**Essential Hypertension in Children: New Mechanistic Insights**

Anne-Maj Sofia Samuelsson

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[11] Harrison M, Maresso K, Broeckel U. "Genetic determinants of hypertension: an

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8 Update on Essential Hypertension

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62652

#### **Abstract**

Paediatric hypertension is on the rise accompanied by concomitant increase of childhood obesity. The origin of paediatric hypertension however remains unknown. New epidemiological evidence suggests that environmental insult in utero or postna‐ tally may lead to hypertension later in life. Independent associations have been reported between maternal obesity and cardiometabolic disorders in the offspring. In the first part, I will focus on functionally mechanistic pathways of essential hypertension with an attempt to elucidate the rather complex interplay of autonomic dysfunction, leptin, melanocortin-4 receptor (MC4R), inflammation, genetic and epigenetic predisposi‐ tions. In the second part, the standalone risk factors will be integrated in a flow chart in attempt to understand the deeper meaning of this regulatory machinery in paediatric hypertension. I will refer to the pathophysiology of early sympathetic-mediated hypertension arising from maternal obesity. Maternal diet-induced obesity in rodents permanently resets the responsiveness to leptin-induced SNS in rat offspring via the hypothalamic paraventricular nucleus (PVN)-MC4R pathway. The stimulus that mediates Leptin-SNS-MC4R activity and promotes hypertension is still unknown and remains as a key for future investigations. Future research needs to identify effective preventive measures in the pregnant mother and child to reduce the risk of paediatric hypertension and prevent future cardiovascular disease.

**Keywords:** essential hypertension, maternal obesity, leptin, melanocortin system, sympathetic activity, hypothalamus

## **1. Introduction**

Hypertension in children and adolescence is becoming an increasing health problem. The prevalence of pre-hypertension is approximately 14% in boys and 6% in girls (age 8–17 years)

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[1, 2], and the prevalence of hypertension is estimated to be 3–4% (age 3–18 years) [3, 4]. One in three of the hypertensive children develops end-organ damage, including ventricular hyper‐ trophy [5], chronic kidney disease [6] and vascular changes [7] and cognitive impairment [8, 9], all predictors for premature morbidity and mortality. Accumulating evidence supports the theory that elevated blood pressure levels in adolescence are a precursor of elevated blood pressure in adulthood, and an important risk factor for future cardiovascular diseases [10]. Another factor is the coexistent epidemic of childhood obesity, which in the US rose from 5 to 11% from the 1960s to the 1990 [11, 12], becoming a concomitant cardiovascular risk factor. Childhood BMI has strong positive concordance with blood pressure [13]. Children who are overweight demonstrate 4.5 and 2.3 times higher risk of developing increased systolic blood pressure and diastolic blood pressure, respectively [14], consistent findings were obtained by Sorof et al. [15] with a three-fold prevalence of childhood hypertension in obese versus lean at school age. Blood pressure in children may also vary by age, sex, race and height [4] but not as solid as BMI, all these inclusion criteria of risk being underdiagnosed [3]. Children within the "normotensive" range of blood pressure demonstrate elevated left ventricular mass [16] and greater risk of developing hypertension in adulthood [17]. Thus, blood pressure in children diverges from adults in that an underestimation of risk may cause severe cardiovascular diseases in adulthood [18]. Recent report indicates that more than 90% of children evaluated for hypertension have no underlying cause identified [19], which suggests that prevalence of essential hypertension is increasing. This revives the discussion of the aetiology and pathogen‐ esis research of essential hypertension to identify important targets of prevention.

## **2. Pathophysiology of childhood hypertension**

The origin of paediatric hypertension evolves a cluster of metabolic and haemodynamic disorders identifies as a polyfactorial disease. Unfavourable metabolic profiles, such as hyperinsulineaemia and dyslipidaemia, at an young age with abnormalities of vascular structure and function leads to adverse cardiovascular outcome [12, 20, 21]. The adverse metabolic profile may originate from an unbalanced autonomic nervous system (ANS). ANS is known as the major adaptor for stress responses which regulate the two neural efferent pathways the parasympathetic and sympathetic system [22]. Long-term increase to stress may lead to increased sympathetic activity and decreased parasympathetic activity, contri‐ buting to obesity, insulin resistance, dyslipidaemia and hypertension [23–25]. Dysregula‐ tion of ANS may therefore predict metabolic abnormalities [26, 27] and hypertension [22]. In children, these associations have barely been investigated. Childhood obesity has been associated with lower parasympathetic activity [28–31], but more conflicting results regard‐ ing the influence of the sympathovagal balance and sympathetic hyperactivity [31–33]. Possible confounding factors and differences in methodology and sample size might explain these differences. Latchman et al. [32] showed that normotensive obese 9-year-old children exhibited reduced baroreflex sensitivity, parasympathetic control as well as increased sympathetic control compared with normotensive lean children. Thus, suggest that auto‐ nomic dysfunction may precede the hypertension in obese children. Obesity is associated

with increased sympathetic nervous system (SNS) activity, with impaired heart rate varia‐ bility [34]. The resting heart rate is positively correlated with sub-capsular skinfold thick‐ ness in children [35]. Similar findings have been obtained in early origin of cardiometabolic disease. Foetuses born to obese mothers demonstrate increased foetal sympathetic activa‐ tion [36], which may predict long-term cardiovascular outcome.

## **3. Maternal obesity and offspring cardiovascular complications**

[1, 2], and the prevalence of hypertension is estimated to be 3–4% (age 3–18 years) [3, 4]. One in three of the hypertensive children develops end-organ damage, including ventricular hyper‐ trophy [5], chronic kidney disease [6] and vascular changes [7] and cognitive impairment [8, 9], all predictors for premature morbidity and mortality. Accumulating evidence supports the theory that elevated blood pressure levels in adolescence are a precursor of elevated blood pressure in adulthood, and an important risk factor for future cardiovascular diseases [10]. Another factor is the coexistent epidemic of childhood obesity, which in the US rose from 5 to 11% from the 1960s to the 1990 [11, 12], becoming a concomitant cardiovascular risk factor. Childhood BMI has strong positive concordance with blood pressure [13]. Children who are overweight demonstrate 4.5 and 2.3 times higher risk of developing increased systolic blood pressure and diastolic blood pressure, respectively [14], consistent findings were obtained by Sorof et al. [15] with a three-fold prevalence of childhood hypertension in obese versus lean at school age. Blood pressure in children may also vary by age, sex, race and height [4] but not as solid as BMI, all these inclusion criteria of risk being underdiagnosed [3]. Children within the "normotensive" range of blood pressure demonstrate elevated left ventricular mass [16] and greater risk of developing hypertension in adulthood [17]. Thus, blood pressure in children diverges from adults in that an underestimation of risk may cause severe cardiovascular diseases in adulthood [18]. Recent report indicates that more than 90% of children evaluated for hypertension have no underlying cause identified [19], which suggests that prevalence of essential hypertension is increasing. This revives the discussion of the aetiology and pathogen‐

esis research of essential hypertension to identify important targets of prevention.

The origin of paediatric hypertension evolves a cluster of metabolic and haemodynamic disorders identifies as a polyfactorial disease. Unfavourable metabolic profiles, such as hyperinsulineaemia and dyslipidaemia, at an young age with abnormalities of vascular structure and function leads to adverse cardiovascular outcome [12, 20, 21]. The adverse metabolic profile may originate from an unbalanced autonomic nervous system (ANS). ANS is known as the major adaptor for stress responses which regulate the two neural efferent pathways the parasympathetic and sympathetic system [22]. Long-term increase to stress may lead to increased sympathetic activity and decreased parasympathetic activity, contri‐ buting to obesity, insulin resistance, dyslipidaemia and hypertension [23–25]. Dysregula‐ tion of ANS may therefore predict metabolic abnormalities [26, 27] and hypertension [22]. In children, these associations have barely been investigated. Childhood obesity has been associated with lower parasympathetic activity [28–31], but more conflicting results regard‐ ing the influence of the sympathovagal balance and sympathetic hyperactivity [31–33]. Possible confounding factors and differences in methodology and sample size might explain these differences. Latchman et al. [32] showed that normotensive obese 9-year-old children exhibited reduced baroreflex sensitivity, parasympathetic control as well as increased sympathetic control compared with normotensive lean children. Thus, suggest that auto‐ nomic dysfunction may precede the hypertension in obese children. Obesity is associated

**2. Pathophysiology of childhood hypertension**

10 Update on Essential Hypertension

A large body of epidemiological literature supports the link between an adverse intrauterine environment and disease in later life, showing inverse association between low birth weights (poor nutrition) with subsequent hypertension [37–40]. Similar findings have been demon‐ strated in animal models of maternal malnutrition and uterine growth restriction (IUGR) [41]. Despite the worldwide obesity epidemic, relative few studies have investigated the influence of maternal obesity on offspring health, with only recent emerging human data suggesting detrimental effects with preterm mortality in the offspring [42]. Epidemiological study demonstrates associations between maternal BMI and increased systolic blood pressure (SBP) in 7-year-old children [43]. The Amsterdam Born Children and their Development (ABCD) study recently reported that maternal pre-pregnancy BMI, in 3074 women, was positively associated with childhood diastolic blood pressure (DBP) and SBP at the age of 5–6 [44]. In the Jerusalem perinatal study (JPS), both gestational weight gain (GWG) and pre-pregnancy BMI were related to cardiovascular risk factors including SBP and DBP in adult offspring, at the age of 32 [45]. A stronger association for maternal pre-pregnancy BMI than paternal BMI with adverse cardiometabolic health in offspring suggests a direct intrauterine mechanisms, instead of life-style-related characteristics or genetic factors [46]. However, the causation is difficult to establish in human cohort studies. Interestingly, a recent study demonstrated an increased risk for cardiovascular mortality in children born to obese mothers, and this association remained after removing the child BMI [42]. Thus, suggests a direct effect of maternal obesity on child cardiovascular function, independent of childhood obesity [42]. The WHO Global Burden of Disease database currently identifies a rapid rise in maternal obesity in the past two decades. In the US, 64% of women of reproductive age are overweight and 35% are obese [47], with a similar pattern in Europe [48] and the rest of the world [49–51]. Obese pregnant women not only develop a higher risk of preeclampsia, preterm labour, stillbirth, caesarean deliveries, there are also a higher incidence of developing diabetes and hypertension in the offspring [52]. The increasing rate of maternal obesity may therefore provide a major challenge to future generations' health. Children born to obese mothers not only are prone to develop obesity but also essential hypertension which is the primary risk factor for developing other cardiovas‐ cular diseases leading to premature death. Whilst further randomised controlled clinical trials of improved design are indicated, there is an important task to revisit the basic science of autonomic function using experimental models that mimics the human condition of essential hypertension.

