What are the Hypertension Mechanisms
Peripheral Resistance: Narrowed arteries increase blood flow resistance, requiring the heart to pump harder.
Excess Sodium: High salt intake leads to fluid retention and increased blood volume, elevating pressure in arteries.
RAAS Activation: Renin release triggers angiotensin production, constricting vessels and promoting fluid retention.
Sympathetic Nervous System: Stress activates this system, raising heart rate and constricting vessels.
Endothelial Dysfunction: Damaged vessel lining disrupts blood vessel tone regulation.
Genetics: Family history can predispose individuals to hypertension.
Obesity: Adipose tissue releases factors that disrupt blood pressure regulation.
Insulin Resistance: Diabetes damages vessels, impairing their flexibility.
Lifestyle Factors: Poor diet, inactivity, alcohol, and smoking contribute to hypertension.
Age: Blood vessels become less flexible with age, contributing to elevated blood pressure.
Hormonal Changes: Pregnancy or medical conditions can raise blood pressure temporarily or chronically.
how can reduced nitric oxide levels can induce hypertension
Nitric Oxide (NO): Vasodilator gas released by blood vessels, relaxing them.
Vasodilation: NO widens vessels, reducing resistance and blood pressure.
Endothelial Dysfunction: Damage to vessel lining reduces NO production.
Constricted Arteries: Reduced NO leads to vessels staying narrow.
Increased Resistance: Constricted vessels raise blood pressure due to greater effort required from the heart.
Hypertension: Chronic elevated pressure from NO deficiency contributes to hypertension.
What is hypertension
- Failure of blood pressure (BP) due to control/compensatory mechanisms
- Consistently elevated: Systolic BP ≥ 140 mmHg & Diastolic BP ≥ 90 mmHg
What is primary hypertension
- Primary Hypertension
o Underlying cause is unknown
o 90% of cases
o Known as Essential or Idiopathic Hypertension
What is secondary hypertension
o A definite cause can be established
o 10% of cases
o Hypertension that occurs secondary to another known primary problem
What is resistant hypertension
- When patients fail to achieve optimum blood pressure targets despite being on 4-5 different anti-hypertensive drugs
- Obesity is a major risk factor for resistant hypertension
What does obesity lead to
o Atherogenic dyslipidemia
o Pro-thrombotic state
o Insulin resistance
o Hypertension
o Endothelial dysfunction
What is Obesity induced hypertension
- Hypertension is a major risk factor for a number of cardiovascular diseases
- 60-70% of cases of hypertension arise from obesity
o The precise mechanisms which link obesity with hypertension remain to be determined
What are the functions of the kidney
- Regulation of water & electrolyte volume & osmolarity
o Sodium, chloride, potassium, phosphate, magnesium - Regulation of acid-base balance
o Hydrogen ions (pH) - Excretion of metabolic waste products and foreign chemicals e.g., nitrogen
- Removal of foreign chemicals from blood
o Drugs, pesticides and food additives - Secretion of hormones
o Renin = controls the formation of angiotensin
o Erythropoietin = stimulates red blood cell production
o 1,25-dihydroxy vitamin D3 - Reduced nitric oxide levels lead to impaired kidney function and high blood pressure (hypertension)
What are the Cardiorenal Syndrome (CRS) statistics
- Heart failure = 1.8% Australian population
- 50% of heart failure develop renal failure
What happens in Heart failure with preserved ejection fraction (diastolic heart failure)
heart struggles to fill (walls of heart are thickened and stiff)
What happens in Heart failure with reduced ejection fraction (systolic heart failure)
Heart struggles to pump (walls of heart are thin and dilated)
What is stage 5 chronic kidney disease
End stage renal disease = eGFR less than 15
What is chronic kidney disease
When kidneys are damaged or diseased they don’t make enough EPO causing the bone marrow to make fewer red blood cells resulting in anemia
How is chronic kidney disease diagnosed
CKD is diagnosed by reduced eGFR, elevated blood urea nitrogen and reduced hemoglobin levels
How does reduced nitric oxide impact kidney function
- Reduced renal perfusion
- Impair sodium and water reabsorption
- Reduced glomerular filtration rate
- Impair tubuleglomerular feedback mechanism
- Impair myogenic response
- Enhanced renal vasoconstrictor responses to renal sympathetic nerve activity, thereby leading to renal ischemia
What is the RAAS (functions, stages, effects)
Function: Regulates blood pressure and fluid balance.
Initiation: Low blood pressure or sodium levels stimulate renin release.
Angiotensin: Renin converts angiotensinogen to angiotensin I.
Angiotensin-Converting Enzyme (ACE): Converts angiotensin I to angiotensin II.
Angiotensin II: Potent vasoconstrictor, raises blood pressure.
Aldosterone: Angiotensin II stimulates adrenal glands to release aldosterone.
Aldosterone’s Role: Increases sodium reabsorption in kidneys, promoting water retention.
Effects: Vasoconstriction, fluid retention, and increased blood pressure.
What are the actions of angiotensin 2
-Potent vasoconstrictor – nitric oxide counteracts this effect
-Activates sodium reabsorption
-Stimulates aldosterone production
What is the key driver of cardiorenal syndrome
Fibrosis
How does fibrosis occur and lead to cardiorenal syndrome
- Renin angiotensin aldosterone system (RAAS) activation increases oxidative stress
- Oxidative stress reduces nitric oxide
- Reduced nitric oxide levels can activate pro-fibrotic pathways, this includes increasing the expressing of plasminogen activator inhibitor-1 (PAI-1). PAI-1 contributes to fibrosis in the heart and the kidney
- Fibrosis leads to impaired function of the heart and the kidney which contributes to cardiorenal syndrome
What is oxidative stress
- Oxidation exceeds reduction = oxidative stress
- Oxidative stress = DNA damage, aging, cell death, multiple pathogeneses
- Oxidative stress is the imbalance between generation of oxidants (ROS and/or RNS) and Antioxidant defenses
How are Inflammatory and phagocytic cells are the main cellular sources of ROS
Lysosomes – Organelles that act as a roving garbage cell. However they can rupture and cause damage to mitochondria and oxidative stress via the released lysosomal enzymes
What are NADPH Oxidases
The NOX1 (NADPH oxidase 1) and other NADPH oxidases are the major sources of ROS in the artery wall in disease such as hypertension, diabetes and ageing
What is diabetes mellitus
Group of metabolic disorders with common underlying feature of hyperglycemia
Defects in insulin action or insulin secretion
Associated with end-stage kidney disease
