dietary components, as Na-matched diets resulted in distinct phenotype development. These findings provide a broad and robust illustration of an environment × treatment interaction that impacts the use and interpretation of a common rodent model of low-renin hypertension.

Angiotensin Type-2 Receptors: Transducers of Natriuresis in the Renal Proximal Tubule.

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.

Identification of novel proteins and mechanistic pathways associated with early-onset hypertension by deep proteomic mapping of resistance arteries

Resistance arteries are small blood vessels that create resistance to blood flow. In hypertension, resistance arteries undergo remodeling, affecting their ability to contract and relax appropriately. To date, no study has mapped the hypertension-related proteomic changes in resistance arteries. Using a novel data-independent acquisition–mass spectrometry (DIA-MS) approach, we determined the proteomic changes in small mesenteric and renal arteries in pre- and early-onset hypertension from the spontaneously hypertensive rat (SHR) model, which represents human primary hypertension. Compared with normotensive controls, mesenteric arteries from 12-week-old SHRs had 286 proteins that were significantly up- or downregulated, whereas 52 proteins were identified as up- or downregulated in mesenteric arteries from 6-week-old SHRs. Of these proteins, 18 were also similarly regulated in SHR renal arteries. Our pathway analyses reveal several novel pathways in the pathogenesis of hypertension. Finally, using a matrisome database, we identified 38 altered extracellular-matrix-associated proteins, many of which have never previously been associated with hypertension. Taken together, this study reveals novel proteins and mechanisms that are associated with early-onset hypertension, thereby providing novel insights into disease progression.

Palmitoleic Acid Protects against Hypertension by Inhibiting NF-κB-Mediated Inflammation.

The role of palmitoleic acid (POA) in hypertension or blood pressure remains uncertain. This study aims to investigate the epidemiological association between circulating POA and primary hypertension in humans, and subsequently evaluate the effects of exogenous POA on blood pressure and aortic remodeling in spontaneously hypertensive rats (SHRs). A case-control study of 349 hypertensive and 1396 normotensive children and adolescents is conducted, and found hypertensive cases show significant lower erythrocyte phospholipid POA than normotensive controls (p<0.001). In conditional logistic regression model, participants in the top quartile of POA have a lower prevalence of primary hypertension than those in the bottom (multivariate-adjusted OR: 0.47, 95% CI: 0.25-0.89). In animal study, 24 SHRs are randomly assigned to n-3 PUFAs (500mg kg-1 ), POA (500mg kg-1 ), or vehicle (olive oil) for 8 weeks. At the end of intervention, as compared to SHRs treated with vehicle, SHRs treated with POA shows significantly decreased systolic blood pressure (SBP), improved aortic remodeling, and also decreased aortic expressions of NF-κB and its downstream proinflammatory cytokines. Circulating POA is inversely associated with risk of primary hypertension, and exogenous POA supplementation can decrease SBP and improve aortic remodeling by inhibiting NF-κB-mediated inflammation.

Impact of sex and pathophysiology on optimal drug choice in hypertensive rats: Quantitative insights for precision medicine

SummaryLess than half of all hypertensive patients receiving treatment are successful in normalizing their blood pressure. Despite the complexity and heterogeneity of hypertension, the current antihypertensive guidelines are not tailored to the individual patient. As a step toward individualized treatment, we develop a quantitative systems pharmacology model of blood pressure regulation in the spontaneously hypertensive rat (SHR) and generate sex-specific virtual populations of SHRs to account for the heterogeneity between the sexes and within the pathophysiology of hypertension. We then used the mechanistic model integrated with machine learning tools to study how variability in these mechanisms leads to differential responses in rodents to the four primary classes of antihypertensive drugs. We found that both the sex and the pathophysiological profile of the individual play a major role in the response to hypertensive treatments. These results provide insight into potential areas to apply precision medicine in human primary hypertension.

Obesity, kidney dysfunction, and inflammation: interactions in hypertension.

