Forms of secondary hypertension associated with RH (modified from Vongpatanasin [14]).
Abstract
Resistant hypertension (RH) is a clinical condition in which the hypertensive patient has become resistant to drug therapy and is often associated with increased cardiovascular morbidity and mortality. Several signaling pathways have been studied and related to the development and progression of RH: modulation of sympathetic activity by leptin and aldosterone, primary aldosteronism, arterial stiffness, endothelial dysfunction, and variations in the renin-angiotensin-aldosterone system (RAAS).
Keywords
- resistant hypertension
- signaling pathways
- blood pressure
- drug resistance
1. Introduction
Systemic arterial hypertension (SAH) stands out as the major independent risk factor related to cardiovascular disease (CVD) and remains the greatest modifiable risk factor, despite the important advance in the knowledge of its pathophysiology and availability of effective methods for its treatment. There are approximately 13.3 billion people with SAH in the world, and in developed Western countries, better controls are obtained on blood pressure (BP) levels.
Resistant hypertension (HAR) affects on average 30% of the adult population, about 1.2 billion individuals worldwide. Although the exact prevalence of HAR is still not established, it is estimated that this condition reaches 12–15% of hypertensive individuals.
2. Resistant hypertension
Resistant hypertension (RH) is characterized by a condition in which the patient requires four or more antihypertensive medications, including a diuretic, regardless of blood pressure control. RH patients can be classified as controlled or uncontrolled according to the achievement of the blood pressure goals [1].
The RH affects approximately 13–25% of the hypertensive population [2, 3, 4] and represents a risk factor for cardiovascular events. Results from the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) showed increased hazard ratios for stroke (1.57), end-stage renal disease (1.95), heart failure (1.88), coronary heart disease (1.44), and all-cause mortality (1.30) in RH compared to nonresistant hypertensive subjects [5].
RH is a multifactorial condition, and several environmental and genetic factors contribute to the development and progression of the disease. Firstly, the identification of pseudoresistance must be performed to identify true resistant hypertensive patients, caused mainly due to poor BP measurements, lack of adherence, suboptimal therapy, and white coat hypertension. In addition, secondary causes of RH, such as primary aldosteronism, pheochromocytoma, renal artery stenosis, or Cushing’s syndrome should be identified since the pharmacological treatment will be specific for each condition. Among the factors associated with an increased risk for RH are: older age, African origin, female gender, overweight, and obesity [1, 6].
The RH presents three relevant characteristics: (1) high incidence of the following comorbidities: obstructive sleep apnea [7], thyroid disorders [7], primary aldosteronism [8, 9], reduced plasmatic renin activity, obesity [6], diabetes
The achievement of the BP goals relies on physician examination and on patient characteristics and compliance to pharmacological and nonpharmacological treatments. It is well know that obesity, excessive alcohol and/or salt intake, sedentary lifestyle, smoking, insulin resistance, difficulty in adopting dietary measures, and lack of adherence to therapeutic treatment affects BP control [12]. In addition, prescription of high-cost medicines by physicians, multiple administration regimens, suboptimal doses, and presence of adverse effects are associated with uncontrolled BP [13].
The factors associated with diagnostic and treatment of RH include lifestyle, detailed history of medication adherence, correct BP measurement, biochemical analysis for dosage of electrolytes, glucose, and creatinine, as well as determination of protein and sodium in the urine [12].
The exclusion of pseudohypertension is also necessary. For example, Mönckeberg’s sclerosis is a condition characterized by the loss of elasticity and thickening of the walls of the muscular arteries caused by a calcification of the tunica media constituted of smooth muscle. In the measurement of blood pressure by noninvasive methods, the patient presents high BP values, while in reality, the pressure is normal; therefore, it is necessary to use invasive measurement methods to correctly measure the BP [12]. In white coat hypertension, also a condition of pseudoresistance, the patient exhibits high values during the verification in the physician’s office. It can be excluded by 24-h ABPM. It is estimated that 30% of patients with elevated BP and with treatment of up to three drugs present this condition of white coat hypertension [12, 14].
In order to complete the diagnosis of RH, there are some clinical situations that are considered as secondary causes of this condition, such as: primary hyperaldosteronism, pheochromocytoma, fibromuscular dysplasia, patients with increased risk of atherogenesis [12], obstructive sleep apnea, renal artery stenosis, renal parenchymal disease, Cushing’s syndrome, and thyroid and parathyroid diseases [10]. These forms of secondary hypertension present high prevalence in association with RH, as can be verified in Table 1. Hyperaldosteronism results from the excessive production of aldosterone, a hormone that is produced in the adrenal glands and that decreases the excretion of sodium and increases the excretion of potassium by the kidneys, sweating, and saliva. The determination of the rate of aldosterone/renin ratio is used as screening tool for hyperaldosteronism diagnostic, and if any alteration is confirmed, diagnostic imaging and blood samples from each side of the adrenal glands are used to corroborate the diagnosis [12]. Obstructive sleep apnea consists of the collapsing of the pharynx walls hampering the adequate respiration of the individual. The patient is then submitted to a nocturnal polysomnography in order to monitor respiration and body functions during sleep for diagnosing the condition [15]. For more information on diagnostic and treatment methods, see Table 1 [14].
