help!! macula densa,aldosterone and lumen sodium concentration

[ketap]

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hello, i need help ..i want to ask you..i have known for several years that the macula densa senses the lumen chloride and when the lumen sodium is low, then the macula densa will stimulates the release of renin and eventually increase the angiotensin II to further constricts the efferent arteriole and also dilates the afferent arteriole...,visa versa..
now , i am confused because if we have a diuretic like furosemide or thiazide that will increase the delivery of chloride in the lumen to the macula densa, it is said that the aldosterone will greatly be stimulated to increase sodium reabsroption in the distal tubule...now, isn't that contradicts the tubuloglomerular feedback mechanism?

thx u for the answer 🙂
best regard,

Ketap

 

[dukejen04]

hello, i need help ..i want to ask you..i have known for several years that the macula densa senses the lumen chloride and when the lumen sodium is low, then the macula densa will stimulates the release of renin and eventually increase the angiotensin II to further constricts the efferent arteriole and also dilates the afferent arteriole...,visa versa..
now , i am confused because if we have a diuretic like furosemide or thiazide that will increase the delivery of chloride in the lumen to the macula densa, it is said that the aldosterone will greatly be stimulated to increase sodium reabsroption in the distal tubule...now, isn't that contradicts the tubuloglomerular feedback mechanism?

thx u for the answer 🙂
best regard,

Ketap

I am not sure if I really understood your question (the English was a bit confusing), but I will attempt to explain some of the mechanisms that will hopefully give you an answer.

First of all- the JG apparatus has several inputs- 1) JG cells (sensitive to blood pressure in the afferent arterioles), 2) the Macula Densa (sensitive to NaCl), and 3) B1 sympathetic input from systemic stimulation. And nothing in the body exists in a vacuum, especially when you're talking about the cardio/renal system!!!


But let's look at each of these drugs separately:

Furosemide is a loop diuretic that acts on the Na/K/2Cl symporter in the ascending Loop, with two effects: 1) Keep all of those ions in the urine (for the moment) and 2) Preventing the renal medulla from becoming hypertonic. Consider the fact that 67% Na and Cl ions are removed in the proximal convoluted tubule, the major effect of Furosomide is NOT going to be a crazy change in the NaCl concentration in the urine. The bigger effect of the drug is that you are NOT making the renal medulla hypertonic, which means when it comes to reabsorbing water later- there's no osmotic drive, so it sticks around. Nonetheless- the NaCl concentration is slightly INCREASED relative to normal, and the Macula Densa will only respond to a decrease in NaCl. So, renin release is suppressed .

Now, Thiazides will prevent Na/Cl re-abosrption in the distal tubule. If Na+ isn't reabsorbed, neither is water. However, some water will still be removed in the Collecting Duct, although the osmotic drive for water moving out will be decreased because osmalarity in the duct is higher than usual (although this is why Thiazides aren't as powerful as loop diuretics, because some water will still be lost). Again, the Macula Densa will see a slight INCREASE in Na/Cl concentration, so it will inhibit Renin release.

Generally, aldosterone is secreted when it is stimulated by Angiotensin II, which is made in response to Renin OR when there is increased K+. In the case of both Loop Diuretics and Thiazides- you have inhibition of Renin and hypokalemia, so there shouldn't be much Aldosterone around (unless you have some kind of pathological Hyperaldosterone problem).

Loop Diuretics and Thiazides will suppress Renin-AngII-Aldosterone system unless BP falls way below normal in which case B1 stimulation (from release of epinephrine/norepinephrine from sensing of hypotension in carotid body) and a low pressure in the JG cells will stimulate Renin release regardless of what ion concentration the Macula Densa is sensing.

Hope that helped!

