Pathophysiology of Hypertension

Jianzhong Sheng MD, PhD

Department of Pathophysiology, School of Medicine

Regulation of ABP:

■ Maintaining B.P. is important to ensure a steady blood flow (perfusion) to tissues.

■ BP is regulated neurally through centers in medulla oblongata: 1. Vasomotor Center (V.M.C.), or (pressor area): Sympathetic fibers. 2. Cardiac Inhibitory Center (C.I.C.), or (depressor area): Parasympathetic fibers (vagus).

cardiac control centers in medulla oblongata

Regulation of ABP (continued)

1. Cardiacaccelerator

center(V.M.C)

2. Cardiacinhibitory

center(C.I.C)

Sympathetic n. fibers Parasympathetic n. fibers Regulatory mechanisms depend on: a. Fast acting reflexes: Concerned by controlling CO (SV, HR), & PR. b. Long-term mechanism:

Concerned mainly by regulating the blood volume.

Regulation of Arterial Blood PressureA. Regulation of Cardiac OutputB. Regulation of Peripheral ResistanceC. Regulation of Blood Volume

Classification of hypertension

1. Essential hypertension

2. Secondary hypertension

Excess sodium intake

Venous constriction

Fluid volume

Reduced nephron number

Decreased filtration surface

Renal sodium

retention

Endothlium derived factors

Obesity

Preload

Hyper- insulinaemia

Cell membrane alteration

Renin angiotensin

excess

Sympathetic nervous over

activity

Genetic alteration

Stress

Blood pressure = Cardiac output X Peripheral resistance

Structural hypertrophy

Functional constriction

HeartContractability

AutoregulationHypertension = Increased CO and/or Increased PR

Some of the factors involved in the control of blood pressure that affect the basic equation: blood pressue = cadiac output x peripheral resistence.

A. Regulation of CO:

■ A fast acting mechanism. ■ CO regulation depends on the regulation of:

a. Stroke volume, & b. Heart rate

Regulation of Arterial Blood Pressure

Mean arterial pressure

Cardiac output = Stroke volume X Heart rate

End Contraction diastolic strength volume (EDV) Stretch

Sympathetic n Parasympathetic n

Frank - Starling

A. Regulation of the CO:

Regulation of Arterial Blood Pressure

B. Regulation of Peripheral Resistance

B. Regulation of Peripheral Resistance (PR):

■ A fast acting mechanism. ■ Controlled by 3 mechanisms: 1. Intrinsic.

2. Extrinsic.

3. Paracrine.

Intrinsic mechanism:Blood vessel tone

Extrinsic mechanism is controlled through several reflex mechanisms, most important:

1. Baroreceptors reflex. 2. Chemoreceptors reflex.

1. Baroreceptors reflex:

■ Baroreceptors are receptors found in carotid sinus & aortic arch.

■ Are stimulated by changes in BP. BP

+ Baroreceptors =

V.M.C

++ C.I.C

=Sympathetic

Vasodilatation & TPR

+Parasympathetic

Slowing of SA node ( HR) & CO

2. Chemoreceptors reflex:■ Chemoreceptors are receptors found in carotid & aortic bodies.■ Are stimulated by chemical changes in blood mainly hypoxia ( O2), hypercapnia ( CO2), & pH changes.

BP

+ Chemoreceptors

++ V.M.C

= C.I.C

+ Sympathetic

Vasoconstriction

& TPR

= Parasympathetic

HR

Haemorrhage

Hypoxia

+ Adrenalmedulla

3. Other Vasomotor Reflexes:

1. Atrial stretch receptor reflex: Venous Return ++ atrial stretch receptors reflex

vasodilatation & BP.2. Thermoreceptors: (in skin/or hypothalamus)

• Exposure to heat vasodilatation.• Exposure to cold vasoconstriction.

3. Pulmonary receptors: Lung inflation vasoconstriction.

4. Hormonal Agents:

■ NA vasoconstriction.■ A vasoconstriction (except in sk. ms.).■ Angiotensin II vasoconstriction.■ Vasopressin vasoconstriction.

Regulation of Arterial Blood PressureC. Regulation of Blood Volume

Regulation of Blood Volume:

■ A long-term regulatory mechanism. ■ Mainly renal: 1. Renin-Angiotensin System. 2. Anti-diuretic hormone (ADH), or vasopressin. 3. Low-pressure volume receptors.

1. Renin-Angiotensin System:

■ Most important mechanism for Na+ retention in order to maintain the blood volume.

■ Any drop of renal blood flow &/or Na+, will stimulate volume receptors found in juxtaglomerular apparatus of the kidneys to secrete Renin which will act on the Angiotensin System leading to production of aldosterone.

Renin

Aldosterone

Adrenalcortex

Corticosterone

Angiotensinogen

(Lungs)

renal blood flow &/or Na+

++ Juxtaglomerular apparatus of kidneys

(considered volume receptors)

Angiotensin I

Convertingenzymes

Angiotensin II(powerful

vasoconstrictor)

Angiotensin III(powerful

vasoconstrictor)

• Renin-Angiotensin System:

N.B. Aldosterone is the main regulator of Na+ retention.

2. Anti-diuretic hormone (ADH), or vasopressin:

■ Hypovolemia & dehydration will stimulate the osmoreceptors in the hypothalamus, which will lead to release of ADH from posterior pituitary gland.

■ ADH will cause water reabsorption at kidney tubules.

3. Low-pressure volume receptors:

■ Atrial natriuritic peptide (ANP) hormone, is secreted from the wall of right atrium to regulate Na+ excretion in order to maintain blood volume.