Conditions | Obstructive sleep apnea | Primary aldosteronism | Renal artery stenosis | Renal parenchyma disease | Use of drugs and alcohol | Thyroid disorders |
---|---|---|---|---|---|---|
Diagnostic tests | Polysomnography | Serum aldosterone, plasma renin activity | Duplex Doppler ultrasonography, computed tomographic angiography, or magnetic resonance angiography | Serum creatinine | History taking | Thyrotropin, free thyroxine |
Treatment | Continuous positive airway pressure | Spironolactone, eplerenone, or surgical resection of tumor in unilateral aldosterone-producing Adenoma | Renal revascularization in selected patients | Correction of underlying causes if possible | Discontinuation of offending agents | According to underlying disorders |
Prevalence in RH (%) | 60–70 | 7–20 | 2–24 | 1–2 | 2–4 | <1 |
References | [7] | [8, 9] | [7] | [1, 7] | [1, 7] | [1, 7] |
A flowchart (Figure 1) summarizes the steps involved in the diagnosis of RH according to the American Heart Association Statement [1, 16].
Although RH is a multifactorial condition, excess sodium, fluid retention, increased activation of the renin-angiotensin-aldosterone system, and higher sympathetic tone are among the most well-described mechanisms of BP elevation in RH. The complex pathophysiology of the development and progression of RH requires further investigation to identify molecular mechanisms that could be translated into diagnostic and more assertive therapeutic strategies. In the following sessions, the signaling pathways and the participation of miRNA in their regulation will be discussed.
3. Renin-angiotensin-aldosterone system
The renin-angiotensin-aldosterone system (RAAS) is responsible for the hemodynamic equilibrium. This is possible due to the effects of this system on the kidneys, which act in the sodium water balance, and also due to the influence in the vascular resistance on the peripheral blood vessels, thus permitting the maintenance of the BP [17]. In order to the RAAS to produce a response, it is necessary for some type of alteration to occur in the circulating blood volume, such as blood loss, dehydration, or even pumping failure by the ventricles [18] (Figure 2).
Juxtaglomerular apparatus comprises afferent arterioles in the distal part of the ascending branch of the loop of Henle in the renal glomeruli. The cells that line these arterioles in the region of the apparatus are called juxtaglomerular cells and are able to recognize the BP inside these vessels [18]. Moreover, the cells that line the loop of Henle in the region of the juxtaglomerular apparatus are called macula densa and respond to changes in the sodium concentration of the filtrate. By detecting these changes, the cells of the dense macula stimulate juxtaglomerular cells to produce an enzyme called renin that is released into the bloodstream. This enzyme is responsible for the production of angiotensin I (AngI) through the cleavage of angiotensinogen, which is synthesized and secreted by the liver. In the pulmonary and renal endothelium, an enzyme called angiotensin-converting enzyme (ACE), which hydrolyzes the circulating AngI in angiotensin II (AngII), is present. The angiotensin 1 receptor (AT1) is activated by AngII, thus promoting a vasoconstrictive response in the blood vessels, in addition to stimulating the adrenal gland to produce aldosterone. The renal tubules respond to the aldosterone by retention of sodium and water, which will promote increased blood volume and consequently, BP elevation [19, 20].