Obesity contributes 65-75% of the risk for human primary (essential) hypertension (HT) which is a major driver of cardiovascular and kidney diseases. Kidney dysfunction, associated with increased renal sodium reabsorption and compensatory glomerular hyperfiltration, plays a key role in initiating obesity-HT and target organ injury. Mediators of kidney dysfunction and increased blood pressure include (i) elevated renal sympathetic nerve activity (RSNA); (ii) increased antinatriuretic hormones such as angiotensin II and aldosterone; (iii) relative deficiency of natriuretic hormones; (iv) renal compression by fat in and around the kidneys; and (v) activation of innate and adaptive immune cells that invade tissues throughout the body, producing inflammatory cytokines/chemokines that contribute to vascular and target organ injury, and exacerbate HT. These neurohormonal, renal, and inflammatory mechanisms of obesity-HT are interdependent. For example, excess adiposity increases the adipocyte-derived cytokine leptin which increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway. Excess visceral, perirenal and renal sinus fat compress the kidneys which, along with increased RSNA, contribute to renin-angiotensin-aldosterone system activation, although obesity may also activate mineralocorticoid receptors independent of aldosterone. Prolonged obesity, HT, metabolic abnormalities, and inflammation cause progressive renal injury, making HT more resistant to therapy and often requiring multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes, and inflammation. More effective anti-obesity drugs are needed to prevent the cascade of cardiorenal, metabolic, and immune disorders that threaten to overwhelm health care systems as obesity prevalence continues to increase.

Abstract P118: Antihypertensive Treatment Guided By Genetics: Pearl-ht, The Randomized Proof-of-concept Trial Comparing Rostafuroxin With Losartan

Primary hypertension contributes to more than 50% of all the worldwide cardiovascular deaths. Current antihypertensive therapy is still targeting the physiological mechanisms regulating blood pressure, but not the “causal” ones. So far, genetic studies have been unable to prove gene causation in human primary hypertension. In this study we compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension (PEARL-HT trial registration: EudraCT: 2010-022073-34, ClinicalTrials.gov: NCT01320397). Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10 -11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in Office Systolic Blood Pressure (OSBP) after two-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis ( LSS and HSD3B1 ), EO transport ( MDR1/ABCB1 ), adducin ( ADD1 and ADD3 ); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P =0.038 and 13.4 (25.4-2.5), P =0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former ( P =0.038); this difference was abolished by rostafuroxin at 10 -11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that the selective blockade of mutant adducin and endogenous ouabain pressor mechanisms by rostafuroxin improves the therapy of primary hypertension in in Caucasians carriers of the related gene variants.

Impact of Sex and Pathophysiology on Optimal Drug Choice in Hypertensive Rats: Quantitative Insights for Precision Medicine

Less than half all of hypertensive patients receiving treatment are successful in normalizing their blood pressure. Despite the complexity and heterogeneity of hypertension, the current antihypertensive guidelines are not tailored to the individual patient. As a step towards individualized treatment, we develop a quantitative systems pharmacology model of blood pressure regulation in the spontaneously hypertensive rat (SHR) and generate sex-specific virtual populations of SHRs to account for the heterogeneity between the sexes and within the pathophysiology of hypertension. We then used the mechanistic model integrated with machine learning tools to study how variability in these mechanisms leads to differential responses in rodents to the four primary classes of antihypertensive drugs. We found that both the sex and the pathophysiological profile of the individual play a major role in the response to hypertensive treatments. These results provide insight into potential areas to apply precision medicine in human primary hypertension.

Mechanisms of hypertension in autoimmune rheumatic diseases.

Patients with autoimmune rheumatic diseases including rheumatoid arthritis and systemic lupus erythematosus have an increased prevalence of hypertension. There is now a large body of evidence showing that the immune system is a key mediator in both human primary hypertension and experimental models. Many of the proposed immunological mechanisms leading to primary hypertension are paralleled in autoimmune rheumatic disorders. Therefore, examining the link between autoimmunity and hypertension can be informative for understanding primary hypertension. This review examines the prevalent hypertension, the immune mediators that contribute to the prevalent hypertension and their impact on renal function and how the risk of hypertension is potentially influenced by common hormonal changes that are associated with autoimmune rheumatic diseases.Linked ArticlesThis article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc

Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms.

Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a common sign-an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62 proposed genes. However, only 21 of them met our inclusion criteria: (i) primary hypertension, (ii) two or more supporting cohorts from different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, and (iii) 600 or more subjects in the primary cohort; when including our exclusion criteria: (i) meta-analyses or reviews, (ii) secondary and monogenic hypertension, (iii) only hypertensive complications, (iv) genes related to blood pressure but not hypertension per se, (v) nonsupporting studies more common than supporting ones, and (vi) studies that did not perform a Bonferroni or similar multiassessment correction. These 21 genes were organized in a four-tiered structure: distant phenotype (hypertension); intermediate phenotype [salt-sensitive (18) or salt-resistant (0)]; subintermediate phenotypes under salt-sensitive hypertension [normal renin (4), low renin (8), and unclassified renin (6)]; and proximate phenotypes (specific genetically driven hypertensive subgroup). Many proximate hypertensive phenotypes had a substantial endocrine component. In conclusion, primary hypertension is a syndrome; many proposed genes are likely to be false positives; and deep phenotyping will be required to determine the utility of genetics in the treatment of hypertension. However, to date, the positive genes are associated with nearly 50% of primary hypertensives, suggesting that in the near term precise, mechanistically driven treatment and prevention strategies for the specific primary hypertension subgroups are feasible.

Impaired Hypothalamic Regulation of Sympathetic Outflow in Primary Hypertension.

The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.

Plasma Cell Depletion Attenuates Hypertension in an Experimental Model of Autoimmune Disease.

Numerous studies show a direct relation between circulating autoantibodies, characteristic of systemic autoimmune disorders, and primary hypertension in humans. Whether these autoantibodies mechanistically contribute to the development of hypertension remains unclear. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by aberrant immunoglobulin production, notably pathogenic autoantibodies, and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Because plasma cells produce the majority of serum immunoglobulins and are the primary source of autoantibodies in SLE, we hypothesized that plasma cell depletion using the proteasome inhibitor bortezomib would lower autoantibody production and attenuate hypertension. Thirty-week-old female SLE (NZBWF1) and control (NZW [New Zealand White]) mice were injected IV with vehicle (0.9% saline) or bortezomib (0.75 mg/kg) twice weekly for 4 weeks. Bortezomib treatment significantly lowered the percentage of bone marrow plasma cells in SLE mice. Total plasma IgG and anti-dsDNA IgG levels were higher in SLE mice compared with control mice but were lowered by bortezomib treatment. Mean arterial pressure (mm Hg) measured in conscious mice by carotid artery catheter was higher in SLE mice than in control mice, but mean arterial pressure was significantly lower in bortezomib-treated SLE mice. Bortezomib also attenuated renal injury, as assessed by albuminuria and glomerulosclerosis, and reduced glomerular immunoglobulin deposition and B and T lymphocytes infiltration into the kidneys. Taken together, these data show that the production of autoantibodies by plasma cells mechanistically contributes to autoimmune-associated hypertension and suggests a potential role for patients with primary hypertension who have increased circulating immunoglobulins.

Redox Stress Defines the Small Artery Vasculopathy of Hypertension: How Do We Bridge the Bench-to-Bedside Gap?

Although convincing experimental evidence demonstrates the importance of vascular reactive oxygen and nitrogen species (RONS), oxidative stress, and perturbed redox signaling as causative processes in the vasculopathy of hypertension, this has not translated to the clinic. We discuss this bench-to-bedside disparity and the urgency to progress vascular redox pathobiology from experimental models to patients by studying disease-relevant human tissues. It is only through such approaches that the unambiguous role of vascular redox stress will be defined so that mechanism-based therapies in a personalized and precise manner can be developed to prevent, slow, or reverse progression of small-vessel disorders and consequent hypertension. Considering the high prevalence of hypertension worldwide, the excess heart disease and stroke that it predisposes to, and the fact that it is the strongest modifiable risk factor for cardiovascular disease, it is not surprising that the American Heart Association funded a Strategically Focused Research Network on hypertension and that the Lancet commissioned a call-to-action and a life-course strategy to address the global burden of raised blood pressure (BP).1 Despite significant advances in understanding the pathophysiology of hypertension and the availability of numerous effective drugs, suboptimal BP control remains the primary predisposing factor for cardiovascular morbidity and mortality. This Hypertension Paradox of more uncontrolled hypertension despite improved therapies, defined by Chobanian,2 is multifactorial and may relate largely to the still unknown genetic basis and elusive causal molecular mechanisms of hypertension. Genetics plays some role in human primary hypertension as evidenced in twin studies and monogenetic forms of hypertension where the kidney is a key target. Genome-wide association studies have been disappointing and have failed to identify specific genes that underpin hypertension. Few loci have been validated or translated into therapeutic targets, with multiple genes and their variants collectively accounting for <2.5% of BP variation. In one of …

DOCA-Salt Hypertension: an Update.

