PathophysiologyPathophysiologyof Hypertensionof Hypertension

Tatár M.Tatár M.

Dept. of PathophysiologyDept. of Pathophysiology

Jessenius Med. SchoolJessenius Med. School

- - venous returnvenous return- extracellular fluid volume- extracellular fluid volume- myocardial contractility- myocardial contractility

- - vasoactive substancesvasoactive substances- thickening of arteriolarthickening of arteriolar wallwall

Essential HypertensionEssential Hypertension

• Hemodynamic effect of hormonal, neural and renal Hemodynamic effect of hormonal, neural and renal dysregulation of blood pressuredysregulation of blood pressure

• Pathogenesis is probably a slow and gradual Pathogenesis is probably a slow and gradual processprocess

• No single or specific causeNo single or specific cause

• Initiating factors may no longer be apparent when Initiating factors may no longer be apparent when hypertension is developed, since they have been hypertension is developed, since they have been „normalised“ by the compensatory interactions„normalised“ by the compensatory interactions

• Initial phase:Initial phase: cardiac output cardiac output • Late phase:Late phase: peripheral peripheral arterioarteriolar resistance, lar resistance,

cardiac output is cardiac output is normalisednormalised

INCREASED EXTRACELLULAR FLUID VOLUMEINCREASED EXTRACELLULAR FLUID VOLUME

INCREASED BLOOD VOLUMEINCREASED BLOOD VOLUME

INCREASED VENOUS RETURNINCREASED VENOUS RETURN

INCREASED CARDIAC OUTPUTINCREASED CARDIAC OUTPUT

AUTOREGULATIONAUTOREGULATION

INCREASED TOTAL INCREASED TOTAL PERIPHERAL RESISTANCEPERIPHERAL RESISTANCE

INCREASED BLOOD PRESSUREINCREASED BLOOD PRESSURE

Mechanisms of EHMechanisms of EH

activity of renin-angiotensin-aldosteronactivity of renin-angiotensin-aldosteron

• Hyperfunction of sympathetic systemHyperfunction of sympathetic system

• Vasoactive substances - endothelial Vasoactive substances - endothelial dysfunctiondysfunction

• Insulin resistanceInsulin resistance obesityobesity

• Arteriolar hypertrophyArteriolar hypertrophy

• Renal defect to excrete sodiumRenal defect to excrete sodium

Increased R-A-A activityIncreased R-A-A activity

J-GJ-G RENINRENIN

ANGIOTENSINOGENEANGIOTENSINOGENE

ANGIOTENSINANGIOTENSIN II ANGIOTENSINANGIOTENSIN IIII

ALDOSTERONALDOSTERON

NaNa++ RETENTION RETENTION

BLOOD PRESSUREBLOOD PRESSURE

VASOCONSTRICTIONVASOCONSTRICTION

negativenegative feed backfeed back

ACEACE

Tissue R-A systemTissue R-A system

- - catecholamine and endothelin release catecholamine and endothelin release - induction of hypertrophy of smooth muscle induction of hypertrophy of smooth muscle cells,cells, cardiomyocytescardiomyocytes

(Beevers et al., 2001)(Beevers et al., 2001)

Hyperfunction of sympathetic Hyperfunction of sympathetic systemsystem

• Primary Primary activity of activity of vasomotor neuronsvasomotor neurons

• Angiotensin II and Angiotensin II and endothelin increases endothelin increases activity of vasomotor activity of vasomotor neuronsneurons

• Norepinephrine Norepinephrine potentiates renin potentiates renin releasingreleasing

Vacoactive substancesVacoactive substances

Endothelin

Digitalis (ouabain) – like substance

Natriuretic peptides

Influence on vascular tone and sodium transportInfluence on vascular tone and sodium transport

Sodium transport across vascular smooth Sodium transport across vascular smooth muscle cell membranemuscle cell membrane

• Sodium retention Sodium retention activation of natriuretic activation of natriuretic mechanismsmechanisms

• Digitalis - like inhibitor of Digitalis - like inhibitor of NaNa++,K,K++,ATP-ase,ATP-ase