 

[ketap]

hello..dukejen04: thx u for answering, sorry if my english was (and still 😛 )confusing..actually what i want to ask is : "is the macula densa senses and responded to the high tubular lumen chloride or low tubular lumen chloride?"

you have answered that in your reply, and i notice that you have answered that the macula densa responds to low tubular lumen Chloride.. now, this is my confusion...i have read also miller's anesthesia textbook and physiology for anesthesiologist textbook and i am confused by their statements that the high chloride in the lumen is the one that will stimulates the macula densa to provoke the release of renin from adjacent afferent arteriole (not the low tubular lumen Chloride)...the end results from renin release is the same though...when there is increased flow to the macula densa, it will stimulates the afferent arteriole to constricts to reduce the GFR...

please help me with this confusion,,,thx u so much ..🙂
warm regards,
Ketap

 

[ketap]

ohh..i forgot to ask you: if the thiazides and furosemide depress the RAAS, then how can they provoke hypokalemia? thx u

 

[dukejen04]

Hi Ketap! For the purposes of Step 1- you probably don't need to be investigating this much detail. Honestly, if you need to read anesthesiology books to try to figure this out, it is too much.

I looked up a few papers as I was investigating your answer, and for the most part, the macula densa is more about sensing low Na+, I could find very little about Cl. In First Aid (the Bible of Step 1), it also only mentions Na+. It is not mentioned at all in BRS Physio, BRS Cell Bio, or BRS Anatomy. So, that's what I would stick with.

While I haven't finished UWorld, I've gone through many questions and nothing came up about the specific sensing of the macula densa, same with Kaplan qbank. If you're personally interested, go to PubMed and do a literature search, but honestly, your time is better spent learning more relevant information for Step 1! I think the most important component to stimulating renin is a drop in renal blood flow.

OK- as for your second question, why do loops/thiazides cause HYPOkalemia? I've read a few explanations for this, but here is the simplified version: An increase in Na+ in the distal tubule causes a greater exchange of Na+ ions for H+/K+ ions at the Principle Cells. Hypokalemia and alkalosis go hand in hand, so sometimes the effects continue to snowball.

Try to keep in mind all of this is happening within a complex system where there are many factors regulating many components- to separate out one piece is very very difficult.

For the purposes of Step 1- I think it is only important to know the basics- Where is the JGA? What kind of cells are there? When is renin secreted, what does it do? What happens in each part of the nephron? Where do the different drugs act, and what are their side effects?

If you know these things, that is going to get you 99% of the way there!! Best of luck!

 

[MrBeauregard]

From the reading I've done, loops and thiazides actually activate RAAS. I think Ketap's confusion lies in the fact that the macula densa senses Na delivery to the distal nephron and then influences renin release, while diuretic therapy as a whole activates RAAS (I've gotten a few questions on this in Kaplan Qbank). Ketap seems to be focusing on the macula densa and then extrapolating that data to the overall effect of diuretics, and this leads to misunderstanding.

 

[dukejen04]

Yeah- they do- but that's a secondary affect from be successful diuretics that actually cause a significant drop in BP. It isn't what I could call a "primary" effect.

I actually ended up reading some papers that took it into more detail, and there are like 15 things at play, but just like anytime you deal with cardio/renal, you could drive yourself mad going in circles by changing things- if you change this, then this, but then if that, then this, etc. LOL. Best not to think about some of these things in too much detail!! Or you'll end up trying to make wrong answers right, lol.

 

[MrBeauregard]

Yeah- they do- but that's a secondary affect from be successful diuretics that actually cause a significant drop in BP. It isn't what I could call a "primary" effect.

I actually ended up reading some papers that took it into more detail, and there are like 15 things at play, but just like anytime you deal with cardio/renal, you could drive yourself mad going in circles by changing things- if you change this, then this, but then if that, then this, etc. LOL. Best not to think about some of these things in too much detail!! Or you'll end up trying to make wrong answers right, lol.

No, it isn't a primary effect, but if you come across a question on the Step about it, the answer will most likely be something along the lines of increased renin/aldosterone/angiotensin. Under the diuretics portion of the renal chapter in FA 2011 (page 475), it speaks about angiotensin being increased and leading to contraction alkalosis. I annotated something right near that after I received a question on it in Kaplan Qbank, and my notes have all 3 parameters of RAAS increased.

You're right about the fact that renal and cardiovascular physiology can drive a person mad. I guess I'm just trying to make the point that if you diurese someone, their body will attempt to counteract your medical therapy with its normal physiologic responses. And I also want to help Ketap understand his/her question (which I actually don't even fully understand 🙂)

 

[OveractiveBrain]

Ill chime in here, not because what's been said is wrong, but because I want to make it easier.

