PATHOPHYSIOLOGY OF HYPERTENSION Samuel Makar

Samuel MakarProf of Pediatrics and Pediatric Nephrology , Cairo University

PATHOPHYSIOLOGY OF HYPERTENSION

SCOPE• Introduction• Definition• BP Measuring• Types• Pathophysiology Overview• Pathophysiology of Specific HTN Diseases

INTRODUCTION• There is increasing evidence that HTN has its antecedents

during childhood and that atherosclerosis is already present in adolescents. Thus, early detection and intervention are crucial.

• The prevalence of primary HTN is increasing among school children and adolescents due to an epidemic of obesity.

• Younger children are more likely to have secondary HTN,

• The definition of HTN as well as normative values of blood pressure (BP) should be well known to clinicians in order to identify HTN

HTN DEFINITION

• Definition of Pediatric HTN:Average SBP and/or DBP ≥ 95th percentile

- gender, age, and height -on 3 or more separate occasions.

• Pre-HTN :BP levels ≥ 90th percentile but < 95th percentile is termed prehypertension.

BP MEASURING• Casual Blood Pressure• Ambulatory BP monitoring (ABPM)• Home BP monitoring (HBPM)

AMBULATORY BP MONITORING (ABPM)

• Provides multiple readings over time enabling computation of the mean, daytime, and nighttime ambulatory BP (ABP) by measuring BP during regular activities and BP variability

• More reliable and reproducible than casual BP

• Detects white coat effect (high casual BP than 24-h or daytime ABP) or reversed white coat effect (low casual BP than 24-h or daytime ABP)

• ABPM correlates better with target organ damage than casual BP

HOME BP

• Self measurement of BP has the following advantages:1. Distinguishing sustained HTN from white coat HTN(WCH)2. Detection of masked HTN3. Assessing response to medication,4. Improving patient adherence to treatment5. Reducing costs by avoiding ABPM or drug therapy.

Midori Awazu, Pedatric Nephrology Textbook 2016

IV Diretriz Brasileira de Hipertensão Arterial. Arq Bras Cardiol 2004

IV Guideline for Ambulatory Blood Pressure Monitoring , Arq. Bras. Cardiol, 2005

TYPES OF HTN

According to the cause:• Primary HTN• Secondary HTN

According to the setting• White coat HTN• Reversed white coat HTN• Persistent HTN

WHITE COAT HTN (WCH)• In Children : BP measured in a physician’s office >95th percentile

whereas average BP being <90th percentile outside of a clinical setting.

• Adults : in the office (equal to or higher than 140/90 mmHg) and by 24-hour ABPM (lower than 130/80 mmHg) or by HBPM (lower than 135/85 mmHg)

(National High Blood Pressure Education Program Working Group on High BloodPressure in Children and Adolescents, Pediatrics, 2004)

WHITE COAT HTN (WCH)

• In WCH casual BP is high, while the BP during ABPM is normal

• WCH is considered relevant when the difference is higher than 20 mmHg and 10 mmHg for systolic pressure and diastolic pressure, respectively

Myers MG et al ,Am J Hypertens 1999

REVERSE WHITE COAT HYPERTENSION (MASKED HTN)

• “Reverse WCH” or “WC normotension ” or Masked HTN (MA)• MH, a high Ambulatory BP in the presence of normal office BP • Recognized as a risk factor for cardiovascular complications in

the adults Pickering TG et al , Hypertension 2002

• High prevalence of MH in renal transplant, CKD, obesity, sickle-cell disease, repaired coarctation of aorta, obstructive sleep apnea, a parental history of HTN, increased BMI, and prehypertension

Lurbe E et al, Hypertension 2005

IV Guideline for Ambulatory Blood Pressure Monitoring , Arq. Bras. Cardiol, 2005

Equals: Cardiac output ( CO) x Systemic vascular resistance (SVR)

Pathophysiology Overview

SV

HR

Preload

SympNS

Remodeling

Rarefaction

StiffnessForce Exerted bycirculating blood

on artery walls

IMPORTANT KEY-PLAYERS IN PATHOPHYSIOLOGY OF HTN

• Systemic Vascular Resistance SVR• RAAS• Other Important Molecules

SYSTEMIC VASCULAR RESISTANCE (SVR)

• SVR mainly a function of small, peripheral arterioles• Cross-sectional area of a vessel decreases, resistance to flow increases

• Remodeling : Thickening of the media is the earliest structural change due to matrix deposition, smooth muscle cell hypertrophy and hyperplasia creating smaller lumen

• Rarefaction : Finally, there may be resorption and loss of blood vessels in the periphery

• Stiffness: In larger vessels, the content of elastin and collagen in the media increases, and the number of smooth muscle cells decreases leading to a loss of elasticity

THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS)

Major stimuli for secretion of Renin:1. Glomerular underperfusion2. Reduced sodium intake 3. Sympathetic Nervous System activity.

