Pathophysiology of Hypertension

1. Pathophysiology of Hypertension Jianzhong Sheng MD, PhD Department of Pathology & Pathophysiology

2. Blood Pressure Definition: the force exerted by the blood against the walls of the bleed vessels Adequate to maintain tissue perfusion during activity and rest Arterial blood pressure: primary function of cardiac output and systemic vascular resistance

3. Blood Pressure Arterial BP = Cardiac Output (CO) x Systemic vascular resistance (SVR) Cardiac Output = stroke volume x beats per min Systemic vascular resistance = force opposing the movement of blood within the blood vessels What is the effect on BP if SVR increased and CO remains constant?

4. Mechanisms that Regulate BP Sympathetic Nervous System Vascular Endothelium Renal System Endocrine System

5. Mechanisms that Regulate BP Sympathetic Nervous System (SNS)– norepinephrine released from sympathetic nerve endings - to receptors alpha1, alpha2, beta1 & beta2 Reacts within seconds Increases Heart Rate - chronotropic Increased cardiac contractility - inotropic Produces widespread vasoconstriction in peripheral arterioles Promotes release of renin from the kidney

6. SNS Receptors Influencing BP

7. Mechanisms that Regulate BP Sympathetic Nervous System (SNS)– Sympathetic Vasomotor Center – located in the medulla – interacts with many areas of the brain to maintain BP within normal range under various conditions Exercise – changes to meet oxygen demand Postural Changes – peripheral vasoconstriction

8. Mechanisms that Regulate BP Sympathetic Nervous System (SNS) – Baroreceptors: specialized nerve cells the carotid arteries and the aortic arch Sensitive to BP changes: Increase: Inhibits SNS– peripheral vessel dilation. Decreased heart rate, and decreased contractility of the heart + increased parasympathetic activity (vagus nerve) decreased heart rate Decrease: Activates SNS– peripheral vessel constriction, increased heart rate, and increased contractility of the heart

9. Mechanisms that Regulate BP Vascular Endothelium Single cell layer that lines the blood vessels Produce vasoactive substances: EDRF Endothelium-derived relaxing factor– Helps maintain low arterial tone at rest Inhibits growth of the smooth muscle layer Inhibits platelet aggregation Vasodilation – prostacyclin Endothelin (ET) potent vasoconstrictor Endothelial dysfunction may contribute to atherosclerosis & primary hypertension

10. Mechanisms that Regulate BP Renal System Control Na+ excretion & extracellular fluid volume Renal - Renin-angiotensin-aldosterone Renin converts angiotensinogen to angiotensin I Angiotensin-converting enzyme (ACE) converts I into angiotsensin II Immediate: Vasoconstrictor – increased systemic vascular resistance Prolonged: Stimulates the adrenal cortex to secret Aldosterone – Na+ and Water retention Renal Medulla - Prostaglandins - vasodilator effect

11. Renin-Angiotensin System

12. Aldosterone Mechanism Increased Aldosterone = Increases sodium reabsorption = Increases water reabsorption = Increases blood volume = Increases cardiac output

13. Mechanisms that Regulate BP Endocrine System Stimulates the SNS with Epinephrine – increases HR and contractility Activates B2-adrenergic receptors in peripheral arterioles of skeletal muscle = vasodilation Activates A1-adrenergic receptors in peripheral arterioles of skin and kidneys = vasoconstiction Adrenal Cortex – Aldosterone – stimulates kidneys to retain Na+ Increased Na+ stimulates posterior pituitary – ADH – reabsorbs ECF/water

14. Regulatory mechanisms in the health person function in response to the demands on the body When Hypertension develops, one or more of these mechanisms are defective Sympathetic Nervous System Vascular Endothelium Renal System Endocrine System Mechanisms that Regulate BP

15. Secondary HypertensionPathophysiology Specific cause of hypertension can be identified 5+% of adult hypertension Causes: Coarctation or congenital narrowing of the aorta Renal disease – renal artery disease / parenchymal Endocrine disorders: Pheochromocytoma, Cushing Syndrome, Hyperaldosteronism Neurological disorders – brain tumors / head injury Sleep apnea Medications – sympathetic stimulants Pregnancy-induced hypertension

16. HypertensionPathophysiology Primary (Essential) Hypertension: Elevated BP without an identified cause Accounts for 95% of all cases of hypertension Cause – unknown Contributing Factors: Increased SNS activity, overproduction of Na+ retaining hormones & vasoconstrictors, increased Na+ intake Risk Factors: Modifiable

17. Some of the factors involved in the control of blood pressure that affect the basic equation: blood pressue = cadiac output x peripheral resistence. Excess sodium intake Reduced nephron number Stress Endothlium derived factors Obesity Genetic alteration Decreased filtration surface Hyper- insulinaemia Renin angiotensin excess Renal sodium retention Cell membrane alteration Sympathetic nervous over activity Fluid volume Venous constriction Heart Contractability Structural hypertrophy Functional constriction Preload Blood pressure = Cardiac output X Peripheral resistance Hypertension = Increased CO and/or Increased PR Autoregulation

18. Ca2+ChannelInhihitor

19. AngiotensionIIReceptorInhibitor

20. Primary HypertensionPathophysiology Heredity – interaction of genetic, environmental, and demographic factors Water & Sodium Retention – 20% of pts with high Na+ diet develop HTN Altered Renin-Angiotensin Mechanism – found in 20% of patients Stress & Increased SNS Activity Insulin Resistance & Hyperinsulinemia Endothelial Cell Dysfunction

21. HypertensionClinical Manifestation Dx is made after multiple readings over several weeks NIH/Joint Committee Definition: Category Systolic Diastolic Optimal <110 and < 80 Normal <120 and <85 High Normal 130-139 or 85-89 Stage 1140-159 or 90-99 Stage 2 160-179 or 100-109 Stage 3 =>180 or => 110

22. Primary HypertensionRisk Factors Age Alcohol Cigarette Smoking Diabetes Mellitus Elevated serum lipids Excess Na+ in diet Gender Family History Obesity Ethnicity Sedentary Lifestyle Socioeconomic Stress

23. Thank you