Renal Physiology and Hormonal Regulation

• Blood pressure is regulated by both long and short term mechanisms.
• The objectives are to understand the roles of various body systems in controlling blood pressure in the short and long term.
• Also to understand the roles of the sympathetic nervous system, renin-angiotensin-aldosterone system, ADH, and ANP in blood pressure regulation.
• It's also important to learn the definition of hypertension, its types, and the main drug groups used to treat it.

Short-Term Blood Pressure Regulation

• Short-term regulation of blood pressure comes from the baroreceptor reflex.
• Baroreceptors are located in the carotid sinus and aortic arch.
• An increase in arterial pressure stretches these sensors, sending information feedback to the medulla via afferent pathways (glossopharyngeal and vagus nerves).
• Efferent impulses are then sent to the heart (causing negative chronotropy and inotropy) and blood vessels (causing vasodilation), which in turn reduces cardiac output and TPR (total peripheral resistance).
• The baroreceptor reflex works well for acute blood pressure changes and produces rapid responses, but doesn't control sustained increases because the threshold for baroreceptor firing resets.
• A 5-10% drop in blood pressure causes low-pressure baroreceptors in the atria and pulmonary vasculature to send signals to the brainstem via the vagus nerve.
• This modulates sympathetic nerve outflow, ADH secretion, and ANP release reduction.
• A 5-150% change in blood pressure causes high-pressure baroreceptors (carotid sinus/aortic arch) to send impulses using the vagus and glossopharyngeal nerves.
• A decrease in blood pressure will increase sympathetic nerve activity and ADH secretion.

Neurohormonal Factors Controlling Blood Pressure

• There are four neurohormonal factors controlling blood pressure: the renin-angiotensin-aldosterone system, the sympathetic nervous system, antidiuretic hormone (ADH), and atrial natriuretic peptide (ANP).
• These factors control sodium balance and extracellular fluid (ECF) volume.

Sympathetic Nervous System

• The sympathetic nervous system causes vasoconstriction via α1-adrenoceptors.
• It increases the force and rate of heart contraction via β1-adrenoceptors.
• It decreases renal blood flow, glomerular filtration rate (GFR), and Na+ excretion.
• Activates Na/H exchanger in PCT and stimulates renin release from juxtaglomerular cells, increase Angiotensin II/Aldosterone levels.

Actions of ADH

• ADH adds aquaporin to the collecting duct.
• Promotes water reabsorption and forms concentrated urine.
• Release of ADH is stimulated by increases in plasma osmolarity or severe hypovolemia.
• It stimulates the apical Na/K/Cl co-transporter in thick ascending limb.
• Reduces Na+ movement into the medulla and the osmotic gradient for water to exit the lumen into peritubular capillaries from the thin descending limb.

Atrial Natriuretic Peptide (ANP)

• ANP acts in the opposite direction to other factors.
• It's synthesized and stored in atrial myocytes, promotes Na+ excretion, and causes vasodilation of the afferent arteriole.
• High blood pressure stretches Atrial Cells, increasing ANP release, resulting in increased Na+ excretion, decreased volume, and decreased blood pressure.
• Low blood pressure causes Atrial Cells to stretch less, reducing ANP release, reduced Na+ excretion, increased volume, and increased blood pressure.
• ANP inhibits Na+ reabsorption along the nephron.

Prostaglandins

• Prostaglandins are vasodilators
• Locally acting prostaglandins (mainly PGE2) enhance glomerular filtration and reduce Na+ reabsorption.
• May have an important protective function by acting as a buffer to excessive vasoconstriction by the sympathetic nervous system and RAAS.

Effect of NSAIDs

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) pathway involved in prostaglandin formation.
• Prostaglandins help maintain renal blood flow and GFR in the presence of vasoconstrictors, if NSAIDs are administered when renal perfusion is compromised, GFR can be further decreased, leading to acute renal failure.
• NSAIDs can exacerbate conditions like heart failure or hypertension by increasing NaCl and water retention.

Renin-Angiotensin System

• Reduced perfusion pressure in the kidney, detected by baroreceptors in the afferent arteriole, increase renin release from the granular juxtaglomerular apparatus.
• Decreased NaCl concentration at the Macula Densa cells (due to low perfusion and low GFR) causes sympathetic stimulation to the JGA, which increases renin release.
• Macula Densa cells release Prostaglandins, causing afferent vasodilation.
• Renin cleaves Angiotensinogen to Angiotensin I, then Angiotensin Converting Enzyme (ACE) cleaves Angiotensin I to Angiotensin II.