Hypertension is a multifaceted disease that is involved in ∼40% of cardiovascular mortalities and is the result of both genetic and environmental factors. Because of its complexity, hypertension has been studied by using various models and approaches, each of which tends to focus on individual organs or tissues to isolate the most critical and treatable causes of hypertension and the related damage to end-organs. Animal models of hypertension have ranged from Goldblatt's kidney clip models in which the origin of the disease is clearly renal to animals that spontaneously develop hypertension either through targeted genetic manipulations, such as the TGR(mRen2)27, or selective breeding resulting in more enigmatic origins, as exemplified by the spontaneously hypertensive rat (SHR). These two genetically derived models simulate the less-common human primary hypertension in which research has been able to define a Mendelian linkage. Several models are more neurogenic or endocrine in nature and illustrate that crosstalk between the nervous system and hormones can cause a significant rise in blood pressure (BP). This review will examine one of these neurogenic models of hypertension, i.e., the deoxycorticosterone acetate (DOCA), reduced renal mass, and high-salt diet (DOCA-salt) rodent model, one of the most common experimental models used today. Although the DOCA-salt model is mainly believed to be neurogenic and has been shown to impact the central and peripheral nervous systems, it also significantly involves many other body organs.

Hypertension and Exercise Training: Evidence from Clinical Studies.

Hypertension is a worldwide prevalent disease, mostly manifested as its primary ethiology, characterized by a chronic, multifactorial, asymptomatic, and usually incurable state. It is estimated that more than one billion of the world population is hypertensive. Also, hypertension is the main cause of the two most frequent causes of death worldwide: myocardial infarction and stroke. Due to the necessity of the cardiovascular system to manage chronically increased levels of blood pressure, hypertension causes severe alterations in multiple organs, as the heart, vessels, kidneys, eyes and brain, thus increasing the risk of health complications. The heart is the main target organ and suffers several adaptations to compensate the increased blood pressure levels; nevertheless, long-term adaptations without proper control are extremely harmful to cardiovascular health. On the other hand, hypertension is a modifiable risk factor and its adequate control is highly dependent on lifestyle. Pharmacological treatment is of great success when adherence is high. Several classes of antihypertensive drugs are prescribed and can effectively maintain blood pressure within acceptable levels. However, non-pharmacological methods, as diet and exercise training, can not only optimize the treatment but also prevent or postpone hypertension development as well as its complications, acting as important complements to the ideal control of elevated blood pressure, and bringing together benefits beyond blood pressure decrease, as a general health status improvement and increased quality of life. There is consistent evidence that regular exercise training promotes several benefits when properly prescribed and practised, acting as "medicine" for dozens of chronic diseases. The effects of exercise training in blood pressure levels and in its mechanisms of control are of clinical relevance and efficacy. This chapter will describe the classical and recent results on the beneficial effects of different modalities of exercise training in the cardiovascular system of human primary hypertension, focusing on the mechanisms influenced by exercise training which help to decrease blood pressure and improve the cardiovascular system.