#### **3.1. Autonomic dysfunction and paediatric hypertension**

The autonomic nervous system (ANS) has two principal divisions, the parasympathetic pathway and the sympathetic pathway which acts either in synergy or in opposition synergy. The autonomic system continuously controls heart rate and blood pressure, respiratory rate and gut motility, body temperature and other essential functions. The autonomic function interacts with the primitive brain, including the limbic system (memory function), brain stem and hypothalamus [53]. Neurons within hypothalamic nuclei, particularly the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMN), make direct or indirect connection with sympathetic and parasympathetic preganglionic neurons and interfere with autonomic balance, sympathetic hyperactivity and neurogenic hypertension [53]. Early stages of hyper‐ tension, particularly in children, are defined by autonomic dysfunction [54]. Excessive sympathetic activity and/or withdrawal of parasympathetic balance are assessed by HR variability (HRV), using the ratio of low to high frequency (LF/HF) power. Pioneering studies conducted by Urbina et al. showed altered HRV in 39 male adolescences and reported trends of higher LF/HF ratio with higher BP, but did not reach statistical significance [65]. In a larger cohort, Sorof et al. [20] reported increased HR and BP variability in obese children with isolated systolic hypertension assessed by office HR/BP measurement and ambulatory blood pressure monitoring (ABPM). Interestingly, obese hypertensive children had higher HR than non-obese hypertensive children, suggesting that obesity is independently related with SNS activation [20]. These initial findings of SNS hyperactivity in hypertensive children, measured by indirect methods, were later confirmed by direct measurement of sympathetic activity using micro‐ neurography [55]. Zhou et al. [56] demonstrated altered vagal and sympathetic activity in hypertensive children, with a greater influence of systolic blood pressure (SBP) than diastolic blood pressure (DBP) on HRV [57]. Genovesi et al. [58] demonstrated baroreflex impairment, in both hypertensive and pre-hypertensive children. Autonomic dysfunction is therefore considered a critical feature in pre-hypertensive children which may predict future cardio‐ vascular health. In children with arterial hypertension, the increase of sympathetic activity during sleep correlate with increase left ventricular mass and left ventricular mass index [59]. Moreover, HRV can predict the severity of children with pulmonary arterial hypertension [60]. This is particular worrisome as historical reference data on child HRV by Massin et al. [61] with current child HRV in Germany [62] showed change in children's ANS in the last 15 years. These changes constitute reduced vagal activity and a shift towards sympathetic dominance [62]. The authors suggest that these changes might be related to the rise in childhood obesity, with a negative association between BMI and ANS activity [62]. The historical samples of Kauzuma et al. [63], however, featured a comparable overweight rate (17%), but still reported much lower mean sympathetic activity. Additional factors including physical inactivity or nutrient composition may influence ANS [64, 65]. Maternal BMI, which recently been associ‐ ated with the offspring ANS activity, may be another important determinant [66]. Several different mechanisms leading to and maintaining central sympathetic hyperactivity in essential hypertension have been identified. An impaired vagal heart rate control exerted by arterial baroreflex impaired volume-sensitive cardiopulmonary reflex, arterial chemorecep‐ tors as well as humoral factors such as leptin and angiotensin II with direct central sympa‐ thoexcitatory effects have all been shown to play at least partial roles in essential hypertension.

## **3.2. Leptin and childhood obesity and hypertension**

**3.1. Autonomic dysfunction and paediatric hypertension**

12 Update on Essential Hypertension

The autonomic nervous system (ANS) has two principal divisions, the parasympathetic pathway and the sympathetic pathway which acts either in synergy or in opposition synergy. The autonomic system continuously controls heart rate and blood pressure, respiratory rate and gut motility, body temperature and other essential functions. The autonomic function interacts with the primitive brain, including the limbic system (memory function), brain stem and hypothalamus [53]. Neurons within hypothalamic nuclei, particularly the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMN), make direct or indirect connection with sympathetic and parasympathetic preganglionic neurons and interfere with autonomic balance, sympathetic hyperactivity and neurogenic hypertension [53]. Early stages of hyper‐ tension, particularly in children, are defined by autonomic dysfunction [54]. Excessive sympathetic activity and/or withdrawal of parasympathetic balance are assessed by HR variability (HRV), using the ratio of low to high frequency (LF/HF) power. Pioneering studies conducted by Urbina et al. showed altered HRV in 39 male adolescences and reported trends of higher LF/HF ratio with higher BP, but did not reach statistical significance [65]. In a larger cohort, Sorof et al. [20] reported increased HR and BP variability in obese children with isolated systolic hypertension assessed by office HR/BP measurement and ambulatory blood pressure monitoring (ABPM). Interestingly, obese hypertensive children had higher HR than non-obese hypertensive children, suggesting that obesity is independently related with SNS activation [20]. These initial findings of SNS hyperactivity in hypertensive children, measured by indirect methods, were later confirmed by direct measurement of sympathetic activity using micro‐ neurography [55]. Zhou et al. [56] demonstrated altered vagal and sympathetic activity in hypertensive children, with a greater influence of systolic blood pressure (SBP) than diastolic blood pressure (DBP) on HRV [57]. Genovesi et al. [58] demonstrated baroreflex impairment, in both hypertensive and pre-hypertensive children. Autonomic dysfunction is therefore considered a critical feature in pre-hypertensive children which may predict future cardio‐ vascular health. In children with arterial hypertension, the increase of sympathetic activity during sleep correlate with increase left ventricular mass and left ventricular mass index [59]. Moreover, HRV can predict the severity of children with pulmonary arterial hypertension [60]. This is particular worrisome as historical reference data on child HRV by Massin et al. [61] with current child HRV in Germany [62] showed change in children's ANS in the last 15 years. These changes constitute reduced vagal activity and a shift towards sympathetic dominance [62]. The authors suggest that these changes might be related to the rise in childhood obesity, with a negative association between BMI and ANS activity [62]. The historical samples of Kauzuma et al. [63], however, featured a comparable overweight rate (17%), but still reported much lower mean sympathetic activity. Additional factors including physical inactivity or nutrient composition may influence ANS [64, 65]. Maternal BMI, which recently been associ‐ ated with the offspring ANS activity, may be another important determinant [66]. Several different mechanisms leading to and maintaining central sympathetic hyperactivity in essential hypertension have been identified. An impaired vagal heart rate control exerted by arterial baroreflex impaired volume-sensitive cardiopulmonary reflex, arterial chemorecep‐ tors as well as humoral factors such as leptin and angiotensin II with direct central sympa‐ thoexcitatory effects have all been shown to play at least partial roles in essential hypertension.

Experimental models of maternal obesity in sheep, non-human primate and rodents provide evidence for the adverse influence on offspring cardiovascular function [67]. In rodents, the perinatal exposure to metabolic milieu of maternal obesity may permanently change the central pathways involved in blood pressure regulation [66]. Leptin, an adipocyte-derived hormone, promotes weight loss by reducing appetite and increasing energy expenditure through hypothalamic sympathetic stimulation to brown adipose tissue [68] and kidney [69] which results in increased arterial pressure [70]. This has been confirmed in chronic infusion of leptin in rats developing increased blood pressure [71]. Transgenic mice overexpressing leptin develops overt obesity with elevations of blood pressure [72]. Selective leptin resistance of the appetite and weight reducing effect of leptin [73], and preservation of the sympathetic action of leptin, been implicated in obesity-related hypertension [74]. In humans, high plasma leptin concentration has been associated with arterial pressure [75] and muscle sympathetic nerve activity [76]. Leptin is also thought to have a neurotrophic role in the development of the hypothalamus [77], and altered neonatal leptin profiles secondary to maternal obesity are associated with permanently altered brain hypothalamic structure and function. In rodent studies, maternal obesity confers persistent sympathoexcitatory hyper-responsiveness and hypertension acquired in the early stages of development [78]. Unrevealing the mechanisms controlling hypothalamic development may help to identify the nature of the hypothalamic dysfunction and develop future therapies. High leptin in cord blood from foetuses of obese mothers [79] might cause permanent changes of the hypothalamic circuits leading to height‐ ened leptin-induced sympathetic activity and blood pressure in juvenile offspring, prior to obesity and metabolic dysfunction [70].

