Biochemistry of Hypertension

Dr. Sudipta Dutta(JR-II)

Deptt. of Biochemistry

JNC-7 Blood Pressure Classification

<80and<120Normal

80–89 or120–139Prehypertension

90–99 or140–159Stage 1 Hypertension

>100 or>160Stage 2 Hypertension

DBP mmHgSBP mmHgBP Classification

Seventh Report of the Joint National Comm2560, 2003.

B

40% greater relative prevalence in African-Americans

Hypertension: Ethnic Variation (United States)

32.4

23.3 22.6

0

5

10

15

20

25

30

35

African African AmericanAmerican

WhiteWhite HispanicHispanic

Ag

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%)

Causes of Hypertension

• “Essential” 90-95%

• Renal 3-5 %– Chronic renal failure– Renovascular disease

• 1o aldosteronism < 1%• Pheochromocytoma < 1%• Hypertension of pregnancy

Identifiable Causes of Hypertension(2o):-

Renovascular disease

Primary aldosteronism Pheochromocytoma

Pseudopheochromocytoma

Sleep apnea Drug-induced or related causes Chronic kidney disease Chronic steroid therapy and Cushing’s syndrome Coarctation of the aorta Thyroid or parathyroid disease

Hypertension

Heart Failure

MyocardialIschemia and

Infarction

StrokeNephrosclerosis

and Renal Failure

Retinopathy

Sequelae of Essential Hypertension:-

Essential or Familial HTN:-

• More than 90% of cases of hypertension do not have a clear cause.

• Hypertension clusters in families and results from a complex

• interaction of genetic and environmental factors.

• The hypertension-related genes identified to date regulate renal salt and water handling.

Many pathophysiologic factors have been implicatedin the genesis of essential hypertension: -

• Increased sympathetic nervous system activity, • psychosocial stress; • overproduction of sodium-retaining hormones and

vasoconstrictors; • long-term high sodium intake; • inadequate dietary intake of potassium and calcium; • increased or inappropriate renin secretion with resultant

increased production of angiotensin II and aldosterone;

Cond:-

• deficiencies of vasodilators, such as prostacyclin, nitric oxide (NO), and the natriuretic peptides;

• alterations in expression of the kallikrein– kinin system that affect vascular tone and renal salt handling;

• abnormalities of resistance vessels, including selective lesions in the renal microvasculature;

• diabetes mellitus; insulin resistance; obesity;• increased activity of vascular growth factors; • alterations in adrenergic receptors that influence heart

rate, inotropic properties of the heart, and vascular tone; • altered cellular ion transport, oxidative stress, vascular

remodeling, and decreased compliance

Pathophysiologic mechanisms of hypertension:-

Associated contributing factors:-

• Hypertension, insulin resistance, dyslipidemia, and obesity often occur concomitantly .

• Associated abnormalities include microalbuminuria, high uric acid levels,hypercoagulability, and accelerated atherosclerosis.

• This corelation of abnormalities, referred to as the insulin resistance syndrome or the metabolic syndrome, which increases cardiovascular disease (CVD) risk.

Hypothesis of primary hypertension

• The haemodynamic hallmark of primary hypertension – a persistently elevated vascular resistance, structural thickening

of the vessel walls or functional vasoconstriction.

Moreover, individual factors often interact, and the interactions are proving to be increasingly complex.

For instance,• insulin resistance is present even before hypertension develops in

those who are genetically predisposed, • The resultant hyperinsulinaemia is associated with sodium

sensitivity, obesity, and increased sympathetic drive as well as impaired endothelium - dependent vascular resistance.

Vasoconstriction

Renin-Angiotensin-Aldosterone System

Angiotensinogen

Angiotensin I

Angiotensin II

ACEACE

ReninRenin

Aldosterone secretion

Sodium & fluid retention

Fromkidney

Fromliver

A. Weder

Response to Hypotension:-

Biochemistry Of RAAS:-Angiotensin II increases blood pressure by various mechanisms:-A) constricting resistance vessels, B) stimulating aldosterone synthesis and release C) renal tubular sodium reabsorption (directly and indirectly through

aldosterone)D) stimulating thirst and release of antidiuretic hormone,E) enhancing sympathetic outflow from the brain. Angiotensin II induces cardiac and vascular cell hypertrophy and hyperplasia

directly by activating :-The angiotensin II type 1 (AT1) receptor and indirectly by stimulating release of

several growth factors and cytokines.