The RAAS constitutes the main signaling pathway involved in the long-term control of the BP. Innumerous regulators participate in this biochemical cascade of communication such as renin, angiotensinogen, AngI and II, ACE 1 and 2, and aldosterone and angiotensin- (1-7) [Ang-(1-7)]. The deregulation of one or more effectors of this system contributes to failures in blood pressure control, usually leading to hypertension [21]. Resistant hypertension is accompanied by intravascular fluid retention that can be attributed, at least in part, to dysregulation in the renin-angiotensin-aldosterone system. Previous studies have found evidence of intravascular volume expansion (higher levels of brain-type natriuretic peptide—BNP and atrial natriuretic peptide—ANP) and aldosterone excess (higher levels of plasma and urinary aldosterone, aldosterone to renin ratio) in resistant hypertension compared to controls [22]. Similarly, another study reported higher volume of fluid by thoracic electrical bioimpedance, suggesting that the intensification of diuretic therapy in those patients could be beneficial [23]. ANP and BNP are hormones that regulate cardiovascular hemodynamics. They are secreted by cardiac atria and cardiac ventricles, respectively, in response to stretch or pressure. Natriuretic effects are mediated by subtype A-natriuretic peptide receptor, which is expressed in several tissues, including kidneys, blood vessels, adrenal glands, and adipose tissue. ANP produces its natriuretic actions by increasing glomerular filtration rate and inhibits sodium transport in proximal tubule and inhibition of aldosterone release in adrenal cells. The latter effect is also attributed to BNP [24]. Aldosterone is one of the most studied RAAS components in RH; several studies had shown that aldosterone excess is a common characteristic of RH. In addition, primary aldosteronism is the most common secondary cause in the patients with RH [8]. This condition is characterized by excessive autonomic secretion of aldosterone by the adrenal gland, being the production of adenomas and idiopathic hyperaldosteronism in the main forms [25, 26]. This secretion, stimulated by renin, promotes the retention of sodium and water, promoting the elevation of blood volume, and consequently the increase of BP. When it is released into the bloodstream, the aldosterone diffuses through the membrane into the cytosol of renal tubular epithelial cells, subsequently binding to a family of NRC2-type mineralocorticoid receptors. This aldosterone-receptor complex will be translocated to the nucleus, activating the synthesis of proteins related to sodium and potassium transport, such as Na+ K+ ATPase (Figure 3) [27].
An important signaling pathway in the primary aldosteronism is the phosphoinositide 3-kinase (PI3K) pathway with the activation of mammalian target of rapamycin (mTOR), when overactivation is involved in the tumorigenesis and metastasis in some types of human tumors such as renal cancer, adrenal carcinoma, and pheochromocytoma [28, 29, 30] (Figure 4) [29]. The PI3K/AKT/mTOR pathway is regulated in response to the signaling of growth factors such as the epidermal growth factor (EGF) through receptor tyrosine kinases (RTKs) [31].
Another stimulus to the release of aldosterone is the action of sphingosine-1-phosphate (S1P) by means of the activation of the PI3K/AKT (protein kinase B) and mitogen-activated protein kinase (MEK)/extracellular regulated kinase (ERK) pathway in glomerular cells of the adrenal glands (Figure 4) [30]. S1P is a bioactive sphingolipid intracellularly formed that acts as a second messenger mediating regulatory processes such as cell differentiation, migration and contraction, modulation of immune response, and angiogenesis, and this molecule is considered to be the key hormone for hemodynamic stability in humans [32, 33]. Its action involves the activation of phospholipase D (PLD), calcium influx (Ca2+) from the extracellular medium and phosphorylation of α and β isoforms of protein kinase C (PKC) [25, 26, 32].
Previous studies had shown excess of aldosterone in uncontrolled RH compared to controlled group. The same study demonstrated that aldosterone was correlated to arterial stiffness [34]. Furthermore, higher aldosterone levels were associated with the T allele for the polymorphism-344 C/T
Angio-(1-7) is a heptapeptide that carries out an important function in the RAAS. This molecule is formed both by the action of ACE 1 (dependent pathway) and the hydrolysis of AngII by the ACE 2 (independent pathway) [36, 37], being the last one in the most important pathway in the formation of Ang-(1-7) [38]. This molecule produces its AngII endogenous counter-regulatory effects on RAAS (vasodilation, cardio protection, natriuresis, and diuresis, angiogenesis inhibition, and cellular growth) [39] through the binding to its specific receptor called Mas, a G protein-coupled receptor [25, 40, 41].
The ACE2/Ang-(1-7)/Mas signaling pathway consists in one of the RAAS axes that opposes, in terms of function, to another classical axis of this system, the ACE/AngII/AT1R. The imbalance of these two opposing axes, mainly in the direction of the ACE/AngII/AT1R axis, predisposes to cardiovascular diseases and other disorders [37, 41].
The Ang-(1-7)/Mas complex regulates different signaling pathways, such as PI3K/AKT and ERK signal, and involves the maintenance of some effectors like nitric oxide (NO) [25, 41], FOXO1 (forkhead box 1) [39] and cyclooxygenase-2 (COX-2) [40] (Figure 5). Studies report that due to the participation of the Ang-(1-7) in these mechanisms, this heptapeptide is related to pathological conditions such as fibrosis and inflammatory processes in some organs, like lungs, liver, and kidneys [42]. Other findings demonstrate that Ang-(1-7), through the interaction with its Mas receptor, stimulates the activation of the nitric oxide synthesis (eNOS) in endothelial cells, promoting vasodilation [25, 36, 41].