#### **3.3. The role of the central melanocortin system**

The melanocortin system is an essential pathway in central regulation of metabolic and cardiovascular function. Central pro-opiomelanocortin (POMC) containing neurons in the arcuate nucleus (ARC) of the hypothalamus and the brain stem (e.g. nucleus of the tractus solitaries, NTS) project to other brain regions involved in energy homeostasis but also cardiovascular regulation [80]. The POMC neurons stimulate melanocortin receptor sub‐ type 3 (MC3R) and 4 (MC4R) and reduce appetite and increase energy expenditure, SNS activity and BP [80]. Mutation of the melanocortin-4 receptor (MC4R) or pro-opiomelanocor‐ tin (POMC) gene estimates for 5–6% of early onset obesity in human [81]. Pharmacological blockade of MC4R causes pronounced obesity in rodents [82], whereas activation of MC4R promotes weight loss by reducing appetite and increase energy expenditure [83, 84]. Con‐ versely, chronic MC4R activation causes sustained increased in BP despite reducing food intake and promoting weight loss [85]. MC4R-deficient rodents demonstrate reduced SNS activity and BP, independent of obesity [86]. Similar observations have been shown in humans, and MC4R deficiency leads to obesity but exhibits lower BP and reduced 24-h noradrenaline excretion compared with obese subjects with normal MC4R function [87, 88]. We and others have also demonstrated a critical role for the POMC-neurons MC4R axis in mediating appetite-suppressing and blood pressure effects of leptin [89, 90]. Rahmouni et al.

[89] showed that acute effect of leptin-induced hypophagia and renal SNS activity which were attenuated and abolished in heterozygous and homozygous MC4R knockout mice, respec‐ tively. Intact POMC neurons-MC4R axis is also required in chronic leptin-induced SNS activity and BP regulation [91]. MC4R antagonism markedly reduced BP in juvenile off‐ spring born to obese dams (OffOb) [90] and spontaneous hypertensive rats (SHR) [92] two experimental models of hypertension that is associated with increased SNS activity in the absence of obesity [70, 93]. MC4R antagonism also attenuates or abolishes the acute pressor responses to leptin that raises BP by SNS stimulation [92]. Collectively, these observations suggest that the MC4R plays a key role in contributing to elevated BP in several forms of hypertension that accompany SNS overactivity. Greatest abundance of MC4R is the paraven‐ tricular nucleus of the hypothalamus (PVN), lateral hypothalamus (LH), the amygdala, the NTS and the preganglionic sympathetic neurons, which are all important sites for regula‐ tion of autonomic function [80]. Although the specific contribution of MC4R in distinct CNS nuclei in mediating the actions of the brain melanocortin system on energy balance, appe‐ tite and glucose homeostasis has been the subject of intense investigation, the particular regions of the brain, where MC4R is the most important in regulation of SNS activity and BP, are still unclear. We have recently shown that the activation of MC4R in the PVN (using simcre genetic-modified mice) demonstrated increased BP in offspring of obese dams that were protected in the MC4R-mutated mice; suggest an important role for MC4R in PVN in contributing to early onset hypertension [90]. One study has also observed that specific neuronal populations including cholinergic preganglionic parasympathetic and sympathet‐ ic neurons are involved in MC4R-mediated hypertension [94]. The specific stimuli that mediate the effect of MC4R to evoke sustained increases in SNS activity to cardiovascularrelevant tissue and promote chronic increase in BP are still unknown and remain an impor‐ tant area for future investigations.

#### **3.4. Common genetic traits in paediatric hypertension**

There has been a great progress in elucidating molecular targets for hypertension from monogenic disorders [95]. Among the most significant findings has been from single-gene disorders with primary effect on blood pressure that acts via common pathway alterations including renin-angiotensin and melanocortin system [95]. Recent genome-wide association studies (GWASs), conducted mostly in Europeans, have identified >30 genomic loci associated with systolic/diastolic BP [96], including candidate genes angiotensinogen [97], angiotensinconverting enzyme (ACE) [98], and alpha 2 adrenergic receptor genes (ADRA2A) [98]. The GWAS analysis is, however, inconsistent between populations, with a great gene-environment interaction, that significantly contributes to the increased risk of hypertension [99]. Obesity is one of the most dominant risk factor of childhood hypertension with a common genetic traits in FTO [100] and downstream of MC4R [101]. Hypertension has been associated with the risk allele A for FTO rs9939609 and the risk allele C for MC4R rs17782313, independent of BMI [102, 103]. Recent study by Sun et al. demonstrated an association of the FTO rs9939609 and MC4R rs17782313 genes with nocturnal blood pressure in the Chinese Han population [104]. The effect sizes are, however, small for each individual genetic variant, typically 1 mmHg for SBP and 0.5 mmHg for DBP [105]. Even collectively, the 30 variants tested in one experiment explain only 1–2% of SBP and DBP variance [105]. Heritability of hypertension is estimated to be between 30 and 40% which is approximately 25 times larger than the phenotypic variation and disease risk currently explained by GWAS SNPs. The observation that only little of the total heritability can be currently be explained by the GWAS has led to the term "missing herita‐ bility" [106]. It is expected that many more yet undiscovered loci, possible including variants in the rare allele spectrum that might have larger effects sizes, will contribute to explain the missing heritability [106]. It has been suggested that epigenetic changes may account for the missing heritability determinants of complex diseases, such as hypertension.

#### **3.5. Epigenetic traits in experimental model of hypertension**

[89] showed that acute effect of leptin-induced hypophagia and renal SNS activity which were attenuated and abolished in heterozygous and homozygous MC4R knockout mice, respec‐ tively. Intact POMC neurons-MC4R axis is also required in chronic leptin-induced SNS activity and BP regulation [91]. MC4R antagonism markedly reduced BP in juvenile off‐ spring born to obese dams (OffOb) [90] and spontaneous hypertensive rats (SHR) [92] two experimental models of hypertension that is associated with increased SNS activity in the absence of obesity [70, 93]. MC4R antagonism also attenuates or abolishes the acute pressor responses to leptin that raises BP by SNS stimulation [92]. Collectively, these observations suggest that the MC4R plays a key role in contributing to elevated BP in several forms of hypertension that accompany SNS overactivity. Greatest abundance of MC4R is the paraven‐ tricular nucleus of the hypothalamus (PVN), lateral hypothalamus (LH), the amygdala, the NTS and the preganglionic sympathetic neurons, which are all important sites for regula‐ tion of autonomic function [80]. Although the specific contribution of MC4R in distinct CNS nuclei in mediating the actions of the brain melanocortin system on energy balance, appe‐ tite and glucose homeostasis has been the subject of intense investigation, the particular regions of the brain, where MC4R is the most important in regulation of SNS activity and BP, are still unclear. We have recently shown that the activation of MC4R in the PVN (using simcre genetic-modified mice) demonstrated increased BP in offspring of obese dams that were protected in the MC4R-mutated mice; suggest an important role for MC4R in PVN in contributing to early onset hypertension [90]. One study has also observed that specific neuronal populations including cholinergic preganglionic parasympathetic and sympathet‐ ic neurons are involved in MC4R-mediated hypertension [94]. The specific stimuli that mediate the effect of MC4R to evoke sustained increases in SNS activity to cardiovascularrelevant tissue and promote chronic increase in BP are still unknown and remain an impor‐

There has been a great progress in elucidating molecular targets for hypertension from monogenic disorders [95]. Among the most significant findings has been from single-gene disorders with primary effect on blood pressure that acts via common pathway alterations including renin-angiotensin and melanocortin system [95]. Recent genome-wide association studies (GWASs), conducted mostly in Europeans, have identified >30 genomic loci associated with systolic/diastolic BP [96], including candidate genes angiotensinogen [97], angiotensinconverting enzyme (ACE) [98], and alpha 2 adrenergic receptor genes (ADRA2A) [98]. The GWAS analysis is, however, inconsistent between populations, with a great gene-environment interaction, that significantly contributes to the increased risk of hypertension [99]. Obesity is one of the most dominant risk factor of childhood hypertension with a common genetic traits in FTO [100] and downstream of MC4R [101]. Hypertension has been associated with the risk allele A for FTO rs9939609 and the risk allele C for MC4R rs17782313, independent of BMI [102, 103]. Recent study by Sun et al. demonstrated an association of the FTO rs9939609 and MC4R rs17782313 genes with nocturnal blood pressure in the Chinese Han population [104]. The effect sizes are, however, small for each individual genetic variant, typically 1 mmHg for SBP and 0.5 mmHg for DBP [105]. Even collectively, the 30 variants tested in one experiment explain

tant area for future investigations.

