1. Ca ++ and P i Homeostasis

2. Ca ++ in the plasma [Ca ++ ] in plasma: 2.5 mM, of which about ½ is bound and thus physiologically inactive. Ratio of free/bound is sensitive to [H + ] and [HPO 4 2- ] according to the solubility product constant

3. Effector Sites –Bone (contains 99% of total body Ca ++ as phosphate salt) –GI tract (mediates uptake from diet, but also carries out some secretion) –Kidney (loss/conservation of plasma Ca ++ and phosphate)

4. Regulatory hormones Parathormone from parathyroids – 4 (usually) located (usually) on ventral surface of thyroid 1,25 diOH cholecalciferol (1,25 diOH D) Calcitonin from thyroid

5. Parathormone (PTH) secretion stimulated by drop in plasma free Ca ++ activity – not total plasma Ca ++ - protects plasma free Ca ++ Effects: –increased bone breakdown (osteoclasts) –Increased activation of “Vitamin” D –Increased renal Ca ++ recovery (connecting tubule segment of DT) –Decreased renal phosphate reabsorption

6. “Vitamin” D (1,25 diOH Cholecalciferol) Synthesis: (Diet, liver synthesis) 7-dehydrocholesterol (Skin) Vit D 3 (Liver - 25- hydroxylase) 12-OH CC Kidney – 1- hydroxylase Kidney - 24- hydroxylase 24,25-diOH CC (inactive) 1,25 diOH CC (active) PO 4 PTH PO 4 UV light

7. 1,25-diOH CC effects Increased Ca ++ uptake in intestine (direct) Increased bone mineralization (indirect – the result of uptake stimulation) Increased bone breakdown (direct, like PTH) Estrogen and testosterone have similar effects; corticosteroids have antagonistic effects Vit. D is necessary for bone growth, but can channel dietary Ca ++ into plasma or bone depending on the levels of PTH.

8. Calcitonin Secreted by thyroid Inhibits bone breakdown Role in Ca ++ homeostasis in humans is apparently minor, but it is used as a drug against osteoporosis – must be injected or applied as a nasal mist.

9. Fate Map of Ca ++ in the body BONE (1 kg) PLASMA INTESTINE KIDNEY FECES 825 mg/d URINE PTH, corticosteroid 1,25 diOH CC calcitonin Diet 1,000mg/d PTH 1,25 diOH CC 500 mg/d 10,000 mg/d 9,825 mg/d 175 mg/d 280 mg/d 325 mg/d

10. Coordinated responses in calcium homeostasis

11. How about phosphate regulation? Remember that decreasing plasma phosphate will increase plasma free calcium

12. Short-term effects of disorders of Ca ++ regulation Hypocalcemia: increased excitability of nerve and muscle with characteristic muscle spasms and contractures and cardiac arrhythmias – CNS agitation- –“grass tetany” in grazing animals that feed on low Ca ++ /high Mg ++ diet Hypercalcemia: depressed excitability of excitable cells – lethargy, memory loss –PTH-secreting parathyroid tumors

13. Long-term effects of homeostatic failure Vit. D deficiency or dietary Ca ++ deficiency –Rickets – malformed bone in children –Osteomalacia – adult rickets Lack of sex steroids after puberty, or treatment with corticosteroids –osteoporosis – loss of bone mass, without morphological abnormality

14. What you need to know about K + regulation Plasma [K + ] = 4 mEq/l Dietary K + partitioned mainly into intracellular compartment Kidney filters K +, essentially all of the filtered load is reabsorbed in the PCT But then, some K + is secreted in the DCT at rates determined by 2 factors: –Aldosterone levels, which are responsive to plasma [K + ] –Plasma [H + ], because the DCT secretes a mix of H + and K + to maintain charge balance against Na + absorption, and the secreted ions compete with one another