• Renin cleaves hepatic-derived angiotensinogen to form angiotensin I (ANG-I)

• ACE in the lungs transforms it to angiotensin II (ANG-II). • ACE also degrades bradykinin, a potent vasodilator, into inactive

metabolites. • ANG-II is a potent vasoconstrictor and thus directly increases BP. • It also stimulates the release of aldosterone from the zona glomerulosa

of the adrenal gland, which results in a further rise in BP from aldosterone-mediated sodium and water retention..

• The functions of Ang-(1–9) are not completely understood, but Ang-(1–7) has vasodilatory and renoprotective effects

• Reduced ACE2 levels are thought to contribute to the pathogenesis of primary HTN via impaired degradation of ANG-II and reduced formation of vasodilator by-products at the level of the renal endothelium .

Stergiou GS et al, Am J Hypertens. 2008

• NB:

Primary HTN is showing more and more to be NOT Primary HTN:

1. ACE 2 Mutation (reduced level of AT1-7)

ATRIAL NATRIURETIC PEPTIDE (ANP)

• Family of natriuretic peptides including B-type (BNP) and the C-type (CNP) natriuretic peptides with similar functions

• ANP has potent diuretic,• Natriuretic ( by inhibiting tubular sodium reabsorption and renin

and aldosterone biosynthesis ) • Vasorelaxant effects. In the kidney • ANP increases glomerular filtration rate (GFR) through

vasodilatation of the afferent arteriole and vasoconstriction of the efferent arteriole .

Beltowski J et al, Clin Res. 2002

ATRIAL NATRIURETIC PEPTIDE (ANP)

• Mutations in the ANP gene appear to be associatedwith the development of HTN in humans

• There is also evidence that ANP gene polymorphisms mayaffect the development of hypertensive sequelaesuch as left ventricular hypertrophy .

Xue H et al Clin Sci (Lond). 2008

• NB:

Primary HTN is showing more and more to be NOT Primary HTN:

1. ACE 2 Mutation (reduced level of AT1-7)2. ANP Polymorphism

RENALASE

• Renalase is a protein composed of 342 amino is recently discovered as a new renal hormone

• Renalase degrades circulating catecholamines(primarily epinephrine) via a mechanism different than monoamine oxidase

Desir G. Pediatr Nephrol 2012

• Renalase knockout mice are hypertensive and have evidence of increased sympathetic tone, suggesting renalase may modulate SNS activity

• Recombinant renalase has been developed and appears to be a potent antihypertensive agent in experimental models .

Desir G. Pediatr Nephrol 2012

• NB:Primary HTN is showing more and more to be

NOT Primary HTN:

1. ACE 2 Mutation (reduced level of AT1-7)2. ANP Polymorphism3. Renalase activity

PATHOPHYSIOLOGY OF SPECIFIC HTN DISEASES

• Primary HTN• Secondary HTN

SECONDARY HTN

A) Mendelian Forms of Hypertension (single-gene mutations )• Most of the mutations found to date affect renal sodium

handling. These disorders lead to 3 groups of diseases:

1. Aberrant distal tubular sodium reabsorption and volume expansion due to hyperaldosteronism (Aldosterone is increased)

2. Defects in steroid biosynthetic enzymes (causing increased mineralocorticoid activity)

3. Activation of sodium channels or transporters (depressed Aldosterone)

GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM (GRA) FAMILIAL HYPERALDOSTERONISM TYPE 1 (FH1)

• (FH-I) is AD

• Early onset of HTN with normal or elevated aldosterone levels despite suppressed plasma renin activity

Lifton RP. Proc Natl Acad Sci U S A. 1995

• Caused by a chimeric gene that results from unequal crossingover between the aldosterone synthase (CYP11B2) gene and the 11β-hydroxylase

• The resulting chimeric gene (CYP11B1/CYP11B2) is expressed in the adrenal fasciculata and encodes a protein product with aldosterone synthase enzymatic activity whose expression is regulated by ACTH.