Local production of angiotensin II in various tissues, including the blood Local production of angiotensin II in various tissues, including the blood vessels, heart, adrenals, and brain, is controlled by ACE and other vessels, heart, adrenals, and brain, is controlled by ACE and other enzymes, including the serine proteinase chymase.enzymes, including the serine proteinase chymase.

Pharmaceutical Utilisation of RAAS:-

Biochemistry of AT Receptors:-

• Activation of the AT1 receptor stimulates various tyrosine kinases, which in turn phosphorylate the tyrosine residues in several proteins, leading to vasoconstriction, cell growth, and cell proliferation

• Activation of the AT2 receptor stimulates a phosphatase that inactivates mitogen-activated protein kinase, a key enzyme involved in transducing signals from the AT1 receptor.Thus, activationof the AT2 receptor opposes the biological effects of AT1 receptor activation, leading to vasodilation, growth inhibition, and cell differentiation

• The physiologic role of the AT2 receptor in adult organisms is unclear, but it is thought to function under stress conditions (such as vascular injury and ischemia reperfusion)

The angiotension II types 1 (AT1) and 2 (AT2)receptors have generally opposing effects

ANGIOTENSIN II AND OXIDATIVE STRESS:-

• Stimulating oxidant production is another mechanism• The upregulation of vascular p22phox messenger RNA (mRNA), a

component of the oxidative enzyme nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase associated with enhanced formation of the oxidant superoxide anion (O2).

• A reduction in NO bioactivity to explain the enhanced vasoconstrictor response to angiotensin II in hypertension

• the oxidation of low-density lipoprotein cholesterol and increased mRNA expression for monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 .

• ACE inhibitors and ARBs limit oxidative reactions in the vasculature by blocking the activation of NAD(P)H oxidase. clinically important vasoprotective effects beyond lowering blood pressure.

PathophysiologicEffects on

CardiovascularSystem

Ang IIAng IIAng IIAng IIAng IAng IAng IAng IAngiotensinogenAngiotensinogenAngiotensinogenAngiotensinogen

Renin

Na+/H2ORetention

K+, Mg++ Loss

AldosteroneAldosteroneAldosteroneAldosterone

ACE

Non-RAASStimulators

Aldosterone: Important Component of Renin-Angiotensin-Aldosterone System

A. Weder

Biochemistry of Aldosterone:-

• Aldosterone has autocrine or paracrine actions on the heart and vasculature

• The heart and blood vessels also express high-affinity mineralocorticoid receptors that can bind both mineralocorticoids and glucocorticoids.

• Activation of these mineralocorticoid receptors lead to stimulate intra- and perivascular fibrosis and interstitial fibrosis in the heart.

• The nonselective aldosterone antagonist spironolactone and the novel selective aldosterone receptor antagonist eplerenone are effective in preventing or reversing vascular and cardiac collagen deposition

• Spironolactone treatment for patients with heart failure reduced circulating levels of procollagen type III, N-terminal aminopeptide, indicating an antifibrotic effect.

RAASRAASAngiotensin IIAngiotensin IIRAASRAASAngiotensin IIAngiotensin II

Non-RAASNon-RAASPotassiumPotassium

Adrenocorticotropic HormoneAdrenocorticotropic Hormone

NorepinephrineNorepinephrine

EndothelinEndothelin

SerotoninSerotonin

Non-RAASNon-RAASPotassiumPotassium

Adrenocorticotropic HormoneAdrenocorticotropic Hormone

NorepinephrineNorepinephrine

EndothelinEndothelin

SerotoninSerotonin

AldosteroneAldosterone

Stimulators of Aldosterone

RAAS = renin-angiotensin-aldosterone system

1o Aldosteronism

Aldosteronesecretion

independent of normal regulators

A. Weder

Biochemistry of NO:-

• Nitric oxide is a potent vasodilator, inhibitor of platelet adhesion and aggregation, and suppressor of migration and proliferation of vascular smooth-muscle cells.