SYNDROME SYNDROME XX

INSULIN INSULIN RESISTANCERESISTANCE

HDLHDL

VLDLVLDL

GLUCOSEGLUCOSEINTOLERANCINTOLERANCEE

HYPERINSULINEMIAHYPERINSULINEMIA

HYPERTENSIONHYPERTENSION

OBESITYOBESITY

INSULININSULINRESISTANCERESISTANCE HYPERINSULINEMIAHYPERINSULINEMIA

ARTERIOLARARTERIOLARHYPERTROPHYHYPERTROPHY

SODIUMSODIUMRETENTIONRETENTION

SYMPATHETICSYMPATHETIC ACTIVITYACTIVITY

HYPERTENSIONHYPERTENSION

(Reaven et al., 1996)(Reaven et al., 1996)

Regulatory cellsRegulatory cells

(tonic (tonic activity)activity)

Hypertrophy of Arteriolar Wall

OBESITYOBESITY STRESSSTRESS NaNa++ RETENTION RETENTION RENALRENALHYPOPERFUSIONHYPOPERFUSION

INSULININSULIN CATECHOLAMINESCATECHOLAMINESNATRIURETICNATRIURETIC HORMONHORMON ANGIOTENSINANGIOTENSIN

PRESSURE-GROWTHPRESSURE-GROWTH EFFECTSEFFECTS

INTRACELLULAR INTRACELLULAR CaCa2+2+

Na+/H+ EXCHANGENa+/H+ EXCHANGE

SMOOTH MUSCLESMOOTH MUSCLE CONTRACTIONCONTRACTION

VASCULAR WALLVASCULAR WALL HYPERTROPHYHYPERTROPHY

PERIPHERAL VASCULARPERIPHERAL VASCULAR RESISTANCERESISTANCE

(Brown, 1997)(Brown, 1997)

Role of KidneysRole of Kidneys

(Johnson et al., 2002)(Johnson et al., 2002)

Renal LesionsRenal Lesions

11stst phase phase - normal kydneys and sodium excretion- normal kydneys and sodium excretion- sympathetic hyperactivity, R-A - sympathetic hyperactivity, R-A

stimulationstimulation

22ndnd phase phase - tubular ischemia - interstitial - tubular ischemia - interstitial inflammation -inflammation -

ultrafiltration and ultrafiltration and Na Na++ reabsorbtion reabsorbtion

33rdrd phase phase - elimination of tubular ischemia; - elimination of tubular ischemia; sodium excretion is normalsodium excretion is normal

renal vasoconstrictionrenal vasoconstriction

increased blood pressureincreased blood pressure

BP is more increased after enhanced salt intakeBP is more increased after enhanced salt intake

Right shift of „pressure-natriuretic“ lineRight shift of „pressure-natriuretic“ line

(Cowley and Roman, 1996)(Cowley and Roman, 1996)

ConclusionsConclusions

• Interaction between increased activity of sympatihetic Interaction between increased activity of sympatihetic and R-A systems and dysregulation of sodium balance and R-A systems and dysregulation of sodium balance and intravascular volumeand intravascular volume

• Endothelial dysfunction – dysbalance between Endothelial dysfunction – dysbalance between vasoconstrictor and vasodilator agentsvasoconstrictor and vasodilator agents

• Hyperinsulinemia – a) direct effect on sodium Hyperinsulinemia – a) direct effect on sodium retention, retention,

b) sympathetic activation through the suppression of b) sympathetic activation through the suppression of regulatory neurons in hypothalamusregulatory neurons in hypothalamus

• Hypertrophy of arteriolar wall – increased Hypertrophy of arteriolar wall – increased vasoconstrictor reactivityvasoconstrictor reactivity

• Genetic factors: dysfunction of membrane Genetic factors: dysfunction of membrane mechanisms of vascular smooth muscle cells; disorder mechanisms of vascular smooth muscle cells; disorder of sodium exchange in nephron epithelial cellsof sodium exchange in nephron epithelial cells

• Acquired renal injury: sodium intake is excreted only Acquired renal injury: sodium intake is excreted only with increased blood pressurewith increased blood pressure