• Consequently, aldosterone synthase activity is ectopically expressed in the adrenal fasciculata under control of ACTH rather than by ANG-II or potassium.Aldosterone secretion becomes linked to cortisol secretion, and maintenance of normal cortisol

• HTN is suppressed by Dexamethazone admmistration

ACTH Cortisol

Aldoster.

ACTH

Dexamethazone

Familial Hyperalsdosteronism I (GRA)

FAMILIAL HYPERALDOSTERONISM TYPE II(NON-GRA)

• Familial hyperaldosteronism type II (FH-II)• Similar to GRA (FH-I), with excess production of

mineralocorticoids, but is not suppressed by dexamethasone

• The molecular basis of the disorder remains to be determined.

FAMILIAL HYPERALDOSTERONISM TYPE III(NON-GRA)

• Familial hyperaldosteronism type III (FH-III) recently identified

• Mutations in the potassium channel KCNJ5 • This results in depolarization of the glomerulosa cells,

leading to increased calcium entry and aldosterone production .

• Massive adrenal hyperplasia with refractory HTN

Geller DS, J Clin Endocrinol Metab.2008

5 KCNJ Aldoster.

Familial Hyperalsdosteronism II and III (Non-GRA)

FIRST GROUP : FAMILIAL HYPERALDOSTERONISM

• Early onset HTN, normal or high Aldosterone

• FH -I ..Chimeric gene… GRA• FH – II… excess production ..Not GRA• FH-III… excess production ..Not GRA

SECONDARY HTN






THE SYNDROME OF APPARENT MINERALOCORTICOIDEXCESS (AME)

• AR

• Early-onset HTN with hypokalemia and metabolic alkalosis

• Accompanied by suppressed plasma renin activity • And the virtual absence of circulating aldosterone.

THE SYNDROME OF APPARENT MINERALOCORTICOIDEXCESS (AME)

• Steroids other than aldosterone activate the mineralocorticoid receptor (MR). i.e.apparent excess of MC action

• Cortisol activates MR with potency similar to aldosterone.• Cortisol, normally, is transformed to Cortisone by 11-hydroxysteroid

dehydrogenase (11HSD) enzyme• Mutation in the gene encoding the renal i11-hydroxysteroid

dehydrogenase (11HSD), results in impaired conversion of cortisol to cortisone .

• In AME, the absence of this enzyme allows cortisol to activate the MR, resulting in HTN mediated by increased sodium retention.

Mineralocorticoid ReceptorMR

AME

Cortisol

Cortisone

Cortisol

Epithelial Na channel ENaC

Aldosterone

Cortisone

3BHSD2 3BHSD2

OTHER STEROIDS CAUSING HTN

Congenital adrenal hyperplasia results from two known defects:1. 11-β-hydroxylase2. 17-α-hydroxylase

SECONDARY HTN






LIDDLE’S SYNDROME

• AD disorder • Gain mutations in the epithelial Na channel (ENaC) (Amiloride

sensitive ) in the collecting ducts, which are responsible for elevatedrenal sodium reabsorption in Liddle’s syndrome

• Severe HTN, metabolic alkalosis, and hypokalemia • Low renin • Low aldosterone.• Unresponsive to Aldosterone antagonist (aldactone) but responsive

to amiloride and triametrene

Mineralocorticoid ReceptorMR

Liddle’s Syndrome

Na reabsorption

Epithelial Na channel ENaC(Amiloride sensitive)

Aldosterone

Aldactone

Amiloridetriametrene

LIDDLE’S SYNDROME AND PSEUDOHYPOALDOSTERONISM TYPE I

• In Liddle's syndrome, gain-of-function mutations in the beta or gamma ENaC subunits have been found.

• In PHA-1, loss-of-function mutations in the alpha, beta, or gamma subunits have been found

GORDON’S SYNDROME (PSEUDOHYPOALDOSTERONISM TYPE II)

• The WNKs [“with no lysine”] mutations of the WNK1 and WNK4 have been found to be responsible for Gordon’s syndrome .