Another study demonstrates that Ang-(1-7), through the interaction with its specific Mas receptor, promotes the increase in nitric oxide (NO) and prostaglandins (PG) synthesis and release, leading to vasodilation and inhibition of cellular growth, opposing to the vasoconstrictor and proliferative effects mediated by the interaction of AngII with its AT1 receptors. The imbalance between these two axes of the RAAS, reflected by the imbalance between theses peptides, which are observed in cardiovascular diseases, can lead to the decrease in NO and consequently to endothelial dysfunction (Figure 5) [43].
3.1. Sympathetic nervous system
Sympathetic nervous system regulates cardiac output and peripheral vascular resistance (vasoconstriction) through release of norepinephrine and epinephrine, resulting in increase in blood pressure. At the renal level, SNS activation increases renin release from juxtaglomerular cells and modulate tubular sodium reabsorption [44]. RH patients have reduced heart rate variability, which is a marker for SNS activity. It was shown that 63% of the patients present a nondipping pattern (BP does not drop at night), which indicate sympathetic overflow. Moreover, sympathetic activation also increases sodium reabsorption and promotes renin secretion, and renal denervation has been investigated for the treatment of resistant hypertension. In spite first studies in humans had shown promising results, randomized and blinded clinical trials demonstrated no benefit on BP control compared to sham procedure [45]. Another intervention that has been tested is baroreflex activation therapy. Carotid sinus stimulation reduces BP in patients with uncontrolled RH, showing the import role of sympathetic activity in this condition [46, 47, 48].
3.2. Adipokines
Adiponectin and leptin are two of the adipokines produced in adipose tissue. Obesity is an important comorbidity in RH, and plasma levels of adiponectin and leptin were reported to be lower and higher, respectively, in RH [34, 49]. Leptin is a peptide hormone that is expressed in a variety of tissues, such as lymphoid tissue, pituitary gland, skeletal muscle, placenta, and ovary [50]. However, white adipose tissue is the main responsible for the synthesis and secretion of this peptide, which has effects to act on the hypothalamus in order to decrease appetite and stimulate sympathetic activity of the nervous system (Figure 6) [51]. Elevated levels of leptin stimulate neurons in the hypothalamus to secrete a precursor protein that is cleaved in α-melanocyte stimulating hormone, which binds to melanocortin 3 and melanocortin 4 receptors. The binding of this peptide to the receptors stimulates the sympathetic nervous system, elevates the energy expenditure, decreases food intake, and activates the hypothalamic-pituitary-adrenal axis [52, 53, 54]. A mechanism that demonstrates which factors are involved in the generation of hypertension associated with obesity is represented below (Figure 6) [51].
3.3. Insulin resistance and hypertension: the role of the caveolin-1 (CAV1 ) gene
It was recently demonstrated that the gene caveolin-1 (
Although the role of
3.4. Vascular stiffness and endothelial dysfunction
Previous studies have showed the participation of vascular stiffness and endothelial dysfunction in the pathogenesis of resistant hypertension. An increased carotid-femoral pulse wave velocity was observed in RH patients compared to non-RH hypertension, demonstrating the impairment of elasticity in these vessels. In addition, flow-mediated dilation was found to be reduced in RH, reflecting an endothelial dysfunction [63].
3.4.1. Epidermal growth factor receptor in the vascular smooth muscle
The activation of the signaling pathway of the epidermal growth factor receptor (EGFR) by matrix metalloproteinase (MMP), stimulated by G protein-coupled receptor (GPCR) agonists, such as catecholamines, endothelin-1 (ET-1) and AngII, leads to the increase of the oxidative stress, and promotes stimulation of the hypertrophic growth and consequently increase in the muscular tone in hypertension (Figure 8) [64]. Among these receptors, adrenoceptors and angiotensin receptors can be mentioned that contribute to the hypertension pathogenesis mainly through the vasoconstrictor effects produced after stimulation [65, 66].
The vasoconstrictor responses promoted by this pathway are mediated by phospholipase C (PLC), DAG, and Ca2+ besides the growth promotion pathway involving the tyrosine receptor and mitogen-activated protein kinases (MAPKs) (Figure 9) [67]. Studies have shown a connection between the GPCR stimulus with the MAPK signaling pathway (through the dependent activation of MPM) in the vascular smooth muscle cells [65, 68, 69, 70]. Associations have been made between GPCR stimulus by MPM’s such as MPM-2, MPM-3, and MPM-7 in cardiomyocytes, fibroblasts, and epithelial and endothelial cells [71] with consequent development of cardiovascular hypertrophy associated with hypertension [72, 73, 74, 75] (Figure 9).