• NO-related vascular relaxation is diminished in hypertensive group.

• Superoxide dismutase (an enzyme that reduces superoxide to hydrogen peroxide) reduces blood pressure and restores NO bioactivity proves oxidant stress contributes to the inactivation of NO and the development of endothelial dysfunction in hypertensive

• AngiotensinII enhances formation of the oxidant superoxide .• Increased oxidant stress and endothelial dysfunction predispose to

hypertension.

• Antihypertensive drugs that interrupt the renin–angiotensin– aldosterone system, including ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists, are effective in reversing endothelial dysfunction.

Interplay of NO, Endothelin in HTN:-

Nitric oxide in arterial smooth muscle:-

A messenger molecule such as acetylcholine binds its receptor on an endothelial cell, activating inward calcium currents. Calcium binds to calmodulin and activates endothelial cell nitric oxide synthase, which converts arginine plus oxygen into citrulline and nitric oxide. Nitric oxide diffuses out of the endothelial cell into an adjacent smooth muscle cell and activates guanylate cyclase by binding to the iron in its haeme group.The increase in cyclic guanosine monophosphate (cGNP) causes smooth muscle relaxation and thus vasodilation.

ENDOTHELIN:-

• potent vasoactive peptide produced by endothelial cells that has both vasoconstrictor and vasodilator properties.

• Endothelin acts in a paracine fashion on underlying smooth-muscle

cells to cause vasoconstriction and elevate blood pressure.

• Endothelin receptor antagonists reduce blood pressure and peripheral vascular resistance in both normotensive and patients with mild to moderate essential hypertension.

Sodium Sensitivity:-

• Multiple mechanisms of sodium sensitivity has been proposed:- • defect in renal sodium excretion,• increased activity of the sodium hydrogen exchanger, • increased sympathetic nervous system activity, • increased calcium entry into vascular smooth muscle, • impaired nitric oxide synthesis. • Blacks have greater frequency of salt sensitivity. Salt sensitivity

increases with age, and perhaps more in women than in men • In a recent study Fujiwora et al reported that modulation of NO

synthesis by salt intake may be involved in a mechanism for salt sensitivity in human.

nephron heterogeneity in essential hypertension:-

• There are ischaemic nephrons with impaired sodium excretion • Renin secretion is high from ischaemic nephrons and low from

hyperfiltering nephrons.• The inappropriate circulating renin angiotensin level impairs sodium

excretion• A loss of nephron number with age and from ischaemia further

impairs sodium excretion.

Cell membrane alterations:-

Hypotheses linking abnormal ionic fluxes to increasedperipheral resistance through increase in cell sodium, calcium,or pH.

Obesity:-

• Obese individuals have higher cardiac output, stroke volume, and

total blood volume and lower peripheral resistance than non obese individuals with similar blood pressure

• The increase in the prevalence of hypertension increased equally with increasing BMI, degree of upper body obesity, and fasting insulin levels, Insulin resistance and hyperinsulinaemia.

Insulin resistance and/or hyperinsulinaemia:-

• Enhanced renal sodium and water reabsorption.• Increased blood pressure sensitivity to dietary salt intake• Augmentation of the pressure and aldosterone responses to AII• Changes in transmembrane electrolyte transport a. Increased intracellular sodium b. Decreased Na+/K+ - ATPase activity c. Increased intracellular Ca2+ pump activity• Increased intracellular Ca2+ accumulation• Stimulation of growth factors, especially invascular smooth muscle.• Stimulation of sympathetic nervous activity• Reduced synthesis of vasodilatory prostaglandins• Impaired vasodilation• Increased secretion of endothelin

Interplay of different factors:-

RAAS- The CPU of Primary HTN:-

Treatment modality of Primary HTN:-

Who is the culprit:-

• Although a number of individual genes and genetic factors have been linked to the development of primary hypertension (formerly called "essential" hypertension), it is likely that multiple genes contribute to the development of the disease in any given individual.