14 Update on Essential Hypertension

**3.4. Common genetic traits in paediatric hypertension**

Recent years have shown a dramatic interest in the epigenetic trait of human disease. Pheno‐ typic variation is regulated independent of changes in DNA sequence, such as DNA methyl‐ ation, histone modification, chromatin remodelling and the action of small noncoding RNAs (microRNA) [107]. These epigenetic modifications change the accessibility of gene promoter sequence (by methyl donor) and binding domain [107]. Several animal studies have charac‐ terise epigenetic modification influenced by the intrauterine environment (maternal stress, nutrition and behaviour) [107]. In cardiovascular disease, recent studies of low-protein diet during pregnancy showed early onset hypertension in the offspring [108]. The renin-angio‐ tensin system showed to be a main target as angiotensin receptor (AT1R) antagonist reversed the hypertension in the offspring [108]. Consistent with these finding, offspring showed a hypomethylated AT1R gene promoter along with the increased expression of AT1R [109], suggesting a role for specific AT1R hypomethylation in regulating elevated blood pressure in this model. Similar epigenetic modification has been shown in the hypothalamic POMC neurons in a rat model of neonatal overfeeding [110]. Hypothalamic POMC showed hyper‐ methylated in the overfed neonates and consequently influence the set point of the melano‐ cortin system which is critical for metabolic and cardiovascular regulation [110]. Fewer studies of epigenetic changes have been conducted in primates, and there is little direct evidence relating this to humans. One study showed a correlation of epigenetic RXRA (retinoid X receptor alpha—induces transcription of PPARs) promoter methylation with increased adiposity in children of mothers with lower carbohydrate intake in two independent cohorts [111]. Although this fails to confirm a causal relationship, it may provide an objective marker in identifying children at risk of obesity and hypertension-induced cardiac hypertrophy [112].

#### **3.6. The role of central inflammation**

Several reports have demonstrated enhanced inflammatory profile with paediatric hyperten‐ sion [113, 114]. The C-reactive protein (CRP) which normally is involved in innate immune responses is heightened both in hypertensive and pre-hypertensive obese children, suggesting that systemic low-grade inflammation may precede hypertension [115]. This has been further confirmed in animal models of hypertension. Spontaneous hypertensive rats (SHR) a genetic model of essential hypertension demonstrate increased renal infiltration of lymphocytes and macrophages and activation of nuclear factor –kappa B (NF-kB) in 3-week-old pre-hyperten‐ sive rats [116]. Serum CRP has also been associated with cardiovascular risk factors in children including BP variability [117], intima media thickness [118], arterial stiffness [119], left ventricular hypertrophy [120]. Obese children and adolescence also demonstrate elevated serum concentration of pro-inflammatory cytokines interleukin-6 (IL-6) IL-1β and ICAM-1 (intercellular cell adhesion molecule-1) with increased ambulatory BP [121]. The pro-inflam‐ matory cytokines may also be increased due to obesity alone, independent of essential hypertension [122]. However, the highest concentration of these molecules was found in children with co-existing hypertension [114]. Mounting evidence suggests that the proinflammatory condition in mother may induce inflammation-induced hypertension in their offspring [123]. An overactive immune response during pregnancy, as shown in obese pregnancy [124], can lead to chronic neuro-inflammation in the foetus [125]. Activated microglia, resident immune cells in the brain, increases pro-inflammatory cytokines release from the PVN, which stimulate preganglionic nerve fibres and sympathetic nerve activity (SNA) [126]. Vice versa, SNA has a direct impact on microglia via adrenergic receptors [127] or indirect via regulating distribution and production of lymphocytes, or modulating the release of pro-inflammatory peptides. SNA is also involved in inflammatory cell recruitment and redistribution, and SNA mobilise inflammatory cells from spleen and bone marrow [128]. In addition, parasympathetic nervous system has anti-inflammatory effects [129]. Vagal afferents sense peripheral inflammation and feedback via the cholinergic anti-inflammatory pathway [129]. There are also important direct effects of cytokines and angiotensin II on the brain that certainly could contribute to SNA [129, 130]. Catheter-base renal denervation is a promising therapeutic approach to treat hypertension [131], and recent animal studies suggest

**Figure 1.** Mechanistic overview of the developmental origin of hypertension.

an improvement of renal inflammation with reduced renal macrophages and levels of cortical TNF-alpha and suggest a potential target for renal injury and dysfunction [132]. Minocyclin treatment, an anti-inflammatory antibiotic that crosses the blood brain barrier, has shown to prevent autonomic dysfunction and hypertension in experimental models of hypertension [126]. The reduction in blood pressure was associated with "de-activation" of the microglia in the PVN [126]. Overall, all these studies suggest a potentially important link between inflam‐ mation, melanocortin system, developing brain and autonomic dysfunction in the environ‐ mental and genetic predisposition of hypertension arising from maternal diet-induced obesity (**Figure 1**).

## **4. Future research and intervention strategies**

Paediatric hypertension has been gaining significant attention in the last decade, mainly due to the increased prevalence worldwide. The estimated prevalence of paediatric hypertension is from 1 to 10%, with a steady rise over time. Alarming rate of childhood obesity and metabolic syndrome with the precondition of maternal obesity may worsen the future cardiovascular morbidity and mortality. This could be hypothetically prevented by early diagnosis and management in children before they even develop the pathophysiological progression state of hypertension. In fact, certain drugs may fail to reduce sympathetic hyperactivity as other stimuli of SNA have become predominant in elevating SNA, which are independent of the standard antihypertensive strategies. The progress and impact of preventive blood pressure screening for children could also inhibit adult hypertension and cardiovascular disease. Therefore, increased alertness to paediatric hypertension including several risk parameters (genetic, maternal, inflammatory, adiposity) and standardise sequential ABPM monitoring to avoid "white-coat" and "masked" hypertension in the diagnosis could improve future statistics in adverse cardiovascular outcome. Research effort should continue with the goal to clarify the aetiology, complexity and inheritable factors of paediatric hypertension. Research efforts should also focus on optimal treatment of these children and on effective preventive measures starting in the pregnant mother to the child at a young age.

## **Author details**

including BP variability [117], intima media thickness [118], arterial stiffness [119], left ventricular hypertrophy [120]. Obese children and adolescence also demonstrate elevated serum concentration of pro-inflammatory cytokines interleukin-6 (IL-6) IL-1β and ICAM-1 (intercellular cell adhesion molecule-1) with increased ambulatory BP [121]. The pro-inflam‐ matory cytokines may also be increased due to obesity alone, independent of essential hypertension [122]. However, the highest concentration of these molecules was found in children with co-existing hypertension [114]. Mounting evidence suggests that the proinflammatory condition in mother may induce inflammation-induced hypertension in their offspring [123]. An overactive immune response during pregnancy, as shown in obese pregnancy [124], can lead to chronic neuro-inflammation in the foetus [125]. Activated microglia, resident immune cells in the brain, increases pro-inflammatory cytokines release from the PVN, which stimulate preganglionic nerve fibres and sympathetic nerve activity (SNA) [126]. Vice versa, SNA has a direct impact on microglia via adrenergic receptors [127] or indirect via regulating distribution and production of lymphocytes, or modulating the release of pro-inflammatory peptides. SNA is also involved in inflammatory cell recruitment and redistribution, and SNA mobilise inflammatory cells from spleen and bone marrow [128]. In addition, parasympathetic nervous system has anti-inflammatory effects [129]. Vagal afferents sense peripheral inflammation and feedback via the cholinergic anti-inflammatory pathway [129]. There are also important direct effects of cytokines and angiotensin II on the brain that certainly could contribute to SNA [129, 130]. Catheter-base renal denervation is a promising therapeutic approach to treat hypertension [131], and recent animal studies suggest

16 Update on Essential Hypertension

**Figure 1.** Mechanistic overview of the developmental origin of hypertension.

Anne-Maj Sofia Samuelsson

Address all correspondence to: anne-maj.samuelsson@kcl.ac.uk

Division of Women's Health, King's College London, Women's Health Academic Centre KHP, London, UK

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## **Oxidative Stress and Essential Hypertension**

Ramón Rodrigo, Roberto Brito and Jaime González

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/64079

#### **Abstract**

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26 Update on Essential Hypertension

Experimental evidence supports a pathogenic role of free radicals or reactive oxygen species (ROS) in the mechanism of hypertension. Indeed, vascular ROS produced in a controlled manner are considered important physiological mediators, functioning as signaling molecules to maintain vascular integrity by regulating endothelial function and vascular contraction‐relaxation. However, oxidative stress can be involved in the occurrence of endothelial dysfunction and related vascular injury. Thus, ROS activity could trigger pathophysiological cascades leading to inflammation, monocyte migration, lipid peroxidation, and increased deposition of extracellular matrix in the vascular wall, among other events. In addition, impairment of the antioxidant capacity associates with blood pressure elevation, indicating potential role of antioxidants as therapeutic antihypertensive agents. Nevertheless, although increased ROS biomark‐ ers have been reported in patients with essential hypertension, the involvement of oxidative stress as a causative factor of human essential hypertension remains to be established. The aim of this chapter is to provide a novel insight into the mechanism of essential hypertension, including a paradigm based on the role played by oxidative stress.

