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Old 04-03-2013
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Drug How thiazides reabsorb Calcium?

What is the exact mechanism by which thiazides reabsorb calcium. In Goljan it says that drug attaches to Cl- channel and inhibits Na+ and Cl- absorption this leaves the Na+ channel open for Ca++ reabsorption. While in Kaplan videos it says that thiazides decrease Na+ reabsorption, hence low intracellular Na+ leads to increase in Na+/Ca++ exchange.

Can anyone explain this. I think I have messed up this concept.
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thiazides block the na-cl symporter ....decreasinf NA+ resorption and decreased NA+ conc.
By lowering the sodium concentration within the epithelial cells, thiazides increase the activity of the Na+/Ca2+- on the basolateral side .

This, lowers the intracellular Ca2+ concentration so that more Ca2+ may diffuse into the cell via apical Ca2+-channels

hope this helps
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Quote:
Originally Posted by npktun View Post
thiazides block the na-cl symporter ....decreasinf NA+ resorption and decreased NA+ conc.
By lowering the sodium concentration within the epithelial cells, thiazides increase the activity of the Na+/Ca2+- on the basolateral side .

This, lowers the intracellular Ca2+ concentration so that more Ca2+ may diffuse into the cell via apical Ca2+-channels

hope this helps
I got your point... but in Goljan it is written that Na+ and Ca++ bind to same channel on luminal side... and if Na+ doesn't bind to the channel this makes room for Ca++... and Ca++ absorption increases. It means both of these mechanisms are working there... right?
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As long as I know there are separate channels for Ca++ in early distal tubule.... this makes me confused...
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As long as I know there are separate channels for Ca++ in early distal tubule.... this makes me confused...
i hate to say but i feel goljan has messed this up ....now i am confused too ....and also till now i knew there was a separate ca2+ channel ......
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i found somewhere ......

Thiazides decrease calcium excretion because they:
1) upregulate NCX due to low intracellular Na concentrations = more calcium reabsorbed ----distal tubule
2) volume depletion causes upregulation of Na reabsorption = enhanced paracellular calcium reabsorption-----proximal tubule

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Originally Posted by npktun View Post
i hate to say but i feel goljan has messed this up ....now i am confused too ....and also till now i knew there was a separate ca2+ channel ......
Yea... I feel the same way. Let's see what others have to say?
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From this Article: Mechanism of calcium transport stimulated by chlorothiazide in mouse distal convoluted tubule cells. F A Gesek and P A Friedman. J Clin Invest. Aug 1992; 90(2): 429438.

1) Thiazides block chloride entry mediated by apical membrane NaCl cotransport (DCT).
2) While at the same time, intracellular chloride is exiting the cell through chloride channels on basolateral membrane. And since the NaCl cotransport does not work on the apical side to replenish the Chloride...this causes intracellular hyperpolarization..and stimulates Ca++ entry on apical membrane by paracellular mechanism.
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Here's another explanation with a graphic included.
https://drive.google.com/file/d/0BxN...ew?usp=sharing

1. Thiazide inhibits DCT apical Na-Cl channel, specifically at Cl- site. At the same time, Na-K ATPase on basolateral (interstitium) side is normally pumping Na+ out of and K+ into the DCT cell. As time goes on, there is not enough Na+ left inside the cell for the ATPase to function (since the NaCl channel is blocked by Thiazide).
2. To replenish this abnormal lack of intracellular Na+ in the DCT cell, the basolateral Na-Ca++ exchanger that normally pumps Na+ into and Ca++ out of the cell (and into the interstitium) is activated. Over time, intracellular calcium is depleted in order to compensate for the Na+...thus driving the paracellular Ca++ reabsorption from the urinary lumen.

Not sure if this is any clearer, but it's best of what I got.
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Old 05-14-2015
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Quote:
Originally Posted by mutant View Post
What is the exact mechanism by which thiazides reabsorb calcium. In Goljan it says that drug attaches to Cl- channel and inhibits Na+ and Cl- absorption this leaves the Na+ channel open for Ca++ reabsorption. While in Kaplan videos it says that thiazides decrease Na+ reabsorption, hence low intracellular Na+ leads to increase in Na+/Ca++ exchange.

Can anyone explain this. I think I have messed up this concept.
Here's my explaination.

We are in the DCT.

At the basolateral side(near the interstitial fluid) we have two pumps.
1. Na-Cl sympoter (pumping both Na and Cl into the cell)
2. Ungated Ca channel(pumping calcium into the cell from the interstitium)

This calcium goes and binds to CALBINDIN(think of it as a square, with 4 binding sites for calcium) this helps keep intracellular FREE CALCIUM LOW so the pump can keep pushing Ca in. CALBINDIN is regulated by vit d3.

At the LUMINAL side(near the blood) we have two pumps as well
1. 3Na-Ca ANTIPORT (pushing 3 na into the cell from the blood; delivering 1 Ca INTO the blood.
2. Ca active transport (ATP based pump) that pushes calcium into the blood.

Note that
1. There are two ways Na can enter. At the basolateral side (SYMPORTING with Chloride) and at the luminal side (ANTIPORTING with Calcium)
2. The active Calcium transport at the luminal side keeps pushing calcium out, so the PTH mediated Ungated calcium channel at the BASOLAT side can keep working!

Thiazides work by blocking th Na-Cl channel at the BASOLATERAL side. So, the 3Na-Ca ANTIPORT(at the luminal side) startes getting super hyped. So since it's the only source of na for the cell, pumps more calcium out, increasing serum calcium!

Also note, vitamin d3 - upregulates CALBINDIN. So it indirectly upregulates the action of PTH at the level of the kidney!

Hope this helps!
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