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

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

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

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

11. Mechanisms of EH  activity of renin-angiotensin-aldosteron  activity of renin-angiotensin-aldosteron Hyperfunction of sympathetic systemHyperfunction of sympathetic system Vasoactive substances - endothelial dysfunctionVasoactive substances - endothelial dysfunction Insulin resistance  obesityInsulin resistance  obesity Arteriolar hypertrophyArteriolar hypertrophy Renal defect to excrete sodiumRenal defect to excrete sodium

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

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

14. Hyperfunction of sympathetic system Primary  activity of vasomotor neuronsPrimary  activity of vasomotor neurons Angiotensin II and endothelin increases activity of vasomotor neuronsAngiotensin II and endothelin increases activity of vasomotor neurons Norepinephrine potentiates renin releasingNorepinephrine potentiates renin releasing

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

17. Sodium transport across vascular smooth muscle cell membrane Sodium retention  activation of natriuretic mechanismsSodium retention  activation of natriuretic mechanisms Digitalis - like inhibitor of Na +,K +,ATP-aseDigitalis - like inhibitor of Na +,K +,ATP-ase

18. SYNDROME X SYNDROME X INSULIN INSULINRESISTANCE  HDL  VLDL GLUCOSE GLUCOSEINTOLERANCE HYPERINSULINEMIA HYPERTENSION OBESITY

19. INSULIN INSULINRESISTANCE HYPERINSULINEMIA ARTERIOLAR ARTERIOLARHYPERTROPHY SODIUM SODIUMRETENTION  SYMPATHETIC ACTIVITY ACTIVITY HYPERTENSION

20. (Reaven et al., 1996) Regulatory cells (tonicactivity)

21. Hypertrophy of Arteriolar Wall OBESITY STRESS Na + RETENTION RENAL RENALHYPOPERFUSION INSULINCATECHOLAMINES NATRIURETIC HORMON HORMON ANGIOTENSIN PRESSURE-GROWTH EFFECTS EFFECTS  INTRACELLULAR Ca 2+  Na+/H+ EXCHANGE SMOOTH MUSCLE CONTRACTION CONTRACTION VASCULAR WALL HYPERTROPHY HYPERTROPHY  PERIPHERAL VASCULAR RESISTANCE RESISTANCE

22. (Brown, 1997)

23. Role of Kidneys (Johnson et al., 2002)

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

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

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