3.4.2. CYP4A (cytochrome P450-4A)/20-HETE (20-hydroxyeicosatetraenoic acid)
20-HETE is an arachidonic acid metabolite formed through reactions catalyzed by the cytochrome P450-4A enzymatic complex (CYP4A) in vascular smooth muscle cells and is related to vascular dysfunction and arterial hypertension (Figure 10) [76]. This molecule has vasoconstrictive action and exerts an important role in vascular function and in the development and progression of cardiovascular diseases [77]. Studies have demonstrated the relationship between genetic variations in precursors of 20-HETE formation and the elevation of this metabolite and the BP in humans [78, 79].
In Dahl SS (salt-sensitive) rats, a genetic model of salt-sensitive hypertension, 20-HETE has been shown to contribute to the increase in total peripheral resistance by reducing the ability of the vascular system to respond to direct vasodilation stimulation by reducing vascular function, thus contributing to an increase in BP [80, 81].
Some studies demonstrate that reactive oxygen species (ROS) are important molecules in the development of oxidative stress, playing an important role in vascular dysfunction in Dahl SS rats [82, 83]. The chronic exposure to low levels of AngII in these animals may lead to an increase in oxidative stress by elevating ROS cellular concentrations, thus contributing to the reduction of vascular relaxation even when these animals are submitted to a sodium restriction diet or are normotensive [84].
4. Concluding remarks and future directions
Due to the difficulty of studying RH in animal and
Epigenetic as well as genetic factors are identified every day and they are associated with variation in blood pressure levels. As reviewed herein, mutation polymorphism in some signaling pathway gene may increase or decrease the expression of some microRNAs, which are involved both in RH development and therapy response as RH-associated complications such as renal failure, coronary artery disease, cardiac hypertrophy, stroke, and among others. Therefore, the use of microRNA as biomarkers in prevention, diagnosis, and therapy of this disease may help to understand the disease, improve pharmacology therapy as well as prevent complications.
Conflict of interest
The authors declare that they have no conflict of interests relating to this paper content.
References
- 1.
Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: Diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008; 117 (25):e510-e526 - 2.
Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011; 124 (9):1046-1058 - 3.
Sarafidis PA, Georgianos P, Bakris GL. Resistant hypertension—Its identification and epidemiology. Nature Reviews Nephrology. 2013; 9 (1):51-58 - 4.
Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. Journal of Hypertension. 2013; 31 (4):766-774 - 5.
Muntner P, Davis BR, Cushman WC, Bangalore S, Calhoun DA, Pressel SL, et al. Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: Results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2014; 64 (5):1012-1021 - 6.
Martins LC, Figueiredo VN, Quinaglia T, Boer-Martins L, Yugar-Toledo JC, Martin JF, et al. Characteristics of resistant hypertension: Ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and vascular stiffness. Journal of Human Hypertension. 2011; 25 (9):532-538 - 7.
Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Obstructive sleep apnea: The most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011; 58 (5):811-817 - 8.
Umpierrez GE, Cantey P, Smiley D, Palacio A, Temponi D, Luster K, et al. Primary aldosteronism in diabetic subjects with resistant hypertension. Diabetes Care. 2007; 30 (7):1699-1703 - 9.
Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: An endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2008; 93 (9):3266-3281 - 10.
Makris A, Seferou M, Papadopoulos DP. Resistant hypertension workup and approach to treatment. International Journal of Hypertension. 2010; 2011 :598694 - 11.
Weber F, Anlauf M. Treatment resistant hypertension—Investigation and conservative management. Deutsches Ärzteblatt International. 2014; 111 (25):425-431 - 12.
Mahfoud F, Himmel F, Ukena C, Schunkert H, Bohm M, Weil J. Treatment strategies for resistant arterial hypertension. Deutsches Ärzteblatt International. 2011; 108 (43):725-731 - 13.
Vidt DG. Contributing factors in resistant hypertension. Truly refractory disease is rarely found in a properly conducted workup. Postgraduate Medicine. 2000; 107 (5):57-60, 3-4, 7-8, 70 - 14.
Vongpatanasin W. Resistant hypertension: A review of diagnosis and management. JAMA. 2014; 311 (21):2216-2224 - 15.
Taler SJ. Treatment of resistant hypertension. Current Hypertension Reports. 2005; 7 (5):323-329 - 16.
Passarelli O, Gonçalves MS, Amodeo C. Fluxograma abordagem diagnóstica da hipertensão resistente. Revista Brasileira de Hipertensão. 2009; 16 (1):7-9 - 17.
Rubin LJ, Simonneau G, Badesch D, Galie N, Humbert M, Keogh A, et al. The study of risk in pulmonary arterial hypertension. European Respiratory Review. 2012; 21 (125):234-238 - 18.
