Mineralocorticoids Aldosterone 90 Deoxycorticosterone Cortisol Cortisone 60 combined

Mineralocorticoids • • • Aldosterone----- 90% Deoxycorticosterone Cortisol Cortisone

• • • 60% combined with plasma proteins 40% present in free form Short half life----- 20 minutes. Degraded mainly in liver Normal blood levels ---- 6 nanograms

Action of Aldosterone • Effect on Sodium ions • Effects on Hydrogen ions • Effects on Potassium

Effects on Hydrogen ions • Aldosterone→ ↑reabsorption of Na+ – Na+ are exchanges with H+ (or K+) – ↑ secretion and excretion of H+ – ↑ ↑aldosterone →excessive loss of H+ alkalosis – ↓ ↓aldosterone→ retention of H+ →acidosis

Effects on Potassium • Potassium secretion & excretion – Na+ are exchanged with K+ – ↑Excretion of K+ – ↑ ↑ aldosterone →hypokalemia →muscle weakness – ↓ ↓ aldosterone →hyperkalemia → cardiotoxicity→ • Weakness of heart contraction • Arrhythmia • Heart failure

• Aldosterone Escape • Circulatory shock

Effects in other areas • Sweat glands, salivary glands and intestinal epithelium

Effects in other areas • Sweat glands, salivary glands and intestinal epithelium – Almost the same effects as on kidney tubules – Reabsorption of Na+, Cl-, HCO 3– Excretion of K+ and H+ • Conservation of salts in hot weather profuse sweating • Conservation of salts when excessive salivation occurs • Important in colonic absorption of electrolytes

Mechanism of action & Regulation of secretion of Aldosterone

Mechanism of action • • • Steroid hormones act through genetic mechanism Lipid soluble aldosterone enters into the tubular cells HR complex formed in cytoplasm HR complex moves into the nucleus Transcription of specific genes Specific m. RNAs formed m. RNAa diffuse back into cytoplasm Action on Ribosomes → translation Translation forms many types of proteins – Enzymes – Membrane transport proteins for transport of Sodium, Potassium and hydrogen etc.

Mechanism of action • Enzyme – Na-K ATPase for pumping of Na+ & K+ at the basolateral membrane of tubular cells • Channel proteins – Inserted in luminal membrane for entry of Sodium • Long latent period for action of aldosterone – Effect starts after 45 minutes – Reaches maximum after several hours

Nongenomic actions • Genetic mechanism has a long latent period • Rapid nongenomic effects have been detected recently – Some receptor protein in the cell membrane – HR complex formation in the cell membrane – c. AMP in tubular cells and vascular muscle cells has been detected within 2 minutes – Another 2 nd messenger Phosphatidylinositol has also been detected • Structure of this special receptor not known • Importance of this nongenomic action not clear

Regulation of secretion • Many factors affect the regulatory mechanism – – Electrolytes ECF Blood volume Blood pressure • Regulation of aldosterone from Z. glomerulosa is independent of regulation of cortisol & androgens from the Z. Fasciculata and Zona Reticularis

Regulation of secretion • Four factors involved in regulation – Potassium concentration – Renin-angiotensin system – Sodium ion concentration – ACTH

Potassium ion concentration • Hyperkalemia stimulates Zona glomerulosa to produce aldosterone • A small percentage increase in K+ concentration → several folds increase in aldosterone production & secretion • Hyperkalemia → ↑Aldosterone → ↑reabsorption of Na+ and ↑ excretion of K+ → ↓K+ concentration to normal level • K+ directly act on Zona glomerulosa

Renin-angiotensin system • ↑ angiotensin II → ↑ aldosterone secretion • This action is also direct • ↓blood flow to kidneys or ↓BP→ ↑renin from JG cells → ↑angiotensin II → ↑aldosterone → ↑conservation of salts and H 2 O → ↑blood volume, flow & BP • BP is also elevated by vasoconstrictor effect of Angiotensin II

