Pathophysiology of Hypertension Tatr M Dept of Pathophysiology

Pathophysiology of Hypertension Tatár M. Dept. of Pathophysiology Jessenius Med. School

- venous return - extracellular fluid volume - myocardial contractility - vasoactive substances - thickening of arteriolar wall

Essential Hypertension • Hemodynamic effect of hormonal, neural and renal dysregulation of blood pressure • Pathogenesis is probably a slow and gradual process • No single or specific cause • Initiating factors may no longer be apparent when hypertension is developed, since they have been „normalised“ by the compensatory interactions • Initial phase: cardiac output • Late phase: peripheral arteriolar resistance, cardiac output is normalised

INCREASED EXTRACELLULAR FLUID VOLUME INCREASED BLOOD VOLUME INCREASED VENOUS RETURN INCREASED CARDIAC OUTPUT AUTOREGULATION INCREASED TOTAL PERIPHERAL RESISTANCE INCREASED BLOOD PRESSURE

Mechanisms of EH • activity of renin-angiotensin-aldosteron • Hyperfunction of sympathetic system • Vasoactive substances - endothelial dysfunction • Insulin resistance obesity • Arteriolar hypertrophy • Renal defect to excrete sodium

Increased R-A-A activity ANGIOTENSINOGENE J-G RENIN ANGIOTENSIN I ACE VASOCONSTRICTION ANGIOTENSIN II ALDOSTERON Na+ RETENTION negative feed back BLOOD PRESSURE

Tissue R-A system (Beevers et al. , 2001) - catecholamine and endothelin release - induction of hypertrophy of smooth muscle cells, cardiomyocytes

Hyperfunction of sympathetic system • Primary activity of vasomotor neurons • Angiotensin II and endothelin increases activity of vasomotor neurons • Norepinephrine potentiates renin releasing

Vacoactive substances Influence on vascular tone and sodium transport Endothelin Digitalis (ouabain) – like substance Natriuretic peptides

Sodium transport across vascular smooth muscle cell membrane • Sodium retention activation of natriuretic mechanisms • Digitalis - like inhibitor of Na+, K+, ATP-ase

INSULIN RESISTANCE HDL HYPERINSULINEMIA SYNDROME X HYPERTENSION OBESITY VLDL GLUCOSE INTOLERANCE

INSULIN RESISTANCE SYMPATHETIC ACTIVITY HYPERINSULINEMIA SODIUM RETENTION HYPERTENSION ARTERIOLAR HYPERTROPHY

(tonic activity) Regulatory cells (Reaven et al. , 1996)

Hypertrophy of Arteriolar Wall OBESITY STRESS Na+ RETENTION RENAL HYPOPERFUSION INSULIN CATECHOLAMINES NATRIURETIC HORMON ANGIOTENSIN PRESSURE-GROWTH EFFECTS INTRACELLULAR Ca 2+ SMOOTH MUSCLE CONTRACTION Na+/H+ EXCHANGE VASCULAR WALL HYPERTROPHY PERIPHERAL VASCULAR RESISTANCE

(Brown, 1997)

Role of Kidneys (Johnson et al. , 2002)

Renal Lesions 1 st phase - normal kydneys and sodium excretion - sympathetic hyperactivity, R-A stimulation renal vasoconstriction 2 nd phase - tubular ischemia - interstitial inflammation ultrafiltration and Na+ reabsorbtion increased blood pressure 3 rd phase - elimination of tubular ischemia; sodium excretion is normal BP is more increased after enhanced salt intake

Right shift of „pressure-natriuretic“ line (Cowley and Roman, 1996)

Conclusions • Interaction between increased activity of sympatihetic and RA systems and dysregulation of sodium balance and intravascular volume • Endothelial dysfunction – dysbalance between vasoconstrictor and vasodilator agents • Hyperinsulinemia – a) direct effect on sodium retention, b) sympathetic activation through the suppression of regulatory neurons in hypothalamus • Hypertrophy of arteriolar wall – increased vasoconstrictor reactivity • Genetic factors: dysfunction of membrane mechanisms of vascular smooth muscle cells; disorder of sodium exchange in nephron epithelial cells • Acquired renal injury: sodium intake is excreted only with increased blood pressure