Think of the macula densa as a flow switch. Its default is to fall to on. As flow moves through the nephron, it switches that switch to off. Increase flow, off; decrease flow on. When the switch is on, Renin is made. Renin - ANG II - Aldo. The effect of aldo is to increase ENac in the Collecting tubule, absorbing Na. A biproduct of absorbing sodium is to kick out K (because there are K leak channels and Na is positively charged, kicking out the K to balance the cells neutrality). Aldo also kicks out Hydrogen ions, and retain bicarb.

1. If low flow in neprhon --> Renin --> Ang II --> Aldo, reabsorb Na and Bicarb, Lose K and H

Why does it do that? Because if you have a low flow state, the kidney thinks the body is volume down. The goal is to reabsorb Na. Whever Na goes, water goes. So, aldo reabsorbs sodium in order for water to be dragged along with it (through aquaporin channels) expanding the vascular volume. This would, theoretically, increase flow to the kidney, increase filtration across the glomerulus, and therefore increase flow through the nephron. The "Macula Densa responding to Na delivered" blah blah just means that if there is a lot of fluid flowing through the nephron, macula densa shuts its face.

2. Macula densa responds to total Na CONTENT and NOT concentration (so "flow" not "concentration")

Ok. So now you apply a diuretic. Lets say its a loop. What does a loop do? It blocks the Na-K-2Cl channel. Does it do anything to water? Not yet. Does it do anything to flow? Nope. The impact of a slightly elevated Na delivery past the Thick Ascending Loop could, in theory, turn off RAS. In theory. The important implication of the Loop Diuretic lays downstream. Youve blocked Na reabsorption. Now you get to the collecting duct. What happens here? Enac. Enac is based on concentration gradient only. So, lets comapre the two states. Before the diuretic you had LESS sodium in the tubule, now, after the diuretic you have MORE sodium in the tubule. What happens? More sodium is reabsorbed. The bidproduct? More K is lost. The collecting tubule will try its darndest to reabsorb all of that sodium, but it cant get it all. So, since water goes where sodium goes, you get diuresis. But the important thing is that you've lost K. Not as a product of aldo, but simply as an increased flow of Na across the Enac channel, leading to more positive charge in teh cell, forcing out more K.

3. Loop Diuretics cause diuresis because Collecting Duct cannot overcome the Na load, and, water goes where sodium goes.

Same thing with Thiazides. They block the distal convoluted tubule. Macula densa already passed. These guys do increase the sodium load to the collecting ducts (above), but to a lesser extent (Thick Ascending Loop does this the best).

4. Thiazides do the same thing as Loops, just a little later in the neprhon (same is used loosely)

If you apply an ACE-i or an ANG-ii blocker, you effectively reduce the amount of Enac channels. This should be a duh, by now. Les Enac, less Na reabsorbed, less K lost, and water goes where sodium goes, diuresis. But feel this now... TAH has the most potent sodium effect, distal convoluted next, and CD last. So youd think that the ACe-i would have the weakest anti-hypertensive effect. Well, they have the weakest DIURETIC effect. But the fact they are directly blocking the vasoconstrictive effects of ANGII make them potent anti-hypertensives, even if they are pretty poor diuretics.

5. ACE-i are great anti-hypertensives, poor diuretics, and get your K up

So what is the effect on the RAS? Well, K does play a little role. Arteriolar distension plays a little role. I get it. But, in the end, what determines the major activation of renin in the whole body system is perfusion ot the kidney. If the kidney thinks you are volume down (because you are, have renal artery stenosis, or have poor forward flow like in CHF) that flow switch will fall to on, and you get activation of RAS. If the kidney thinks you are volume up or euvolemic, it will turn that switch to off, and turn off the RAS.

7. If you think of it in terms of fluid status, life becomes ALOT more easy

 

[OveractiveBrain]

now , i am confused because if we have a diuretic like furosemide or thiazide that will increase the delivery of chloride in the lumen to the macula densa, it is said that the aldosterone will greatly be stimulated to increase sodium reabsroption in the distal tubule...now, isn't that contradicts the tubuloglomerular feedback mechanism?

