Mineralocorticoids

3. Mineralocorticoids • Aldosterone----- 90% • Deoxycorticosterone • Corticosterone • Cortisol • Cortisone

4. 60% combined with plasma proteins • 40% present in free form • Short half life----- 20 minutes. • Degraded mainly in liver • Normal blood levels ---- 6 nanograms

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

6. 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

7. 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

8. Aldosterone Escape • Circulatory shock

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

10. Effects in other areas • Sweat glands, salivary glands and intestinal epithelium • Almost the same effects as on kidney tubules • Reabsorption of Na+, Cl-, HCO3- • 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

11. Mechanism of action&Regulation of secretion ofAldosterone

12. 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 mRNAs formed • mRNAa 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.

13. 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

14. 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 • cAMP in tubular cells and vascular muscle cells has been detected within 2 minutes • Another 2nd messenger Phosphatidylinositol has also been detected • Structure of this special receptor not known • Importance of this nongenomic action not clear

15. 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

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

17. 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

18. Renin-angiotensin system • ↑ angiotensin II → ↑ aldosterone secretion • This action is also direct • ↓blood flow to kidneys or ↓BP→ ↑renin from JG cells → ↑angiotensin I → ↑angiotensin II → ↑aldosterone → ↑conservation of salts and H2O → ↑blood volume, flow & BP • BP is also elevated by vasoconstrictor effect of Angiotensin II

19. Effect of ACE inhibitor on aldosterone level of Na depleted dogs

20. 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

21. 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

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

23. 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

24. Addison’s disease • Mineralocorticoid deficiency • ↓Na, Cl,, HCO3 reabsorption • ↓ H2O 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

25. 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

26. 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

27. 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

28. 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

29. Buffalo Torso

30. Moon Face

31. Hirsutism

32. 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

33. Purplish striae

34. 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

35. 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

36. 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