Maron BA, Leopold JA. The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference Series). Pulmonary Circulation. 2014; 4 (2):200-210 - 19.
Santos RA, Ferreira AJ, Simoes ESAC. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Experimental Physiology. 2008; 93 (5):519-527 - 20.
Briet M, Schiffrin EL. Aldosterone: Effects on the kidney and cardiovascular system. Nature Reviews Nephrology. 2010; 6 (5):261-273 - 21.
Oudit GY, Crackower MA, Backx PH, Penninger JM. The role of ACE2 in cardiovascular physiology. Trends in Cardiovascular Medicine. 2003; 13 (3):93-101 - 22.
Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, et al. Characterization of resistant hypertension: Association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Archives of Internal Medicine. 2008; 168 (11):1159-1164 - 23.
Taler SJ, Textor SC, Augustine JE. Resistant hypertension: Comparing hemodynamic management to specialist care. Hypertension. 2002; 39 (5):982-988 - 24.
Boomsma F, van den Meiracker AH. Plasma A- and B-type natriuretic peptides: Physiology, methodology and clinical use. Cardiovascular Research. 2001; 51 (3):442-449 - 25.
de Almeida PWM, Lima RD, Gomes ERD, Rocha-Resende C, Roman-Campos D, Gondim ANS, et al. Functional cross-talk between aldosterone and angiotensin-(1-7) in ventricular myocytes. Hypertension. 2013; 61 (2):425-430 - 26.
de Almeida PW, Melo MB, Lima Rde F, Gavioli M, Santiago NM, Greco L, et al. Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure. Hypertension. 2015; 66 (2):389-395 - 27.
Freel EM, Connell JM. Mechanisms of hypertension: The expanding role of aldosterone. Journal of the American Society of Nephrology. 2004; 15 (8):1993-2001 - 28.
De Martino MC, van Koetsveld PM, Pivonello R, Hofland LJ. Role of the mTOR pathway in normal and tumoral adrenal cells. Neuroendocrinology. 2010; 92 (Suppl. 1):28-34 - 29.
Su H, Gu Y, Li F, Wang Q, Huang B, Jin X, et al. The PI3K/AKT/mTOR signaling pathway is overactivated in primary aldosteronism. PLoS One. 2013; 8 (4):e62399 - 30.
Brizuela L, Rabano M, Gangoiti P, Narbona N, Macarulla JM, Trueba M, et al. Sphingosine-1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3K/PKB and MEK/ERK 1/2 pathways. Journal of Lipid Research. 2007; 48 (10):2264-2274 - 31.
Battelli C, Cho DC. mTOR inhibitors in renal cell carcinoma. Therapy. 2011; 8 (4):359-367 - 32.
Brizuela L, Rabano M, Pena A, Gangoiti P, Macarulla JM, Trueba M, et al. Sphingosine 1-phosphate: A novel stimulator of aldosterone secretion. Journal of Lipid Research. 2006; 47 (6):1238-1249 - 33.
Spiegel S, Milstien S. Sphingosine-1-phosphate: An enigmatic signalling lipid. Nature Reviews. 2003; 4 (5):397-407 - 34.
de Faria AP, Demacq C, Figueiredo VN, Moraes CH, Santos RC, Sabbatini AR, et al. Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension. Hypertension Research. 2013; 36 (12):1067-1072 - 35.
Fontana V, de Faria AP, Barbaro NR, Sabbatini AR, Modolo R, Lacchini R, et al. Modulation of aldosterone levels by -344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension. Journal of the American Society of Hypertension. 2014; 8 (3):146-151 - 36.
Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007; 49 (1):185-192 - 37.
Rabelo LA, Alenina N, Bader M. ACE2-angiotensin-(1-7)-Mas axis and oxidative stress in cardiovascular disease. Hypertension Research. 2011; 34 (2):154-160 - 38.
Santos RA, Ferreira AJ, Pinheiro SV, Sampaio WO, Touyz R, Campagnole-Santos MJ. Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs. Expert Opinion on Investigational Drugs. 2005; 14 (8):1019-1031 - 39.
Ferreira AJ, Santos RA, Bradford CN, Mecca AP, Sumners C, Katovich MJ, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension. 2010; 55 (2):207-213 - 40.
Gironacci MM, Longo Carbajosa NA, Goldstein J, Cerrato BD. Neuromodulatory role of angiotensin-(1-7) in the central nervous system. Clinical Science. 2013; 125 (2):57-65 - 41.