• Wild-type WNK1 and WNK4 inhibit the thiazide-sensitive Na-Cl co-transporter in the distal tubule. Mutations of these proteins are associated with gain of function and increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion.

• Increased WNK1 expression also decreases potassium excretionby inhibiting the renal outer medullary potassium channel(ROMK).

GORDON’S SYNDROME (PSEUDOHYPOALDOSTERONISM TYPE II)

• AD HTN

• hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate.

• Thiazides responsive• This syndrome maybe associated with short stature, intellectual

impairment, dental abnormalities, muscle weakness

RENOVASCULAR HTN (RVH)• 10%(5–25 %) of all secondary HTN in children.

• RVH is second only to coarctation of the aorta as a correctable cause of HTN in children.

RENOVASCULAR HTN (RVH)• Fibromuscular dysplasia (FMD ) is the most common cause of

RVH in children.

• FMD Significantly different from that in adults ( with the classic “string of beads” in the main artery )

• FMD in children produces focal unilateral isolated web like stenosis, and the majority of the lesions are in branch vessels or accessory arteries.

RENOVASCULAR HTN (RVH)

Genetic syndromes such as• NF-I• Tuberous sclerosis• Williams’ syndrome,• Marfan’s syndrome,• Turner’s syndrome• Alagille syndrome• Vasculitidies such as

• Takayasu’s disease, polyarteritis nodosa, Kawasaki

RENOVASCULAR HTN (RVH)

Other etiologies of RVH include

• Extrinsic compression of the renal arteries,

• Radiation,

• Umbilical artery catheterization

• Trauma

• Congenital rubella syndrome

• Aneurysms

• AVM/AVF,

• Transplant renal artery stenosis

RENOVASCULAR HTN (RVH)• The stenosis needs to occlude at least 70%of the lumen before it

begins to reduce renal blood flow and raise arterial pressure

• In the late phase, HTN persists despite removal of the stenosis or ischemic kidney, due to hypertensive damage to the contralateral kidney and probably also due to systemic vascular changes

CKD/AKI HTN• Depends on the etiology of underlying kidney disease rather

than on the degree of renal dysfunction (children with congenital urogenital anomalies such as renal dysplasia often do not have HTN because of tubulopathy leading to salt and water wasting.)

• HTN resulting from renal parenchymal disease is multifactorial in origin. • impaired excretion of salt and water, • reduced renal blood flow• Activation of the RAAS

POST-RX HTNThe major contributing factors :• History of pre-transplant HTN• Persistent native kidney presumably via persistent release of

renin • Effects of immunosuppressive medications • Transplant renal artery stenosis• Chronic allograft dysfunction

POST-RX HTNCalcineurin inhibitors cause:

• Increased production of the vasoconstrictor endothelin

• Decreased production of vasodilatory substances

• Activation of the SNS .

• Afferent artery vasoconstriction.

• Na retention .

• Many studies suggest that calcium channel blockers can minimize calcineurin-induced vasoconstriction thereby ameliorating HTN and preventing chronic graft injury.

Rose C et al , Eur J Pediatr. 2001

HYPERTENSION IN ENDOCRINE DISEASES• Pheochromocytomas and paragangliomas• Primary hyperaldosteronism (PAL)• Cushing’s syndrome• Glucocorticoid-remediable aldosteronism (GRA)• Familial hyperaldosteronism II and III• Reninoma.• Primary hyperparathyroidism (PHPT)• Hyperthyroidism( activation of the RAAS and increased sodium

reabsorption ) • Diabetes mellitus (DM).

Drug Induced HTN

PRIMARY (ESSENTIAL) HTN• Most HTN in adults has no identifiable underlying etiology;

therefore, the term “essential HTN” has been utilized for those hypertensive individuals without underlying secondary causes.

PRIMARY (ESSENTIAL) HTN

• In children, primary HTN was traditionally considered uncommon, accounting for less than 25 % of hypertensive children in the early 1990s.