Angiotensin II Actions

• There are two types of Angiotensin II receptors, AT1 and AT2, both G-protein coupled, but the main actions of Angiotensin II are via the AT1 receptor.
• It causes vasoconstriction, which works on vascular smooth muscle cells, increases TPR, thus increasing BP.
• It also causes vasoconstriction of afferent and efferent arterioles.
• Angiotensin II stimulates the adrenal cortex to synthesize and release aldosterone, which stimulates Na+ and water reabsorption.
• Stimulates thirst mechanism, ADH at the hypothalamus, and breaks down bradykinin (a vasodilator).
• The renin-angiotensin system can be inhibited by ACE inhibitors, preventing angiotensin II generation, or angiotensin (AT1) receptor antagonists, which block the action of angiotensin II.
• Aldosterone action can be blocked by the aldosterone antagonist spironolactone, which has a diuretic effect; these drugs are used for hypertension and heart failure treatment.
• Angiotensin II is a potent vasoconstrictor acting on vascular smooth muscle.
• Stimulates the adrenal cortex to synthesize and releases aldosterone.
• It acts on the nervous system both centrally and peripherally to enhance sympathetic nerve activity.
• Directly effects on the kidney to increase renal tubule sodium ion reabsorption, and stimulates the thirst mechanism.

Hypertension Definition

• Hypertension is a sustained increase in blood pressure, defined as systole ≥140 mmHg and/or diastole ≥90 mmHg.
• There are two classes of hypertension: essential and secondary.
• Essential hypertension, which accounts for 95% of cases, has an unknown cause, but genetic and environmental factors are involved.
• Secondary hypertension has definable causes, and treatment focuses on the primary cause such as renovascular disease, chronic renal disease, hyper-aldosteronism, or Cushing's syndrome.

Grades of Blood Pressure

• Optimal BP is below 120 mmHg systolic and below 80 mmHg diastolic.
• Normal BP is below 130 mmHg systolic and 85 mmHg diastolic.
• High normal BP is between 130-139 mmHg systolic and 85-89 mmHg diastolic.
• Grade 1 hypertension is between 140-159 mmHg systolic and 90-99 mmHg diastolic.
• Grade 2 hypertension is between 160-179 mmHg systolic and 100-109 mmHg diastolic.
• Grade 3 hypertension is ≥180 mmHg systolic and >110 mmHg diastolic.
• Isolated systolic hypertension Grade 1is between 140-159 mmHg systolic and < 90 mmHg diastolic.
• Isolated systolic hypertension Grade 2 is ≥ 160 mmHg systolic and < 90 mmHg diastolic.

Renovascular Disease

• This is caused by occlusion of the renal artery, decreasing perfusion pressure in the kidney.
• The reduced perfusion causes the affected kidney to release renin and activating RAAS.
• The other kidney compensates through vasoconstriction and Na+ retention.

Adrenal Causes of Hypertension

• Conn's Syndrome - Aldosterone-secreting adenoma result in hypertension and hypokalemia.
• Cushing's Syndrome - Excess cortisol, at high concentrations, activates aldosterone receptors, leading to Na+ and water retention.
• Pheochromocytoma - Tumour of the adrenal medulla secretes noradrenaline and adrenaline.

Managing Hypertension

• Hypertension is important because it can be asymptomatic yet have damaging effects.
• Secondary hypertension treatment involves addressing the underlying cause.
• Essential hypertension treatment targets stroke volume, heart rate, or TPR to reduce BP.
• Hypertension increases myocardial demand and atherosclerosis can lead to ischemic heart diseases.

Treatment of Hypertension

• ACE Inhibitors prevent conversion of Angiotensin I to Angiotensin II.
• Angiotensin II receptor antagonists block angiotensin II receptors.
• Thiazide Diuretics inhibit NaCC co-transporter on apical membrane of DCT and can cause hypokalemia (more K+ lost in urine).
• Ca2+ channel blockers reduce Ca2+ entry into smooth muscle cells.
• α1 receptor blockers reduce sympathetic tone.
• Beta Blockers block β1-receptors in the heart, reducing heart rate and contractility.
• Non-pharmacological approaches: diet, exercise, reduced Na intake, reduced alcohol intake.

Explore the intricate mechanisms of renal physiology and hormonal regulation. Questions cover water reabsorption in the collecting duct, ANP's role in blood pressure, and NSAIDs' effects on renal function. Delve into the impact of Angiotensin II, macula densa cells, and hormonal imbalances on kidney function.