Gomes ER, Lara AA, Almeida PW, Guimaraes D, Resende RR, Campagnole-Santos MJ, et al. Angiotensin-(1-7) prevents cardiomyocyte pathological remodeling through a nitric oxide/guanosine 3′,5′-cyclic monophosphate-dependent pathway. Hypertension. 2010; 55 (1):153-160 - 42.
Passos-Silva DG, Verano-Braga T, Santos RA. Angiotensin-(1-7): Beyond the cardio-renal actions. Clinical Science. 2013; 124 (7):443-456 - 43.
Touyz RM, Tabet F, Schiffrin EL. Redox-dependent signalling by angiotensin II and vascular remodelling in hypertension. Clinical and Experimental Pharmacology and Physiology. 2003; 30 (11):860-866 - 44.
Grassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. Journal of the American Society of Hypertension. 2016; 10 (5):457-466 - 45.
Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. The New England Journal of Medicine. 2014; 370 (15):1393-1401 - 46.
Heusser K, Tank J, Brinkmann J, Menne J, Kaufeld J, Linnenweber-Held S, et al. Acute response to unilateral unipolar electrical carotid sinus stimulation in patients with resistant arterial hypertension. Hypertension. 2016; 67 (3):585-591 - 47.
Gavioli M, Lara A, Almeida PWM, Lima AM, Damasceno DD, Rocha-Resende C, et al. Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. PLoS One. 2014; 9 (7):e100179 - 48.
Paschon V, Higa GSV, Resende RR, Britto LRG, Kihara AH. Blocking of connexin-mediated communication promotes neuroprotection during acute degeneration induced by mechanical trauma. PLoS One. 2012; 7 (9):e45449 - 49.
de Haro Moraes C, Figueiredo VN, de Faria AP, Barbaro NR, Sabbatini AR, Quinaglia T, et al. High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension. Journal of Human Hypertension. 2013; 27 (4):225-230 - 50.
Dardeno TA, Chou SH, Moon HS, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in human physiology and therapeutics. Frontiers in Neuroendocrinology. 2010; 31 (3):377-393 - 51.
Rahmouni K, Correia ML, Haynes WG, Mark AL. Obesity-associated hypertension: New insights into mechanisms. Hypertension. 2005; 45 (1):9-14 - 52.
Morrison CD. Leptin signaling in brain: A link between nutrition and cognition? Biochimica et Biophysica Acta. 2009; 1792 (5):401-408 - 53.
Ste Marie L, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97 (22):12339-12344 - 54.
Kang YS. Obesity associated hypertension: New insights into mechanism. Electrolyte & Blood Pressure. 2013; 11 (2):46-52 - 55.
Williams TM, Lisanti MP. The Caveolin genes: From cell biology to medicine. Annals of Medicine. 2004; 36 (8):584-595 - 56.
Pojoga LH, Underwood PC, Goodarzi MO, Williams JS, Adler GK, Jeunemaitre X, et al. Variants of the caveolin-1 gene: A translational investigation linking insulin resistance and hypertension. The Journal of Clinical Endocrinology and Metabolism. 2011; 96 (8):E1288-E1292 - 57.
Hnasko R, Lisanti MP. The biology of caveolae: Lessons from caveolin knockout mice and implications for human disease. Molecular Interventions. 2003; 3 (8):445-464 - 58.
Pojoga LH, Yao TM, Sinha S, Ross RL, Lin JC, Raffetto JD, et al. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. American Journal of Physiology Heart and Circulatory Physiology. 2008; 294 (3):H1258-H1265 - 59.
Cohen AW, Razani B, Wang XB, Combs TP, Williams TM, Scherer PE, et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. American Journal of Physiology-Cell Physiology. 2003; 285 (1):C222-C235 - 60.
Cohen AW, Combs TP, Scherer PE, Lisanti MP. Role of caveolin and caveolae in insulin signaling and diabetes. American Journal of Physiology Endocrinology and Metabolism. 2003; 285 (6):E1151-E1160 - 61.
Karlsson M, Thorn H, Parpal S, Stralfors P, Gustavsson J. Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes. Federation of American Societies for Experimental Biology Journal. 2002; 16 (2):249-251 - 62.
Oh YS, Cho KA, Ryu SJ, Khil LY, Jun HS, Yoon JW, et al. Regulation of insulin response in skeletal muscle cell by caveolin status. Journal of Cellular Biochemistry. 2006; 99 (3):747-758 - 63.
Figueiredo VN, Yugar-Toledo JC, Martins LC, Martins LB, de Faria AP, de Haro Moraes C, et al. Vascular stiffness and endothelial dysfunction: Correlations at different levels of blood pressure. Blood Pressure. 2012; 21 (1):31-38 - 64.