• However, recently the rate has increased (up to 90 % in some USA series) mainly due to increased obesity

Din-Dzietham R et al. Circulation. 2007

SYMPATHETIC NERVOUS SYSTEMACTIVATION

Children with primary HTN :• Resting tachycardia compared to normotensive children• heightened cardiovascular reactivity to stress• Elevated plasma norepinephrine levels

• NB:Primary HTN is showing more and more to be

NOT Primary HTN:

1. ACE 2 Mutation (reduced level of AT1-7)2. ANP Polymorphism3. Renalase activity

QUESTIONS

• Choose one correct answer :

A) Familial hyperaldosteronism type III (FH-III) has been recently identified with mutations in the potassium channel KCNJ5 and is Glucocorticoid remediable

B) Familial Hyperaldosteronism Type I (Glucocorticoid Remediable Aldosteronism) shows early onset of HTN with normal or elevated aldosterone

levels despite suppressed plasma renin activity

C) A chimeric gene under the effect of TSH is formed in Familial Hyperaldosteronism Type I (Glucocorticoid Remediable Aldosteronism)

D) Cortisone causes HTN much more than Cortisol

• Choose one correct answer :• A) Liddle’s Syndrome is an AD disease with gain of function of

Thiazide sensitive NCC in distal Tubules

• B) Gordon ‘s Syndrome is caused by a gain of function in the Amiloride sensitive ENaC in the collecting ducts

• C) Aldactone is the drug of Choice in Liddle’s Syndrome to treat both hypokalemia and HTN in one act

• D) Gordon’ s Syndrome shows Type IV RTA

• Choose one correct answer :• A) Renalase maybe decreased in Primary HTN

• B) ANP polymorphism may contribute to the pathophysiology of primary HTN

• C) ACE 2 mutations can lead to more vasoconstriction in primary HTN

• D) All of the above

In 2008,American Heart Association issued a guidelinetrying to standardize the use of ABPM in children,including the detailed recommendations for theuse of ABPM and for the interpretation of the data

Urbina E et al . Hypertension. 2008

Subsequently, the European Society ofHypertension recommended the use of ABPM inchildren in certain settings Lurbe E et al . J Hypertens. 2009;

functional changes specifically decreased

relaxation and increased contraction [9].

Decreased relaxation has been attributed primarily to endothelial

dysfunction,

and increased contraction has been attributed to enhanced smooth muscle cell vasoreactivity. Sensitivity to vasoconstrictors may

also be increased.

Decreased relaxation is an effect of impaired endothelial production of vasodilatorysubstances (mainly nitric oxide [NO] and prostacyclin) or increased production of vasoconstricting substances (endothelin, platelet-derived growth factor [PDGF]), or both.

Sympathetic Innervation/CNS

Renal vessels, tubules, and the juxtaglomerular

apparatus are innervated by the renal sympathetic

nerves. Renal sympathetic nerve activity (RSNA)

influences renal hemodynamics, solute and water

handling, and hormonal release. Increased RSNA

is found in animal models of HTN and also in

hypertensive humans [13]. SNS activation, as

confirmed by increased circulating noradrenaline,

muscle sympathetic nerve traffic, and systemic

noradrenaline spillover, has for many decades

been established as almost universally present in

primary HTN

Increased RSNAconstricts the renal vasculature

and decreases GFR and renal blood flow. The

hypertensive response to chronic renal adrenergic

stimulation is associated with a sustained increase

in plasma renin activity and is dependent on an

increase in plasma angiotensin II (ANG-II) concentration

[16]. Sympathetic nerve activation appears

to enhance the response to circulatingANG-II [17].

The renal effects of ANG-II on proximal tubular

chloride and water reabsorption are decreased by

75 % in animals after experimental renal denervation.

Thus only about 25 % of ANG-II effect is

mediated directly via type 1 angiotensin receptors,

with the majority of the effect being dependent on

intact renal innervation. In experimental renal sympathetic

nerve stimulation, ANG-II enhanced the

renal venous outflow of norepinephrine, an effect

that was blocked by an ANG-II receptor antagonist

The AT2 receptor is a seven-transmembranetype,G protein-coupled receptor comprising363 amino acids. It has low amino acid sequencehomology (~34 %) with AT1A or AT1B receptors[36]. The expression of the AT2 receptor isupregulated by sodium depletion [48] and isinhibited by ANG-II and growth factors such asPDGF and EGF [49]. Under physiologic conditions,the AT2 receptor mainly antagonizesAT1-mediated actions. Cardiovascular effects ofthe AT2 receptor generally appear to be oppositeto those of the AT1 receptor and may be protective[50, 51]. In the kidney, stimulation of the AT2receptor promotes natriuresis through interactionswith the renal dopaminergic system [52].