PP.04.05] ACCELERATED DEVELOPMENT OF IMMUNE CELLS IN CHILDREN WITH PRIMARY HYPERTENSION

Objective: Immune system plays a role in pathogenesis of primary hypertension (PH) and activation of immune cells is associated with subclinical hypertensive arterial injury. One of the markers of maturation of immune cells is increased number and percentage of memory cells. We hypothesized that children with PH have faster maturation of immune cells. Design and method: The distribution of peripheral T cell subsets (CD4+ and CD8+) expressing CD45 common leukocyte antigen (CD45Ag) isoforms: CD45RA (naive cells), CD45RO (memory cells) and CD31 (pecam-1, a marker of early thymic emigrants) was evaluated by three-color flow cytometry in a group of 11 PH adolescents and 16 healthy, age matched controls. Results: Hypertensive children had higher proportion of “memory” CD8 cells (CD8/CD8RO+) than their healthy counterparts (17.0 range: 11.9–23.8 vs 10.9 9.1–14.1; p = 0.03), lower of CD8/CD8RA+ cells (72.3 range: 66.5–81.9 vs 81.6 77.4–84.3; p = 0.05), and lower CD8RA/CD8RO+ ratio than the controls (5.1 range: 2.7–6.9 vs 7.4 5.5–8.9; p = 0.028). Percentage of CD4 and CD8 T bearing “naive” or “memory” phenotype correlated with brachial and aortic pulse pressure. Additionally, CD8RA/RO+ ratio was associated with pulse pressure (p = 0.03, r = −0.337) and aortic pulse pressure (p = 0.03, r = −0.384). There was also negative correlation of percentage of CD4/CD31+ with both absolute and standardized values of carotid wall cross sectional area (p = 0.01, r = −0.433 p = 0.016, r = −0.410, respectively). Conclusions: Adolescents with PH present subtle alterations in maturation of immune system manifested by: a) the decreased number of early thymic emigrants within CD4+ T cell suggesting accelerated thymic senescence, b) the increased population of more mature cells expressing “memory” markers, c) the associations with indirect indices of arterial stiffness and carotid artery remodelling and d) shift towards “memory” phenotype in T cells. Altogether these findings indicate that early stage of human primary hypertension and arterial remodelling may be related to certain defects in T cell development that result in accelerated maturation and senescence of immune system.

The Effect of Creatine Kinase Inhibition on Contractile Properties of Human Resistance Arteries.

Creatine kinase (CK) is a main predictor of blood pressure, and this is thought to largely depend on high resistance artery contractility. We previously reported an association between vascular contractility and CK in normotensive pregnancy, but pregnancy is a strong CK inducer, and data on human hypertension are lacking. Therefore, we further explored CK-dependency of vascular contractility outside the context of pregnancy in normotensive and hypertensive women. Nineteen consecutive women, mean age 42 years (SE 1.3), mean systolic/diastolic blood pressure respectively 142.6 (SE 5.9)/85.6 (3.4) mm Hg (9 hypertensive), donated an omental fat sample during abdominal surgery. We compared vasodilation after the specific CK inhibitor 2,4-dinitro-1-fluorobenzene (DNFB; 10(-6) mol/l) to sodium nitroprusside (10(-6) mol/l) in isolated resistance arteries using a wire myograph. Additionally, we assessed predictors of vasoconstrictive force. DNFB reduced vascular contractility to 24.3% (SE 4.4), P < 0.001, compared to baseline. Sodium nitroprusside reduced contractility to 89.8% (SE 2.3). Maximum contractile force correlated with DNFB effect as a measure of CK (r = 0.8), and with vessel diameter (r = 0.7). The increase in contractile force was 16.5 mN [9.1-23.9] per unit DNFB effect in univariable and 10.35 mN [2.10-18.60] in multivariable regression analysis. This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure.

PP.41.21

Objective: Evidence suggests that uric acid is a possibly causal factor for human primary hypertension. Aim of our study was to investigate the relationship between hyperuricemia and severity of hypertension. Design and method: We studied 660 consecutive never treated newly diagnosed essential HTN patients (51 ± 13 years, 46.8% female), free of diabetes and overt cardiovascular or other systemic disease, who visited our antihypertensive outpatient clinic. All patients underwent office, home and 24-hour ABPM measurements. Subjects with isolated office hypertension were excluded from the study. Based on gender-specific upper limit of normal for uricemia (6.1 for females and 7.2 mg/dl for males), study population was categorized in normouricemic (NU, n = 583) and hyperuricemic (HU, n = 77). Results: Prevalence of hyperuricemia was 11.7%, significantly higher in males (16.2% vs. 6.5%, p < 0.001). In the whole population, uric acid levels were significant positive correlated with office and 24 hour systolic (r = 0.148 and 0.164, p < 0.001 for all) and diastolic (0.164 and 0.159, p < 0.001 for all) blood pressure levels. Moreover, HU compared to NU presented significantly higher levels of office and 24 hour systolic and diastolic blood pressure levels. Stage II and stage III BP categories were more prevalent in HU compared to NU, with 1/4 of HU being stage III hypertensives. Conclusions: Plasma uric acid levels are associated with higher levels of blood pressure and severe stages of hypertension are more prevalent in hyperuricemic patients.