Fernandez-Patron C. Therapeutic potential of the epidermal growth factor receptor transactivation in hypertension: A convergent signaling pathway of vascular tone, oxidative stress, and hypertrophic growth downstream of vasoactive G-protein-coupled receptors? Canadian Journal of Physiology and Pharmacology. 2007; 85 (1):97-104 - 65.
Hao L, Du M, Lopez-Campistrous A, Fernandez-Patron C. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circulation Research. 2004; 94 (1):68-76 - 66.
Aguiar CJ, Rocha-Franco JA, Sousa PA, Santos AK, Ladeira M, Rocha-Resende C, et al. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Communication and Signaling: CCS. 2014; 12 :78 - 67.
Nagareddy PR, MacLeod KM, McNeill JH. GPCR agonist-induced transactivation of the EGFR upregulates MLC II expression and promotes hypertension in insulin-resistant rats. Cardiovascular Research. 2010; 87 (1):177-186 - 68.
Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999; 402 (6764):884-888 - 69.
Resende RR, Andrade LM, Oliveira AG, Guimaraes ES, Guatimosim S, Leite MF. Nucleoplasmic calcium signaling and cell proliferation: Calcium signaling in the nucleus. Cell Communication and Signaling: CCS. 2013; 11 (1):14 - 70.
Roy A, Fields WC, Rocha-Resende C, Resende RR, Guatimosim S, Prado VF, et al. Cardiomyocyte-secreted acetylcholine is required for maintenance of homeostasis in the heart. Federation of American Societies for Experimental Biology Journal. 2013; 27 (12):5072-5082 - 71.
Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: Metalloproteinase inhibitors as a new therapy. Nature Medicine. 2002; 8 (1):35-40 - 72.
Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001; 104 (4):545-556 - 73.
Fujino T, Hasebe N, Fujita M, Takeuchi K, Kawabe J, Tobise K, et al. Enhanced expression of heparin-binding EGF-like growth factor and its receptor in hypertrophied left ventricle of spontaneously hypertensive rats. Cardiovascular Research. 1998; 38 (2):365-374 - 74.
Rocha-Resende C, Roy A, Resende R, Ladeira MS, Lara A, de Morais Gomes ER, et al. Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals. Journal of Molecular and Cellular Cardiology. 2012; 53 (2):206-216 - 75.
Arantes LA, Aguiar CJ, Amaya MJ, Figueiro NC, Andrade LM, Rocha-Resende C, et al. Nuclear inositol 1,4,5-trisphosphate is a necessary and conserved signal for the induction of both pathological and physiological cardiomyocyte hypertrophy. Journal of Molecular and Cellular Cardiology. 2012; 53 (4):475-486 - 76.
Lukaszewicz KM, Lombard JH. Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat. Clinical Science. 2013; 124 (12):695-700 - 77.
Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiological Reviews. 2002; 82 (1):131-185 - 78.
Ward NC, Tsai IJ, Barden A, van Bockxmeer FM, Puddey IB, Hodgson JM, et al. A single nucleotide polymorphism in the CYP4F2 but not CYP4A11 gene is associated with increased 20-HETE excretion and blood pressure. Hypertension. 2008; 51 (5):1393-1398 - 79.
Liu H, Zhao Y, Nie D, Shi J, Fu L, Li Y, et al. Association of a functional cytochrome P450 4F2 haplotype with urinary 20-HETE and hypertension. Journal of the American Society of Nephrology. 2008; 19 (4):714-721 - 80.
Drenjancevic-Peric I, Greene AS, Kunert MP, Lombard JH. Arteriolar responses to vasodilator stimuli and elevated P(O2) in renin congenic and Dahl salt-sensitive rats. Microcirculation. 2004; 11 (8):669-677 - 81.
Durand MJ, Lombard JH. Introgression of the Brown Norway renin allele onto the Dahl salt-sensitive genetic background increases Cu/Zn SOD expression in cerebral arteries. American Journal of Hypertension. 2011; 24 (5):563-568 - 82.
Drenjancevic-Peric I, Lombard JH. Reduced angiotensin II and oxidative stress contribute to impaired vasodilation in Dahl salt-sensitive rats on low-salt diet. Hypertension. 2005; 45 (4):687-691 - 83.
Durand MJ, Moreno C, Greene AS, Lombard JH. Impaired relaxation of cerebral arteries in the absence of elevated salt intake in normotensive congenic rats carrying the Dahl salt-sensitive renin gene. American Journal of Physiology Heart and Circulatory Physiology. 2010; 299 (6):H1865-H1874 - 84.
Lenda DM, Boegehold MA. Effect of a high salt diet on microvascular antioxidant enzymes. Journal of Vascular Research. 2002; 39 (1):41-50