Increased renal perfusion pressure

Increased pressure and flow vasa recta

Increased renal interstitial pressure Washout of medullary solute gradient

Superficial nephronsDecreased sodium resorption in proximal tubule Possible thick ascending limb

Deep nephronsDecreased sodium resorption in proximal tubule Possible thin descending limbPossible thick ascending limb

Proposed mechanism of pressure natriuresis.

Low birth weight and impaired renal development

Reduction in FSA

(Filtration surface area)

Acquired glomerular

sclerosis

Systemic/glomerular hypertension

Fig. 3 :

Na+ ingestionCentral venous volume Venous tone

Kidneys

Na+ excretion

Na+(+Cl + H2O) Plasma volumeretention

[Ca 2+ ]i [Na +]iVenous smooth muscle

[Na +]i [Ca 2+ ]i platelets

Endothelium[Na +]i [Ca 2+ ]i

ADHAdolsteroneReninANPOuabain

Arterial smoothMuscle [Na +]i [Ca 2+ ]i Sympathetic neurons

[Na +]i [Ca 2+ ]i

Blood pressure

Cardiovascularreflex activity

Arterial tone

(-)

CatecholamineRe-uptake

Catecholaminerelease

(-)

(-)

(-)

NO

(-)

(+)

Angiotensinogen

Angiotensin II

Angiotensin I

Arenalcortex

Kideney CNSIntestine HeartVascularSmoothmuscle

PeriphealNervoussystem

Aldosterone

Distal nephronreabsorption

Sodium and Waterreabsorption

Thirst Saltappetite

Adrenergicfacilitation

Sympatheticdischarge

Vasopressionrelease

Contracctility

Cardiacoutput

Maintain or increase ECFV

Total periphral resistance

Vasoconstriction

Renin

Converting enzyme Angiotension III

Angiotensinase A

Macula densa signal

Renal arteriolar pressure

Renal nerve activity

High renin(Dry vasoconstriction)

Pathophysiologic differenceArterioles

Low renin(wet vasoconstriction)

HigherHighLowLowHighHighLowYes

Peripheral resistanceAldosteronePlasma volumeCardiac outputHaematocritBlood ureaBlood viscosityTissue perfusionPostural hypotension

HighLow to HighHighHighLowLowHighNO

Clinical examplesHigh renin essential hypertesionRenovascular and malignant hypertension

Low renin essential hypertesionPrimary aldosteronism

Vascular sequelae(+) Stroke (-)(+) Heart attack (-)(+) Renal damage (-)(+) Retinopathy encephalopathy (-)

Treatments(+) Converting enzyme inhibitors (-)(+) Beta blockers (-)(-) Calcium channel blockers (+) (-) Diuretics (+)(-) Alpha blockers (+)

PRA Body Na+

HighVASOCONSTRICTION

Malignant hypertensionUnilateral renovascular hypertensionHigh renin essential hypertensionPheochromocytoma

VOLUME

Low

Medium Medium-renin essential hypertensionBilateral renovascular hypertension

Normal

LowLow-renin essential hypertesionPrimary hyperaldosteronism

High

Normal BP = (PRA, plasma renin activity) X (Na+ Volume)

Genetics Stress

Resetting ofcadiovascularcenters

Cadiovascularcenters

Increasedsympatheticoutflow

Renin-angiotensionsystem

Increased arterialpressure Increased

vascularresistance

Endothelium derivedrelaxing factors

Endothelium derivedcontracting factors

Endothelium and platelet derived mitogens

Vascularhypertrophy

Renin-angiotensin

Sympatheticnervous system

Other(genetic)

Episodichypertension

Norepinephrineangiotensin II

Peritubular capillarypressure

Peritubular capillaryflow

Capillary damagetubulointerstitial injury

Ischaemia NO Adenosine Ang II RSNA

Capillary injuryCapillary rarefaction Renal vascular Resistance

Tubuloglomerularfeed back

Pressurenatriuresis

NaCl excretion

Salt-dependenthypertension

Na-K ATPase(co-transport)

Na fluxes K fluxes

Ca binding

Ca ATPaseothers

Na-H antiport (Na-Li counter T)

Cell Na

Cell Ca

Cell pH

Na retention

Contractility

Growth

Depolarisation

Na+ / H + exchange

Renal proximal tubule cells Vascular smooth muscle cells

Na reabsorption

Vascular volume expansion

Cell Na and pH

Vascular tone Growth

Vascular wall thickness

Peripheral resistance

Hypertension

Cai2+

Acetycholine

Ca2+ Calmodulin

NO synthase

Arginine +O2 Citrulline + NO

Endothelial cell

Fe

Guanyate Cyclase

GTP cGMP Relaxation

NO

Smooth muscle cell

Type 2 diabetesmellitus

Dyslipidaemia

Obsity + Androgen increased abdominal fat Release of free fatty acids

Peripheralinsulin resistance

Increasedpancreaticinsulin secretion

Decreasedhepatic insulinextraction

Hyperinsulinaemia

Attenuatedvasodilation

Increasedsympatheticnervousactivity

Sodiumretention

Vascularhypertrophy

Hypertension

X

Lipolysis

Normal humaninsulin

Sympatheticactivation

IncreasedBlood pressure

DecreasedBlood pressure

Vasodilation

No increase in blood pressure

Obesity or hypertension insulin

Potentiatedsympatheticactivation

Impaireddepressor action

Augmented Pressure action

ImpairedDepressor action

Elevated blood pressure

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