This statement is false

Specifically, no. Aldo doesnt increase reabsorption, simply the concentration of Sodium in the lumen. Enac is always there. More sodium in the lumen shifts more sodium into the cell. That's simple chemisty.

 

[Morsetlis]

Whoa I feel smarter after reading that.

 

[futuredoctor10]

Ill chime in here, not because what's been said is wrong, but because I want to make it easier.

Think of the macula densa as a flow switch. Its default is to fall to on. As flow moves through the nephron, it switches that switch to off. Increase flow, off; decrease flow on. When the switch is on, Renin is made. Renin - ANG II - Aldo. The effect of aldo is to increase ENac in the Collecting tubule, absorbing Na. A biproduct of absorbing sodium is to kick out K (because there are K leak channels and Na is positively charged, kicking out the K to balance the cells neutrality). Aldo also kicks out Hydrogen ions, and retain bicarb.

1. If low flow in neprhon --> Renin --> Ang II --> Aldo, reabsorb Na and Bicarb, Lose K and H

Why does it do that? Because if you have a low flow state, the kidney thinks the body is volume down. The goal is to reabsorb Na. Whever Na goes, water goes. So, aldo reabsorbs sodium in order for water to be dragged along with it (through aquaporin channels) expanding the vascular volume. This would, theoretically, increase flow to the kidney, increase filtration across the glomerulus, and therefore increase flow through the nephron. The "Macula Densa responding to Na delivered" blah blah just means that if there is a lot of fluid flowing through the nephron, macula densa shuts its face.

2. Macula densa responds to total Na CONTENT and NOT concentration (so "flow" not "concentration")

Ok. So now you apply a diuretic. Lets say its a loop. What does a loop do? It blocks the Na-K-2Cl channel. Does it do anything to water? Not yet. Does it do anything to flow? Nope. The impact of a slightly elevated Na delivery past the Thick Ascending Loop could, in theory, turn off RAS. In theory. The important implication of the Loop Diuretic lays downstream. Youve blocked Na reabsorption. Now you get to the collecting duct. What happens here? Enac. Enac is based on concentration gradient only. So, lets comapre the two states. Before the diuretic you had LESS sodium in the tubule, now, after the diuretic you have MORE sodium in the tubule. What happens? More sodium is reabsorbed. The bidproduct? More K is lost. The collecting tubule will try its darndest to reabsorb all of that sodium, but it cant get it all. So, since water goes where sodium goes, you get diuresis. But the important thing is that you've lost K. Not as a product of aldo, but simply as an increased flow of Na across the Enac channel, leading to more positive charge in teh cell, forcing out more K.

3. Loop Diuretics cause diuresis because Collecting Duct cannot overcome the Na load, and, water goes where sodium goes.

Same thing with Thiazides. They block the distal convoluted tubule. Macula densa already passed. These guys do increase the sodium load to the collecting ducts (above), but to a lesser extent (Thick Ascending Loop does this the best).

4. Thiazides do the same thing as Loops, just a little later in the neprhon (same is used loosely)

If you apply an ACE-i or an ANG-ii blocker, you effectively reduce the amount of Enac channels. This should be a duh, by now. Les Enac, less Na reabsorbed, less K lost, and water goes where sodium goes, diuresis. But feel this now... TAH has the most potent sodium effect, distal convoluted next, and CD last. So youd think that the ACe-i would have the weakest anti-hypertensive effect. Well, they have the weakest DIURETIC effect. But the fact they are directly blocking the vasoconstrictive effects of ANGII make them potent anti-hypertensives, even if they are pretty poor diuretics.

5. ACE-i are great anti-hypertensives, poor diuretics, and get your K up

So what is the effect on the RAS? Well, K does play a little role. Arteriolar distension plays a little role. I get it. But, in the end, what determines the major activation of renin in the whole body system is perfusion ot the kidney. If the kidney thinks you are volume down (because you are, have renal artery stenosis, or have poor forward flow like in CHF) that flow switch will fall to on, and you get activation of RAS. If the kidney thinks you are volume up or euvolemic, it will turn that switch to off, and turn off the RAS.

7. If you think of it in terms of fluid status, life becomes ALOT more easy

Great explanation 👍

 

[ketap]

thx u for the help,Friends..i will rethink about it...thx u very much🙂