**Keywords:** essential hypertension, oxidative stress, antioxidants, endothelial dysfunc‐ tion, nitric oxide

## **1. Introduction**

Hypertension is a major risk factor for cardiovascular disease [1]. Recently, a growing body of evidence has involved oxidative stress in the mechanism of development of hyperten‐ sion. Indeed, reactive oxygen species (ROS) contribute to regulating the biological processes occurring in the vascular wall, both in normal physiological conditions, as well as in the occurrence of hypertension [2–4]. Available evidence of the contribution of oxidative stress in

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the pathogenesis of human hypertension includes enhancement of ROS production, togeth‐ er with decreased bioavailability of both nitric oxide (NO) and antioxidants. The first‐ formed ROS is superoxide anion radical, which is produced from NADPH oxidase (NOX), an enzyme subjected to regulation by hormones such as angiotensin II (AT‐II), endothelin‐1 (ET‐ 1), and urotensin II (UT‐II), among others. Furthermore, mechanical stimuli known to occur in blood pressure elevation further contribute to increased ROS production. It is of interest to mention that increased intracellular calcium concentration may result from ROS‐induced vasoconstriction, thus enhancing the development of hypertension [2]. The regulation of vasomotor tone depends upon a delicate balance between vasoconstrictor and vasodilator forces, the latter being likely to be modulated by oxidative stress. This view has stimulated the interest for searching novel antihypertensive therapies aimed to decrease ROS genera‐ tion and/or increase NO bioavailability. The present study was aimed to present an update of the available studies related to the role of oxidative stress in the mechanism of development of blood pressure elevation, as well as the role of antioxidants in the prevention or treat‐ ment of this derangement.

## **2. Pathophysiology of hypertension**

#### **2.1. Endothelial dysfunction**

The response to cardiovascular risk factors is expressed in alterations of endothelial function, a chronic inflammatory process characterized by loss of antithrombotic factors and an increase in vasoconstrictor and prothrombotic products, thus elevating the risk of cardiovascular events. Consequently, an impairment of the ability of endothelium to induce vasodilation leads to hypertension. Recently, it has been argued that ROS play a key role in this pathological process.

#### **2.2. Role of vascular oxidative stress in hypertension**

The occurrence of oxidative stress is due to an imbalance between ROS generation and the antioxidant potential in the body, the latter being overwhelmed by the increased ROS con‐ centration in the steady state. It should be noted that although ROS are mediators of normal biological effects related to vascular function at the cell level, the increased levels of these species can give rise to pathological changes, as those observed in cardiovascular disease. ROS behave as redox‐sensitive blood pressure modulators [5–7]. Accordingly, increased ROS concentration has been demonstrated both in patients with essential hypertension and in various animal models of hypertension [8–12]. In addition, this derangement is accompanied by a decreased antioxidant potential [13]. Therefore, these data provide evidence of the involvement of vascular oxidative stress in the mechanism of development of essential hypertension [2, 3, 14]. Furthermore, a strong association between blood pressure and oxidative stress‐related parameters has been found, such as plasma 8‐isoprostane levels [15]. Interestingly, studies performed in mice models having genetic deficiency in ROS‐generating enzymes showed that these animals had lower blood pressure than control with wild‐type mice [16, 17]. Moreover, at the cellular level, it has been reported that ROS production is enhanced in cultured vascular smooth muscle cells (VSMC) isolated from both hypertensive rats and isolated arteries of hypertensive human patients; these findings are associated with amplified, redox‐dependent signaling and reduced antioxidant bioactivity [18]. These reports could support the view that the modulation of oxidative stress could be expressed in blood pressure lowering in the case of known antihypertensive agents, such as β‐adrenergic blockers, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, and calcium channel blockers [19, 20].

#### *2.2.1. Vascular ROS sources*

the pathogenesis of human hypertension includes enhancement of ROS production, togeth‐ er with decreased bioavailability of both nitric oxide (NO) and antioxidants. The first‐ formed ROS is superoxide anion radical, which is produced from NADPH oxidase (NOX), an enzyme subjected to regulation by hormones such as angiotensin II (AT‐II), endothelin‐1 (ET‐ 1), and urotensin II (UT‐II), among others. Furthermore, mechanical stimuli known to occur in blood pressure elevation further contribute to increased ROS production. It is of interest to mention that increased intracellular calcium concentration may result from ROS‐induced vasoconstriction, thus enhancing the development of hypertension [2]. The regulation of vasomotor tone depends upon a delicate balance between vasoconstrictor and vasodilator forces, the latter being likely to be modulated by oxidative stress. This view has stimulated the interest for searching novel antihypertensive therapies aimed to decrease ROS genera‐ tion and/or increase NO bioavailability. The present study was aimed to present an update of the available studies related to the role of oxidative stress in the mechanism of development of blood pressure elevation, as well as the role of antioxidants in the prevention or treat‐

The response to cardiovascular risk factors is expressed in alterations of endothelial function, a chronic inflammatory process characterized by loss of antithrombotic factors and an increase in vasoconstrictor and prothrombotic products, thus elevating the risk of cardiovascular events. Consequently, an impairment of the ability of endothelium to induce vasodilation leads to hypertension. Recently, it has been argued that ROS play a key role in this pathological

The occurrence of oxidative stress is due to an imbalance between ROS generation and the antioxidant potential in the body, the latter being overwhelmed by the increased ROS con‐ centration in the steady state. It should be noted that although ROS are mediators of normal biological effects related to vascular function at the cell level, the increased levels of these species can give rise to pathological changes, as those observed in cardiovascular disease. ROS behave as redox‐sensitive blood pressure modulators [5–7]. Accordingly, increased ROS concentration has been demonstrated both in patients with essential hypertension and in various animal models of hypertension [8–12]. In addition, this derangement is accompanied by a decreased antioxidant potential [13]. Therefore, these data provide evidence of the involvement of vascular oxidative stress in the mechanism of development of essential hypertension [2, 3, 14]. Furthermore, a strong association between blood pressure and oxidative stress‐related parameters has been found, such as plasma 8‐isoprostane levels [15]. Interestingly, studies performed in mice models having genetic deficiency in ROS‐generating enzymes showed that these animals had lower blood pressure than control with wild‐type

ment of this derangement.

28 Update on Essential Hypertension

**2.1. Endothelial dysfunction**

process.

**2. Pathophysiology of hypertension**

**2.2. Role of vascular oxidative stress in hypertension**

There are various ROS sources formed in blood vessels, from both enzymatic and non‐ enzymatic origin. Together with the mitochondrion, the major enzymatic sources comprise NADPH oxidase (NOX), xanthine oxidase (XO), and uncoupled NO synthase.

## *2.2.1.1. NADPH oxidase*

In the vascular wall, as well as in the kidney, superoxide anion is mainly produced enzymat‐ ically through NOX activity; consequently, the upregulation of this enzyme exerts an impor‐ tant pathogenic role in the development of renal dysfunction and vascular damage [12, 21]. The enhanced activity of NOX in hypertension is achieved through mechanical and humoral signals, with AT‐II being the most studied stimulus. However, it is important to remark that ET‐1 and UT‐II cooperatively participate in NOX activation. In addition, NOX‐derived superoxide anion is able to inactivate NO, thus producing peroxynitrite anion. The latter induces downregulation of prostacyclin synthase, further allowing the development of hypertension. Finally, oxidative stress leads to eNOS uncoupling [16, 22]. Therefore, several effects contribute to the impairment of endothelial function related to oxidative stress. In summary, increased superoxide anion, decreased NO bioavailability, and decreased prosta‐ cyclin synthesis contribute to the impairment of endothelium‐dependent vasodilation. Thus, NOX activation in the vascular wall results in several effects contributing to the mechanism of development of hypertension [23].

#### *2.2.1.2. Uncoupled endothelial NO synthase*

The vascular tone is modulated by vasoconstriction‐vasodilation balance, and NO bioavaila‐ bility constitutes an important component of the latter process. The NO production is partly dependent upon the activity of eNOS. However, other factors, such as L‐arginine and tetra‐ hydrobiopterin (BH4) availability, are also required as substrate and coupling factor, respec‐ tively. Deficiency or oxidation of either of these two factors will result in decreased NO production. The initial ROS source is NOX‐dependent superoxide generation. Furthermore, peroxynitrite is formed through the reaction between NO and superoxide [24]. The activity and function of eNOS are changed due to the peroxidant ability generated by peroxynitrite, and this enzyme produces more superoxide instead of NO [22, 25]. This vicious cycle results in BH4 oxidation, thereby promoting eNOS uncoupling and enhancement in ROS production.

## *2.2.1.3. Xanthine oxidase*

This enzyme system provides an important endothelial source of superoxide in the vascular wall [23, 26]. XO‐catalyzed reactions lead to oxygen reduction to produce superoxide from purine metabolism. It has been reported that spontaneously hypertensive rats demonstrate increased levels of both endothelial XO activity and ROS production, together with increased arteriolar tone [21]. Furthermore, it was suggested that XO may contribute to end‐organ damage in hypertension [27].

#### *2.2.1.4. Mitochondrial dysfunction*

The mitochondrion could behave as both a ROS source and target. Superoxide is produced in the intermembrane space, but it is rapidly carried to the cytoplasm [28]. Either ubiquinol or coenzyme Q could be a source of superoxide when these mitochondrial components are partially reduced; but these molecules behave as antioxidants when they are fully reduced [29]. Superoxide produced by mammalian mitochondria in vitro mostly comes from complex I. This high rate of complex I‐dependent superoxide production can be very effectively decreased through mild uncoupling. In addition, it was found that patients with hypertension show reduced activity of antioxidant enzymes [30].

#### *2.2.2. Role of vascular wall components*

In response to mechanical and hormonal stimuli, the endothelium releases agents participating in the regulation of vasomotor tone. Particularly relevant is the ability of endothelium to exert a protective role through the generation of vasorelaxing factors. In addition, pathophysiolog‐ ical conditions result in increased released of endothelium‐derived vasoconstricting factors, such as ET‐1, AT‐II, UT‐II, superoxide anions, vasoconstrictor prostaglandins, and thrombox‐ ane A2, all of them capable of producing vasoconstrictor effects. It should be mentioned that VSMC contribute to modulating blood pressure not solely in short‐term regulation of the blood vessel diameter, but also in the structural remodeling occurring during long‐term adaptation, both processes being mediated by ROS. It is of interest considering that the adventitia can also participate in the development of hypertension, which is achieved through ROS contribution in either reduction of NO bioavailability or vascular remodeling.

