Ca ++ and P i Homeostasis

1. Ca++ and Pi 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 [HPO42-] 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: UV light (Liver - 25-hydroxylase) 12-OH CC (Diet, liver synthesis) 7-dehydrocholesterol (Skin) Vit D3 PO4 Kidney - 24-hydroxylase Kidney – 1-hydroxylase PTH PTH PO4 1,25 diOH CC (active) 24,25-diOH CC (inactive)

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) 280 mg/d PTH, corticosteroid 1,25 diOH CC calcitonin Diet 1,000mg/d PLASMA PTH 1,25 diOH CC 500 mg/d 9,825 mg/d KIDNEY INTESTINE 325 mg/d 10,000 mg/d 175 mg/d URINE FECES 825 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