Effect of ACE inhibitor on aldosterone level of Na depleted dogs

Sodium ion concentration • ↓Na+ concentration of 10 -20 % → ↑ aldosterone (double) • ↓ total body sodium → ↓Blood volume & BP → ↑ renin-angiotensin activity → ↑ aldosterone secretion • ↓ total body sodium → ↓available Na+ in tubular fluid → ↓No. of Na+ absorbed → ↓excretion of K+ →Hyperkalemia → ↑aldosterone secretion

ACTH • ACTH has only permissive role • Small amount of ACTH required to maintain Zona glomerulosa • ↑ACTH does not further stimulate aldosterone secretion • Total absence of ACTH → atrophy of Zona glomerulosa & absence of secretion of aldosterone

Abnormalities of Adrenal cortical secretion • Hypoadrenalism----Addisons disease • Hyperadrenalism----- Cushing syndrome

Addison’s Disease • Failure of adrenal gland to produce Hormones • Primary atrophy of adrenal cortex- most common • Due to Autoimmunity against adrenal cortices • Tuberculous destruction of the gland • Cancerous destruction of the gland

Addison’s disease • Mineralocorticoid deficiency – – – – – ↓Na, Cl, , HCO 3 reabsorption ↓ H 2 O reabsorption ↑Loss of water and electrolytes in urine ↑ RBC concentration in blood Hyperkalemia Acidosis ↓ ECF volume ↓ COP ↓ Blood pressure Death may occur within a few days

Addison’s disease • Glucocorticoid deficiency – Inability to maintain blood glucose between meals → hypoglycemia between meals – ↓ mobilization of Amino acids and fatty acids – ↓ metabolic activities – Sluggish energy metabolism – Muscle weakness – Deteriorating effects of even minor stress – Minor respiratory infection may kill the patient

Addison’s disease • Melanin pigmentation – In the skin and mucous membrane – Patchy distribution of hyper pigmented areas – ↓ cortisol→↑ ACTH→↑MSH as well – ACTH itself has Melenocyte stimulating activity

Cushing’s Syndrome • Hypersecretion of cortisol (and androgens) resulting into complex metabolic disorders • Causes – Adenoma of Adenohypophysis →↑ACTH (Cushing’s disease) – Oversecretion of CRF by the hypothalamus – Ectopic ACTH production e. g. abdominal carcinoma – Primary Adenoma of adrenal cortex itself (ACTH level is very low) – Therapeutic use of large amounts of glucocorticoid for long durations

Cushing’s Syndrome • Special fat distribution – buffalo torso • Moon face – edema more evident on face • Hirsutism – hair on the face of women due to oversecretion of androgens • ↑Blood pressure due some mineralocorticoid activity of cortisol • Hyperglycemia – 200 mg/dl or more • Greatly reduced tissue proteins (except plasma and liver proteins) • Very weak skeletal muscles

Buffalo Torso

Moon Face

Hirsutism

Cushing’s Syndrome • Deficiency of collagen fibers in SC tissue→ tearing of SC tissue → purplish striae • Osteoporosis • Atrophy of the lymphoid organs • Suppressed immunity • Frequent infections

Purplish striae

Treatment • Surgical removal pituitary tumor • Destruction of tumor by radiations • Drugs blocking steroid synthesis – Ketoconazole – Metyrapone – Aminoglutethimide • Inhibitors of ACTH secretion – Serotonin antagonists – GABA-tranaminase inhibitors • Surgical removal of both the adrenal glands – Total or subtotal adrenalectomy

Conn’s disease • Primary aldosteronism – A small tumor of zona Glomerulosa – Excessive secretion of Aldosterone only – Sometimes aldosterone secretion from the Z. Fasciculata and Z. Reticularis • Treatment – Surgical removal of the tumor – Partial or subtotal adrenalectomy

Conn’s disease • • • Excessive reabsorption of water and electrolytes ↑ECF volume ↑ Blood volume ↑blood pressure Hypokalemia Alkalosis Very slight ↑ Na concentration in ECF Occasional periods of muscle paralysis ↓plasma renin concentration