#### *2.2.3. Role of vascular hormones and factors*

#### *2.2.3.1. Nitric oxide*

NO plays a key role as a paracrine regulator of vascular tone. It is involved in the physiological regulation responsible for the maintenance of the health of vascular endothelium through processes such as inhibition of leukocyte‐endothelial cell adhesion, VSMC proliferation and migration, and platelet aggregation. The effect of decreased NO bioavailability is particularly relevant, leading to reduction of vasodilatory capacity in the vasculature, thereby providing a mechanism of hypertension. The formation of NO from the substrates oxygen and L‐arginine is catalyzed by the enzyme eNOS, being the predominant isoform of NOS family in the vascular wall. This enzyme can be rapidly activated by receptor‐mediated agonist stimulation, shear stress, and allosteric modulators [31]. It is of interest to mention that NO diffuses easily to the adjacent VSMC, thus binding to receptors such as soluble guanylyl cyclase. The numerous NO biological properties include not only vasorelaxing and antiproliferative actions but also antagonizing the effects of AT‐II, endothelins and ROS, among other vasoconstrictors. Though L‐arginine, a substrate for eNOS, could be considered as a promising factor in preserving NO formation, it failed to prevent blood pressure elevation and left ventricle remodeling in a model based on chronic treatment with the methyl ester of N‐nitro‐L‐arginine (L‐NAME), an inhibitor of eNOS [32]. Furthermore, NO‐deficient hypertension was completely prevented by the ACE inhibitor captopril, yet without improving NOS activity. Another reported effect for NO consists of its ability to exert an ACE downregulation effect. NO half‐life can be prolonged by thiols, as these compounds protect NO from oxidation and are able to form nitrosothiols [33, 34]. It should be remarked that reduced NO levels can be the result of its combination with superoxide to form peroxynitrite, a compound capable of enhancing oxidative stress by oxidizing BH4, destabilizing eNOS, and producing more superoxide [22, 24, 25]. The impor‐ tance of the balance between NO and AT‐II in the regulation of the sympathetic tone has been reported.

#### *2.2.3.2. Renin‐angiotensin system*

*2.2.1.3. Xanthine oxidase*

30 Update on Essential Hypertension

damage in hypertension [27].

*2.2.1.4. Mitochondrial dysfunction*

reduced activity of antioxidant enzymes [30].

in either reduction of NO bioavailability or vascular remodeling.

*2.2.2. Role of vascular wall components*

*2.2.3. Role of vascular hormones and factors*

*2.2.3.1. Nitric oxide*

This enzyme system provides an important endothelial source of superoxide in the vascular wall [23, 26]. XO‐catalyzed reactions lead to oxygen reduction to produce superoxide from purine metabolism. It has been reported that spontaneously hypertensive rats demonstrate increased levels of both endothelial XO activity and ROS production, together with increased arteriolar tone [21]. Furthermore, it was suggested that XO may contribute to end‐organ

The mitochondrion could behave as both a ROS source and target. Superoxide is produced in the intermembrane space, but it is rapidly carried to the cytoplasm [28]. Either ubiquinol or coenzyme Q could be a source of superoxide when these mitochondrial components are partially reduced; but these molecules behave as antioxidants when they are fully reduced [29]. Superoxide produced by mammalian mitochondria in vitro mostly comes from complex I. This high rate of complex I‐dependent superoxide production can be very effectively decreased through mild uncoupling. In addition, it was found that patients with hypertension show

In response to mechanical and hormonal stimuli, the endothelium releases agents participating in the regulation of vasomotor tone. Particularly relevant is the ability of endothelium to exert a protective role through the generation of vasorelaxing factors. In addition, pathophysiolog‐ ical conditions result in increased released of endothelium‐derived vasoconstricting factors, such as ET‐1, AT‐II, UT‐II, superoxide anions, vasoconstrictor prostaglandins, and thrombox‐ ane A2, all of them capable of producing vasoconstrictor effects. It should be mentioned that VSMC contribute to modulating blood pressure not solely in short‐term regulation of the blood vessel diameter, but also in the structural remodeling occurring during long‐term adaptation, both processes being mediated by ROS. It is of interest considering that the adventitia can also participate in the development of hypertension, which is achieved through ROS contribution

NO plays a key role as a paracrine regulator of vascular tone. It is involved in the physiological regulation responsible for the maintenance of the health of vascular endothelium through processes such as inhibition of leukocyte‐endothelial cell adhesion, VSMC proliferation and migration, and platelet aggregation. The effect of decreased NO bioavailability is particularly relevant, leading to reduction of vasodilatory capacity in the vasculature, thereby providing a mechanism of hypertension. The formation of NO from the substrates oxygen and L‐arginine is catalyzed by the enzyme eNOS, being the predominant isoform of NOS family in the vascular

There is cumulated evidence supporting that the renin‐angiotensin system (RAS) contributes to the development of cardiovascular disease. The production of AT‐II, a potent vasoactive peptide, occurs in vascular beds having important ACE activity. Increased AT‐II production above normal levels is able to induce vascular remodeling and endothelial dysfunction, as well as increases in levels of blood pressure. At the cell level, AT‐II acts as a potent NOX activator, thus leading to enhancement of ROS production [35, 36]. It was reported that the expression of NOX subunits, oxidase activity, and ROS production are all increased in rat and mice models of hypertension achieved by AT‐II infusion [37]. In addition, the effect of AT‐II is not only confined to increasing NADPH oxidase activity but also upregulating SOD, likely as a compensation mechanism against ROS increase. Consequently, ROS levels and oxidative stress biomarkers may appear normal despite the occurrence of an oxidative challenge. However, the consequences of oxidative stress will be apparent when ROS production becomes overwhelming and the compensatory mechanisms are inadequate, thus explaining the pathophysiological consequences [38]. Pharmacological inhibition of ACE by captopril and enalapril prevented blood pressure rise in young spontaneously hypertensive rats. The hypotensive effect of captopril is higher than that of enalapril, which could be due to the antioxidant role of its thiol group [39]. Interestingly, NO not only antagonizes the vascular effects of AT‐II on blood pressure, cell growth, and renal sodium excretion but also downre‐ gulates the synthesis of ACE and AT1 receptors. In addition, upregulation of eNOS expression has been reported as a consequence of ACE inhibition [40]. Recently, a relationship through Ca2+/calmodulin‐dependent protein kinase II has been proposed to link the actions of AT‐II and ROS in cardiovascular pathological conditions [41].

## *2.2.3.3. Acetylcholine*

The endothelium‐dependent vasodilation by acetylcholine (Ach) in vascular vessels occurs mainly via NO production. NO rapidly diffuses to the underlying VSMC, thereby inducing relaxation in these cells. Under oxidative stress conditions, a diminution in NO bioavailability should be expected, thus leading to significantly reduced ACh‐mediated vasodilation [40].

## *2.2.3.4. Endothelin‐1*

Vascular endothelium, among others vascular tissues, produces potent vasoconstrictor isopeptides known as endothelins. ET‐1 is the major endothelin generated by endothelial cells, and is probably the most important in cardiovascular physiology and disease. It has been demonstrated that large concentration of exogen ET‐1 acts as potent vasoconstrictor capable of altering arterial pressure. ET‐1 mediates its effect through two receptors, ETA and ETB. ETA exerts its effects via activation of NOX, XO, lipoxygenase, uncoupled NOS, and mitochondrial respiratory chain enzymes. ETB induces relaxation on endothelial cells [42]. The vasocon‐ stricting action of ET‐1 is counteracted by vasodilators such as prostacyclin (PGI2) and/or NO, and it has been seen that many factors that stimulate ET‐1 synthesis (e.g. thrombin, AT‐II) also cause the release of the vasodilators above mentioned. Several studies reported in primary hypertension demonstrate an increased ET‐1 vasoconstrictor tone, apparently dependent on decreased endothelial ETB‐mediated NO production, contributing to NO bioavailability impairment.

### *2.2.3.5. Urotensin‐II*

UT‐II is the most potent vasoconstrictor identified [43]. It acts through the activation of NOX. UT receptors have been identified in several other organs besides vascular bed, suggesting that vasoconstriction is not its only effect [44, 45]. UT‐II has also been shown to act as a potent vasodilator in some models [46]. Nevertheless, the role of UT‐II in disease is not fully elucidated yet.

### *2.2.3.6. Norepinephrine*

VSMC is innervated primarily by the sympathetic nervous system through three types of adrenergic receptors: α1, α2 and β2. VSMC proliferation is stimulated by norepinephrine. Interestingly, blood pressure is increased by over‐expression of inducible nitric oxide synthase (iNOS) through central activation of the sympathetic nervous system, mainly mediated by an increase in oxidative stress [5].