gene

(CYP11B1) on chromosome 8. Aldosterone

synthase is the rate-limiting enzyme for aldosterone

biosynthesis in the adrenal glomerulosa, and

11β-hydroxylase is an enzyme involved in cortisol

biosynthesis in the adrenal fasciculata whose

expression is regulated by adrenocorticotropic

hormone (ACTH). The resulting chimeric gene

(CYP11B1/CYP11B2) is expressed in the adrenal

fasciculata and encodes a protein product with

aldosterone synthase enzymatic activity whose

expression is regulated by ACTH. Consequently,

aldosterone synthase activity is ectopically

Congenital adrenal hyperplasia results from

two known defects in either 11-β-hydroxylase

or17-α-hydroxylase activity and may cause

HTN. These defects lead to overproduction of

21-hydroxylated steroids, which activate mineralocorticoid

receptors, resulting in increased

sodium reabsorption in distal tubules [295, 296].

HYPERTENSION IN ENDOCRINE DISEASES• Pheochromocytomas and paragangliomas

• Although most pheochromocytomas are sporadic,

• there is a familial predisposition in patients

• Multiple endocrine neoplasia type II(MEN II)

• Von Hippel–Lindau disease

• NF-I and familial paraganglioma [399–401].

• Rarely, in tuberous sclerosis, Sturge–Weber syndrome, and ataxia telangiectasia.

HYPERTENSION IN ENDOCRINE DISEASESPrimary hyperaldosteronism (PAL) is now

believed to be much more common than previously

thought [397, 412, 413].

PAL was first

reported by Conn as aldosterone-producing adenoma

(APA) [414] and commonly results from

adrenal hypertrophy (“idiopathic hyperaldosteronism”;

IHA)

Hypertension in Dialysis Patients

Children receiving chronic dialysis have a significant

incidence of HTN: 54–68 % of children

receiving hemodialysis and 50–63 % of children

receiving peritoneal dialysis in the NAPRTCS

dialysis database were receiving antihypertensive

The aldosterone/MR cascade exerts its effects in the so-called aldosterone-sensitive distal nephron (ASDN), which includes the late distal convoluted tubule, connecting tubule, and collecting duct. Upon binding of aldosterone, MR undergoes conformational changes, dissociation from chaperone proteins, dimerization, and translocation to the nucleus, where it binds to the responsive elements in the promoter regions of target genes to regulate transcription. Among the aldosterone-induced genes, serum/glucocorticoid regulated kinase 1 (SGK1) plays a major role in the control of sodium reabsorption. Studies have clarified the detailed mechanism of epithelial sodium channel (ENaC) regulation by SGK1 (Fig. 1). Nedd4-2 (neural precursor cell expressed, developmentally downregulated 4-2) is a HECT domain–containing E3 ubiquitin ligase that interacts with the C terminus of ENaC subunits and maintains the plasma membrane ENaC at low levels through ubiquitination-dependent mechanisms. Aldosterone-induced SGK1 phosphorylates the Nedd4-2, which disrupts the tonic inhibition of ENaC by Nedd4-2, leading to indirect stimulation of sodium transport. SGK1 phosphorylation of Nedd4-2 results in 14-3-3 binding and suppresses Nedd4-2–ENaCinteraction [11]. ENaC mutations in Liddle’s syndrome also affect the Nedd4-2 interaction, leading to constitutive ENaC expression and increased sodium reabsorption [12]. SGK1 may also modulate ENaC activity though a mechanism independent of Nedd4-2 [13].Fig. 1

The major pathophysiologic mechanism in

most dialysis patients seems to be volume overload

related to sodium and water retention. Evidence in

favor of fluid overload being the major mechanism

can be found in the many studies that demonstrate

correction of HTN by increased fluid removal in

both peritoneal dialysis and hemodialysis patients

[359, 360]. However, numerous other factors have

been implicated, including overactivity of the SNS,

activation of the RAAS, erythropoietin treatment,

parathyroid hormone, and nocturnal hypoxemia

[361]. Recent studies have also implicated altered

endothelial cell function, with increased vasoconstrictors

such as endothelin and a reduction of

vasodilators such as NO being involved in the

pathogenesis of dialysis HTN

POST-RX HTNHTN is a common complication following renal

transplantation.

