Role, distribution and regulation of ions

Sodium

• is the major cation of the ECF (~140mmol)
• Determines ECF volume
• Determines resting membrane potential and excitability

Absorption is unregulated symport with nutrients from the GIT, 0.5g/day requirement

Distribution

• 45% in bone matrix
• 50% in ECF at ~140mM
• 5% in ICF at ~10mM

Elimination

• Matches intake
• ~10% in sweat
• ~10% in stool
• Remainder in urine
• Freely filtered; 65% absorbed in PCT by secondary active symport with glucose, AAs, and bicarbonate, 20% in LoH by the NKCC2 transport and paracellularly by a positive transtubular voltage, 6% in DCT by NCC2, variable in collecting duct by the ENAC/ROMK system.

Regulation

• Glomerulotubular balance (~65% filtered Na load reabsorbed regardless of GFR)
• Low tubular flow / [Na] at JGA \(\to\) renin \(\to\) ATII \(\to\) increases Na/K ATPase activity across nephron \(\to\) more reabsoption in PCT and LoH
• Aldosterone upregulates ENAC and ROMK
• ANP increases GFR, inhibits ENAC

Potassium

• is the major ICF cation; controls ICF tonicity / volume
• determines resting membrane potential and membrane excitability
• extracellular messenger (e.g. for nociceptors)

Absorption is unregulated paracellular ~90% bioavailable

Distribution

• 90% ICF ~150mM
• 8% bone
• 2% ECF ~3.5-5 mM
• \([K^+]_{ECF}\) tightly regulated. \(\uparrow[K] \to\) less negative RMP \(\to\) overexcitability \(\to\) VT

The ICF:ECF ratio is increased by

• High Na/K ATPase activity (\(\beta-2\) agonists, insulin,
• Increased K/H exchanger activity (alkalosis)

And decreased by

• Low intracellular ATP (opens \(K_{ATP}\) channels)
• Opening of nicotinic channels (e.g. suxamethonium in SCI)

Elimination

• 10mmol/day in sweat, 10mmol/day in faeces, remainder in urine. Of this:
• 60% in PCT by solvent drag
• 20% in LoH by NKCC2 and positive transtubular voltage
• variable in the distal nephron by ENAC/ROMK system (principal cells) and hydrogen antiport (\(\alpha\)-intercalated cells).

Regulation

• Aldosterone release directly stimulated by low serum K \(\to\) upregulates ROMK, ENAC, and basolateral Na/K ATPase in distal nephron \(\to\) more excretion
• ROMK excretion also increased by \(\uparrow\) sodium delivery or flow rate to distal nephron, low Mg. Inhibited by low pH.

Magnesium

• divalent cation
• mainly intracellular
• ubiquitous enzyme cofactor (e.g. adenylate cyclase)
• L-type calcium channel blocker \(\to\) vasodilator, antiarrhythmic
• NMDA channel blocker ("coincidence detector")
• ROMK channel blocker

Absorption is paracellular and unregulated, driven by electrochemical gradient and solvent drag, bioavailability ~30%.

Distribution

• Bone hydroxyapatite ~60%
• ICF ~40%, 20mM, tightly regulated
• ECF <1%, 0.5mM, of which 40% is protein bound, 10% is complexed with phosphate/citrate (same as calcium)

Elimination

• Freely filtered at glomerulus
• 15% reaborbed by solute drag in PCT
• 60% reaborbed by the positive transtubular voltage at the loop of Henle
• ~15% reabsorbed at the DCT; this is regulated by plasma Mg levels
• After a bolus, the half life is ~4 hours.

Regulation

• Mg GIT absorption increased + DCT reabsorption increased in hypomagnesaemia
• Low \([Mg]_{plasma} \ \to \ \uparrow\)PTH, liberating Mg from bone matrix

Calcium

• Is a divalent cation
• is a structure component of bone matrix
• is a coagulation cofactor
• is an intracellular signalling molecule, responsible for
• excitation-contraction coupling in muscles
• neurotransmitter release in neurons
• hormone release in glands
• raises the threshold potential, stabilizing excitable membranes

Absorption is tightly regulated, ~10-50% bioavailability

Distribution

• 99% in bone hydroxyapatite
• 1% ECF, 2.1-2.6mM, of which 40% is protein bound, 10% is complexed with phosphate/citrate, so free plasma calcium is 1.05-1.3mM
• ~none in ICF (<0.1mM)

Elimination

• Unbound calcium filtered
• Reabsorbed by solvent drag in PCT and by positive transtubular voltage in LoH
• Reabsorption in distal nephron is regulated by...

Regulation

• Cholesterol \(\xrightarrow{light}\) vit D3 \(\xrightarrow{liver}\) 1-OH-vitD \(\xrightarrow{kidney \ \uparrow \text{by low Ca}}\) 1,25-OHvitD \(\to\) increased calcium GIT absorption, DCT reabsorption
• Low [Ca] \(\to\) PTH release from parathyroid \(\to\) iincreased osteoclast activity, decreased osteoblast activity \(\therefore\) net bone reabsorption, \(\uparrow\) 1,25-OHvitD, direct and indirect \(\uparrow\) increased calcium GIT absorption, DCT reabsorption
• High [Ca] \(\to\) calcitonin release from thyroid \(\to\) decreased 1,25-OHvitD, decreased osteoclast activity

Phosphate

• is the major intracellular anion
• acts as second messenger (e.g. IP3)
• has a metabolic role (as G6P and ATP)
• forms bone hydroxyapatite
• is an important buffer system in ICF and urine
• Forms 2,3DPG \(\to\) right-shifts ODC

Absorption

• Active and passive from GIT. Increased by 1,25-OHvitD. ~65% bioavailable

Distribution

• ~85% in bone hydroxyapatite
• ~15% in ICF
• <1% in ECF

Elimination

• Elimintated in stool and urine
• Renally, freely filtered, then reabsorption is regulated

Regulation

• High serum phosphate or 1,25-OHvitD stimulates FGF23 release from osteocytes \(\to\) decreased PO4 reabsorption, decreased vitD hydroxylation.
• Renal elimination increased by acidosis (by titration to H2PO4- in urine), PTH
• Reabsorption increased by vitamin D, calcitriol, thyroxine
• Liberation from bone matrix increased by PTH