### *2.2.3.7. Prostaglandins*

PGI2 is considered one of the most important vasodilators depending on the endothelium and relaxes the vascular musculature. A large amount of substances that generate an increase in PGI2 release have been described, such as thrombin, arachidonic acid, histamine, and seroto‐ nin. Prostaglandin H2 is formed by the prostaglandin H2 synthase, which uses arachidonic acid as a substrate. Then, prostaglandin H2 is converted to PGI2, a vasoactive molecule. Oxidative stress‐related conditions, such as hypertension, impair the PGI2‐mediated vasodi‐ lation. It has been demonstrated that peroxynitrite inhibits the enzymatic activity of prosta‐ cyclin synthase. Thus, the isoform prostaglandin H2 synthase‐2 may mediate vascular dysfunction under such conditions.

## *2.2.3.8. Homocysteine*

*2.2.3.3. Acetylcholine*

32 Update on Essential Hypertension

*2.2.3.4. Endothelin‐1*

impairment.

yet.

*2.2.3.5. Urotensin‐II*

*2.2.3.6. Norepinephrine*

*2.2.3.7. Prostaglandins*

increase in oxidative stress [5].

The endothelium‐dependent vasodilation by acetylcholine (Ach) in vascular vessels occurs mainly via NO production. NO rapidly diffuses to the underlying VSMC, thereby inducing relaxation in these cells. Under oxidative stress conditions, a diminution in NO bioavailability should be expected, thus leading to significantly reduced ACh‐mediated vasodilation [40].

Vascular endothelium, among others vascular tissues, produces potent vasoconstrictor isopeptides known as endothelins. ET‐1 is the major endothelin generated by endothelial cells, and is probably the most important in cardiovascular physiology and disease. It has been demonstrated that large concentration of exogen ET‐1 acts as potent vasoconstrictor capable of altering arterial pressure. ET‐1 mediates its effect through two receptors, ETA and ETB. ETA exerts its effects via activation of NOX, XO, lipoxygenase, uncoupled NOS, and mitochondrial respiratory chain enzymes. ETB induces relaxation on endothelial cells [42]. The vasocon‐ stricting action of ET‐1 is counteracted by vasodilators such as prostacyclin (PGI2) and/or NO, and it has been seen that many factors that stimulate ET‐1 synthesis (e.g. thrombin, AT‐II) also cause the release of the vasodilators above mentioned. Several studies reported in primary hypertension demonstrate an increased ET‐1 vasoconstrictor tone, apparently dependent on decreased endothelial ETB‐mediated NO production, contributing to NO bioavailability

UT‐II is the most potent vasoconstrictor identified [43]. It acts through the activation of NOX. UT receptors have been identified in several other organs besides vascular bed, suggesting that vasoconstriction is not its only effect [44, 45]. UT‐II has also been shown to act as a potent vasodilator in some models [46]. Nevertheless, the role of UT‐II in disease is not fully elucidated

VSMC is innervated primarily by the sympathetic nervous system through three types of adrenergic receptors: α1, α2 and β2. VSMC proliferation is stimulated by norepinephrine. Interestingly, blood pressure is increased by over‐expression of inducible nitric oxide synthase (iNOS) through central activation of the sympathetic nervous system, mainly mediated by an

PGI2 is considered one of the most important vasodilators depending on the endothelium and relaxes the vascular musculature. A large amount of substances that generate an increase in PGI2 release have been described, such as thrombin, arachidonic acid, histamine, and seroto‐ nin. Prostaglandin H2 is formed by the prostaglandin H2 synthase, which uses arachidonic acid as a substrate. Then, prostaglandin H2 is converted to PGI2, a vasoactive molecule.

It has been proposed that homocysteine plays an important role in the pathophysiology of primary hypertension [3]. An increase in homocysteinemia augments the proliferation of VSCM, thus altering the elasticity of vascular wall; it generates an oxidative stress state and diminishes NO bioavailability, thus impairing vasodilation. All the mechanisms exposed contribute to elevated blood pressure [47]. Homocysteine could also lead to endothelium oxidative damage [3]. The administration of vitamins B6, B12, and folic acid has been proposed as a potential adjuvant treatment in hypertension, probably by correcting the increased homocysteinemia [3, 48]. Despite the above mentioned, further randomized controlled trials are required to establish the efficacy of these therapeutic agents in the treatment of hyperten‐ sion.

A hypothesis for the role of vascular oxidative stress in hypertension is depicted in **Figure 1**.

Besides the key role of ROS production in the vasculature and its relation to hypertension, it has been demonstrated that hypertensive stimuli, such as high salt and AT‐II, also increase the production in the kidney and the central nervous system, contributing either to generate hypertension or to the untoward sequels of this disease [49, 50]

**Figure 1.** Schematic summary of the role of vascular oxidative stress in the pathogenesis of hypertension. NO: nitric oxide, eNOS: nitric oxide synthase, BH4: tetrahydrobiopterin, and mPTP: mitochondrial permeability transition pore.

## **3. Antioxidants in hypertension**

This section refers to the antihypertensive role of endogenous and exogenous antioxidants that have demonstrated their ability to alter the blood vessels' function and to participate in the main redox reactions involved in the pathophysiology of hypertension.

## **3.1. Vitamin C**

Vitamin C (or ascorbate) is a potent and widely used antioxidant, characteristically water‐ soluble. It has been described that this antioxidant could act as an enzyme modulator on the vascular wall, upregulating eNOS and downregulating NOX [51]. An inverse relationship between vitamin C plasma levels and arterial pressure in both healthy and hypertensive population has been demonstrated in several studies [15]. Antioxidant supplementation improves vascular function and reduces blood pressure in both experimental models [52, 53] and in patients [54, 55]. Ascorbate may improve vasodilation, probably by increasing NO bioavailability [56–58]. Vitamin C could protect BH4 from oxidation, which leads to an increase in the enzymatic activity of eNOS.

Despite the rationale of using vitamin C as an antihypertensive molecule, several clinical trials with methodological differences (including number of patients and follow‐up) have yielded inconsistent outcomes [59–64]. The absence of antihypertensive effect observed in trials using the administration of ascorbate could be due to the lack of consideration of its pharmacological characteristics, mainly pharmacokinetics. It was determined in experimental conditions that the antihypertensive effect of ascorbate is reachable at a plasma concentration of 10 mM [57]. This concentration allows ascorbate to efficiently compete against the reaction between NO and superoxide, which is increased in oxidative stress–related conditions such as hyperten‐ sion. The plasma level mentioned earlier is not reachable through oral administration of vitamin C. Daily oral doses of vitamin C between 60 and 100 mg are sufficient for the renal ascorbate threshold to occur. Plasma is completely saturated at doses of 400 mg daily, leading to a steady state level of 80 μM [65]. Therefore, it is plausible to propose that the antihyper‐ tensive effect of ascorbate would only be reachable with a high‐dose infusion.

### **3.2. Vitamin E**

Vitamin E is a lipid‐soluble antioxidant which has received significant attention during the last decades. An epidemiological association between high dietary vitamin E intake and a lower incidence of cardiovascular disease has been established [58]. A growing body of evidence indicates that vitamin E, besides its antioxidant properties, could act as a biological modifier and is also capable of regulating mitochondrial generation of free radicals in a dose‐ dependent manner.

Interestingly, some studies fail to demonstrate the beneficial effects of vitamin E in cardiovas‐ cular disease patients [66–69]. Moreover, one trial proving vitamin E supplementation showed an increase in blood pressure and cardiac frequency in type 2 diabetes patients [70]. Probably, vitamin E by itself is unlikely to achieve enough levels to counteract all components of oxidative stress acting in primary hypertension [71].

## **3.3. Association of vitamins C and E**

Alfa‐tocopheroxyl radical is reduced in vivo by ascorbate; therefore vitamin C may be needed for achieving the beneficial effects of vitamin E [72]. In fact, both antioxidants may act synergistically to generate appropriate conditions for NO synthesis in endothelium [73]. Therefore, the association between vitamins C and E provides a reinforcement of their biological properties in a synergistic manner and could lead to a significant antihypertensive effect; however, further studies are required [74].

Despite the fact that some short‐term studies have demonstrated that the supplementation of both antioxidants reduces blood pressure [60, 63, 64, 75], long‐term clinical trials have failed to support this hypothesis. However, most of these studies have some serious methodological bias, mainly lack of rigorous exclusion criteria [76].

#### **3.4. Allopurinol**

**3. Antioxidants in hypertension**

in the enzymatic activity of eNOS.

**3.1. Vitamin C**

34 Update on Essential Hypertension

**3.2. Vitamin E**

dependent manner.