Phenotypic variation of HTN:-

• The identification of variants (allelic) genes that contribute to the development of hypertension is complicated by the fact that

• The 2 phenotypes that determine BP, i.e., cardiac output and total peripheral resistance, are controlled by intermediary phenotypes, including

• The autonomic nervous system, • vasopressor/vasodepressor hormones, • the structure of the cardiovascular system, body fluid volume and

renal function, and many others. • These intermediary phenotypes are also controlled by complex

mechanisms including BP itself. • So, there are many genes that could participate in the development

of hypertension(i:e; polygenic in nature)

Factors influencing HTN:-

• genetic variations or genes that are overexpressed or under-expressed as well as the intermediary phenotypes that they regulate to cause high BP.

• Factors that increase BP, such as obesity and high alcohol and salt intake are called “hypertensinogenic factors”; some of these factors have inherited, behavioural, and environmental components.

• There are interactions between genetics and environmental factors that influence intermediary phenotypes such as sympathetic nerve activity, renin angiotensin aldosterone and renin - kallikrein - kinin systems and endothelial factors, which is turn influence other intermediary phenotypes such as sodium excretion, vascular reactivity, and cardiac cartractility.

• These and many other intermediary phenotypes determine total vascular resistance and cardiac output and consequently BP.

Mutation-?mendelian-?monogenic!!!!

• Mutations in at least 10 genes have been shown to raise or lower BP through common pathways by increasing or decreasing salt and water reabsorption by the nephron.

• The genetic mutations responsible for 3 rare forms of mendellian (monogenic) hypertension syndromes:-

A) gluco-corticoid remediable aldosteronism (GRA), B) Liddle’s syndrome C) apparent mineralocorticoid excess (AME)-Mutations in the HSD II B2

gene causes a rare monogenic juvenile hypertensive syndrome.

• In AME, compromised HSD II enzyme activity results in over stimulation of the mineralo corticoid receptor (MR) by cortisol; causing sodium retention, hypokalaemia, and salt dependent hypertension has been identified,

• In a fourth, autosomal dominant hypertension with brachydactyly the gene is not yet identified but has been mapped to chromosome 12 (12 p).

Monogenic cause of HTN:-

• The best studied monogenic cause of hypertension is the Liddle syndrome, a rare but clinically important disorder in which constitutive activation of the epithelial sodium channel predisposes to severe, treatment-resistant hypertension

• Epithelial sodium channel activation has been traced to

mutations in the subunits of the channel, resulting in inappropriate sodium retention at the renal collecting duct level.

• Patients with the Liddle syndrome typically present with volume-dependent, low renin and low-aldosterone hypertension.

Genetic polymorphism:-

Polymorphisms and mutations in genes such as:-

• angiotensin gene, angiotensin converting enzyme,• B2 adrenergic receptor, adducin, angiotensinase-C• renin binding proteins, G-protein B3 subunit• atrial natriuretic factor and the insulin receptor..

A circulating inhibitor of (Na+ + K+) ATPase associated with essential hypertension:-

An increase in the circulating concentration of an inhibitor of (Na+ - K+) ATPase like renal deoxycorticosterone acetate (DOCA)

is responsible for the increased peripheral vascular resistance in essential hypertension.

Evidence for relatively high levels of a Na+ pump inhibitor in essential hypertension has come from bioassay and cytochemical assays of plasma and urine from normotensive and hypertensive individuals.

Angiotensinogen gene polymorphism:-

• In genetic studies from widely separated geographical areas, there is evidence of genetic linkage between the angiotensinogen gene (AGT) and hypertension

• It demonstrated association of AGT molecular variants M235T with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects with different AGT genotypes.

• A common variant in the angiotensin-converting enzyme (ACE)

gene that has been associated in some studies with blood pressure variation in men also found.

Good genes-be fortunate:-

Genes that protect against the development of hypertension.

• One example is Gitelman's syndrome in which loss-of-function mutations in the thiazide-sensitive Na-Cl cotransporter in the distal tubule are associated with lower blood pressures than in individuals without this defect.

Secondary Hypertensions:-

Pheochromocytoma• Pl. free

metanephrine

99% sensitive and 89% specific

JAMA 287: 1427-1434, 2002

1o Aldosteronism• Plasma aldosterone-

renin ratio (ARR)PRA (ng/mL/hr)

Plasma aldosterone (ng/dl)

• ARR > 30 suggests 1o Aldosteronism

AJ Kid Dis 37:699-705, 2001

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