85% of deceased donor recipients and 79 % of live donor recipients

are receiving antihypertensive medications immediately post-transplant (decreasing to 69 % and 59 %, respectively 5 yrs after TX) [370].

Endothelin-1Endothelin-1 (ET-1) is an endothelial-derived,potent vasoconstrictive peptide containing21 amino acids [110]. Three isopeptides ofendothelin (ET-1, ET-2, ET-3), encoded by separategenes, have been identified [111]. EndothelialET-1 synthesis is activated by vasoactive hormones,growth factors, hypoxia, shear stress, lipoproteins,free radicals, endotoxin, andcyclosporine and is inhibited by NO, natriureticpeptides, heparin, and prostaglandins [112]. Apartfrom endothelial cells, ET-1 is also produced by

•ET-1 primarily appears to be a locally acting•paracrine substance. ET-1 closes membrane K+

•channels [115], which prevents cellular efflux of•K+, thereby favoring membrane depolarization,

•leading to smooth muscle cell contraction. In the•kidney, ET-1 causes constriction of both afferent

•and efferent glomerular arterioles, thereby reducing•both renal plasma flow and glomerular filtration

•rate [116]. It blocks reabsorption of sodium•by inhibiting tubular Na+/K+–ATPase activity in

•the proximal tubule and collecting duct [117].•Endothelin signals through two receptor subtypes

•NO is a vasodilator, and the balance between

•NO and various endothelium-derived vasoconstrictors

•and the SNS maintains physiologic vascular

•tone [133]. In addition, NO suppresses

•platelet aggregation, leukocyte migration, and cellular

•adhesion to the endothelium. It attenuates

•vascular smooth muscle cell proliferation

•and migration, as well as inhibits activation and

•expression of certain adhesion molecules and

•has an influence on production of superoxide

•anion [134].

•Endothelium-dependent relaxation is decreased

•in patients with primary HTN [135] and appears to

•be related to defective L-arginine transport.

•Treatment

•with inhibitors of NO synthesis induces a

•hypertensive response, while L-arginine treatment

•prevents the development of HTN in salt-sensitive

•rats [137] and also causes a rapid reduction in

•systolic and diastolic pressures when infused into

•both healthy subjects and patients with primary

•HTN [138]. Methylated L-arginine derivatives,

•including NG-NG-dimethylarginine (asymmetric

•dimethylarginine, ADMA), an endogenous inhibitor

•of NOS, and symmetric dimethylarginine, its

•inactive isomer, are present in human plasma and

•urine. Elevated levels of ADMAand other markers

•of oxidative stress have been demonstrated in

•patients with primary HTN and have been postulated

•to contribute to the endothelial dysfunction

•that accompanies HTN [139].

2011Rep.. Hypertens. Curr.Fujita T S and Shibata

UP TO DATE• INTRODUCTION• Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type

1 are rare genetic disorders associated with abnormalities in the function of the collecting tubule sodium channel, also called the epithelial sodium channel (ENaC) or the amiloride-sensitive sodium channel:

• ●ENaC function is increased in Liddle's syndrome, leading to manifestations similar to those caused by mineralocorticoid excess, such as hypertension and, in some patients, hypokalemia and metabolic alkalosis. Presentation at a young age, which occurs in most patients, suggests the possibility of a genetic disorder rather than an adrenal adenoma. In addition, plasma and urinary aldosterone levels are reduced, not increased as in primary aldosteronism.

• ●ENaC function is decreased in autosomal recessive pseudohypoaldosteronism type 1, resulting in aldosterone resistance. Affected patients present in infancy with sodium wasting, hypovolemia, and hyperkalemia. These findings are similar to those in other forms of

ANG II• Angiotensin II and angiotensin III (ANG-II, ANG-III) induce

aldosterone synthesis• Potassium, endothelin, adrenocorticotropic hormone (ACTH)

and vasopressin stimulate its secretion .• Inhibitors of aldosterone secretion include atrial natriuretic

peptide, somatostatin, and dopamine. Dietary sodium restriction increases aldosterone secretion in order to restore plasma volume.

• Aldosterone acts via type I mineralocorticoid receptors causing retention of sodium and potassium excretion. It also activates the SNS

PATHOPHYSIOLOGY OF HYPERTENSION Samuel Makar

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