This section refers to the antihypertensive role of endogenous and exogenous antioxidants that have demonstrated their ability to alter the blood vessels' function and to participate in the

Vitamin C (or ascorbate) is a potent and widely used antioxidant, characteristically water‐ soluble. It has been described that this antioxidant could act as an enzyme modulator on the vascular wall, upregulating eNOS and downregulating NOX [51]. An inverse relationship between vitamin C plasma levels and arterial pressure in both healthy and hypertensive population has been demonstrated in several studies [15]. Antioxidant supplementation improves vascular function and reduces blood pressure in both experimental models [52, 53] and in patients [54, 55]. Ascorbate may improve vasodilation, probably by increasing NO bioavailability [56–58]. Vitamin C could protect BH4 from oxidation, which leads to an increase

Despite the rationale of using vitamin C as an antihypertensive molecule, several clinical trials with methodological differences (including number of patients and follow‐up) have yielded inconsistent outcomes [59–64]. The absence of antihypertensive effect observed in trials using the administration of ascorbate could be due to the lack of consideration of its pharmacological characteristics, mainly pharmacokinetics. It was determined in experimental conditions that the antihypertensive effect of ascorbate is reachable at a plasma concentration of 10 mM [57]. This concentration allows ascorbate to efficiently compete against the reaction between NO and superoxide, which is increased in oxidative stress–related conditions such as hyperten‐ sion. The plasma level mentioned earlier is not reachable through oral administration of vitamin C. Daily oral doses of vitamin C between 60 and 100 mg are sufficient for the renal ascorbate threshold to occur. Plasma is completely saturated at doses of 400 mg daily, leading to a steady state level of 80 μM [65]. Therefore, it is plausible to propose that the antihyper‐

Vitamin E is a lipid‐soluble antioxidant which has received significant attention during the last decades. An epidemiological association between high dietary vitamin E intake and a lower incidence of cardiovascular disease has been established [58]. A growing body of evidence indicates that vitamin E, besides its antioxidant properties, could act as a biological modifier and is also capable of regulating mitochondrial generation of free radicals in a dose‐

Interestingly, some studies fail to demonstrate the beneficial effects of vitamin E in cardiovas‐ cular disease patients [66–69]. Moreover, one trial proving vitamin E supplementation showed an increase in blood pressure and cardiac frequency in type 2 diabetes patients [70]. Probably,

tensive effect of ascorbate would only be reachable with a high‐dose infusion.

main redox reactions involved in the pathophysiology of hypertension.

XO has been proposed as an important enzymatic source of free radicals in the endothelium [24]. It produces uric acid by catalyzing the two final steps of purine metabolism. It has been demonstrated that XO activity is positively correlated with arteriolar tone and blood pressure [77, 78]. Moreover, allopurinol, an XO inhibitor, is capable of improving endothelial function in some experimental models. Treatment with allopurinol decreased blood pressure in a young people‐based study [79], hypertensive murine models [80], and CKD patients [81]. Despite the evidence supplied by small studies, a small number of randomized controlled trials have not demonstrated benefit using XO inhibitors [82].

#### **3.5. Selenium**

Selenium is an essential trace element and a key part of several proteins. Its antioxidant properties are carried out mainly by selenocysteine residues, which are an integral constituent of glutathione peroxidase (GSH‐Px), thioredoxin reductases (TR), and selenoprotein P [83]. It has been proposed that the maintenance of full GSH‐Px and TR activity by proper selenium dietary intake could be useful for the prevention of cardiovascular disease. From a molecular point of view, selenium is capable of preventing the activity of nuclear factor kappa B (NF‐κB) [84], conferring selenium anti‐inflammatory and antioxidant properties. The inhibition of NF‐ kB is probably the result of the binding of selenium to the factor thiols [85].

Several trials have proved the antioxidant properties of selenium [84, 86–91]. Low‐dose selenium showed to provide significant protection of coronary endothelium against oxidative damage in humans [83]. In spontaneously hypertensive rats, selenium supplementation was associated with an increased antioxidant response and protection against cardiac oxidative injury, as well as a reduction in disease severity and mortality [92]. Besides, in hypertensive pregnancies, reduced selenium levels are associated with a decrease in GSH‐Px activity [93]. Therefore, it is plausible to propose that selenium deficiency could be an independent risk factor of cardiovascular disease, including hypertension [94].

#### **3.6. N‐acetylcysteine**

N‐acetylcysteine (NAC) is a sulfhydryl group donor that holds great attention for its antioxi‐ dant properties and potential benefits in cardiovascular disease. In salt‐sensitive hypertension, NAC is capable of improving renal dysfunction and decreasing blood pressure [95]. The antihypertensive effect of NAC is mainly due to NO‐dependent mechanisms and is probably mediated by the inhibition of oxidative stress [96]. NAC effectively prevents BH4 oxidation by the increased superoxide present in primary hypertension [97]. Besides this, NAC can protect against oxidative injury directly by scavenging ROS and inhibiting lipid peroxidation [98, 99].

## **3.7. Polyphenols**

Polyphenols have been defined as the most abundant antioxidants in human diet. They exert several protective mechanisms, including ROS scavenging, iron chelating and modulation of antioxidant enzymes [100, 101]. NAC also possibly increases the endothelium‐NO production [102, 103]. In this regard, NO levels increase after the consumption of polyphenols by humans [104]. Polyphenols improve endothelial function by increasing glutathione and inhibiting pro‐ oxidant enzymes such as NOX and XO [105]. Despite this, some studies using polyphenols and antioxidant vitamins have shown an increase in blood pressure [106]. Therefore, the evidence is still insufficient to establish polyphenols as a first‐line treatment in hypertension.

A summary of the antioxidant approaches as clinical interventions on essential hypertension is presented in **Table 1**.



**Table 1.** Clinical trials accounting for strategies using antioxidants in essential hypertension.

## **4. Conclusions and perspectives**

Therefore, it is plausible to propose that selenium deficiency could be an independent risk

N‐acetylcysteine (NAC) is a sulfhydryl group donor that holds great attention for its antioxi‐ dant properties and potential benefits in cardiovascular disease. In salt‐sensitive hypertension, NAC is capable of improving renal dysfunction and decreasing blood pressure [95]. The antihypertensive effect of NAC is mainly due to NO‐dependent mechanisms and is probably mediated by the inhibition of oxidative stress [96]. NAC effectively prevents BH4 oxidation by the increased superoxide present in primary hypertension [97]. Besides this, NAC can protect against oxidative injury directly by scavenging ROS and inhibiting lipid peroxidation

Polyphenols have been defined as the most abundant antioxidants in human diet. They exert several protective mechanisms, including ROS scavenging, iron chelating and modulation of antioxidant enzymes [100, 101]. NAC also possibly increases the endothelium‐NO production [102, 103]. In this regard, NO levels increase after the consumption of polyphenols by humans [104]. Polyphenols improve endothelial function by increasing glutathione and inhibiting pro‐ oxidant enzymes such as NOX and XO [105]. Despite this, some studies using polyphenols and antioxidant vitamins have shown an increase in blood pressure [106]. Therefore, the evidence is still insufficient to establish polyphenols as a first‐line treatment in hypertension.

A summary of the antioxidant approaches as clinical interventions on essential hypertension

**Details of study Results Reference**

acetylcholine

treatment

In hypertensive patients but not in control subjects, vitamin C increased the impaired vasodilation to

Forearm blood flow response to acetylcholine was significantly enhanced with intra‐arterial infusion of vitamin C in hypertensive group before antihypertensive

Significant diminution of mean systolic blood pressure and diastolic blood pressure, with no differences between the increasing doses of vitamin C

Reduced systolic blood pressure and pulse pressure in ambulatory elderly patients, but not in adult group

In short‐term trials, vitamin C supplementation reduces

systolic and diastolic blood pressure

[107]

[108]

[109]

[110]

[111]

factor of cardiovascular disease, including hypertension [94].

**3.6. N‐acetylcysteine**

36 Update on Essential Hypertension

[98, 99].

**3.7. Polyphenols**

is presented in **Table 1**.

for 10 minutes. Randomized trial

placebo‐controlled trial

Meta‐analysis

controlled trial

Intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). Randomized, placebo‐

Intra‐arterial infusion of vitamin C at 24 mg/min

Oral administration of 500, 1000, or 2000 mg of vitamin C once daily. Randomized, double‐blind,

Chronic supplementation of 600mg/daily of vitamin C. Randomized, placebo‐controlled trial

Included 29 trials of vitamin C supplementation.

There is a growing amount of evidence supporting the view that oxidative stress is involved and plays a key role in the pathophysiology of primary hypertension. In this regard, ROS act as mediators of the major physiological vasoconstrictors, increasing intracellular calcium concentration. In this review, we propose an integrative view of how oxidative stress is involved in the genesis of hypertension, mainly by reducing bioavailability of NO.

Antioxidant therapy can curtail the development of hypertension in animal models, but remains controversial in humans. Possible confounding factors in patients include co‐existing pathologies and treatments and lack of selection of treatments according to ROS levels, among others. However, the dietary intake of antioxidants and polyphenols could have an effect on the primary prevention or reduction of hypertension. Though existing molecular basis and in‐ vitro evidence support the use of diverse antioxidants, clinical evidence continues to be controversial. It is necessary to perform basic/clinical trials that augment the current findings, which could eventually help to elucidate the role of antioxidants as novel therapy for essential hypertension. It is important to mention that the potential role of antioxidants in treatment of hypertension probably is reachable only at early stages of the disease, when endothelial dysfunction predominates over structural vascular damage.

In summary, oxidative stress plays a key role in the pathophysiology of hypertension, and antioxidants appear to be a promising treatment or co‐adjuvant therapy, but further well‐ designed and conducted trials are required to establish them as a major alternative of phar‐ macology agents.

## **Author details**

Ramón Rodrigo\* , Roberto Brito and Jaime González

\*Address all correspondence to: rrodrigo@med.uchile.cl

Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile

## **References**


[10] Redon J, Oliva MR, Tormos C, Giner V, Chaves J, Iradi A et al. Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension 2003;41:1096– 1101. DOI: 10.1161/01.hyp.0000068370.21009.38

**Author details**

38 Update on Essential Hypertension

Ramón Rodrigo\*

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s0140‐6736(04)17018‐9

Hypertens 2004;17:852–860.

0000157169.27818.ae

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200206000‐00036

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2006;71:247–258. DOI: 10.1016/j.cardiores.2006.05.001

Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University

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