Slide 1

So, Dear Chairman thanks a lot for leaving me alone with the slides. Here it is ok. Ladies and Gentlemen talking about the relationship between salt and blood pressure there will always be a talk about our internal environment.

Slide 2

It was Claude Bernard about 150 years ago who coined that concept of the internal environment and he just found out that or he just stated for the first time that our cells cannot be brought safely to the external environment and therefore, have to be surrounded by a watery solution which is our internal environment and that this internal environment must be maintained constantly. It’s no wonder that nature just generated many different mechanisms to maintain this internal environment and one of these mechanisms, for the maintenance of our internal environment, is blood pressure.

Slide 3

So linking salt with blood pressure, I will not get along without bothering you a little bit with basic physiology on the prevailing theory on salt and water balance and then I will show you some data that just do not fit with the prevailing theory on water free sodium accumulation, the extrarenal sodium balance and then in the end we will just come to the point where we must ask ourselves why does sodium elevate blood pressure.

Slide 4

So, the traditional concept of salt and water balance is based on a typical two compartment model where sodium is the primary cation of the extracellular space and potassium is the primary cation of the intracellular space and these cations exert osmotic activity in their respective spaces and act to hold water. Thereby, we believe that the extracellular sodium content inevitably determines the extracellular volume, while the intracellular potassium content inevitably determines our internal volume, the intracellular volume and this idea is based on the concept of isosmolality to prevent fluid shift from the intra to the extracellular space, so the sodium concentration in the extracellular space roughly matches the sodium concentration in the intracellular space and volume is maintained constant.

Slide 5

So what happens if we send an Indian from the Amazonian region to Heidelberg where we have just learnt eats about 12g of salt so what happens is first that’s what we believe that we will accumulate the sodium load in the extracellular space and the first hit now will be osmoregulation, so he will develop first and will accumulate because the osmolality has increased. So he will accumulate water in the extracellular space and he will suppress vasopressin and accumulate water and this will lead to a slight increase of the extracellular volume. So first hit is osmoregulation and if he continues to eat more salt, he also will accumulate even more water and now a critical space of the extracellular volume is transgressed. Now the Indian gets a problem with his volume so what he does is that he just suppresses the renin-angiotensin aldosterone system and renal sympathetic nerves and that will lead to an increase in sodium excretion and therefore, he will correct by this mostly aldosterone activity his extracellular volume, so it’s all about osmo and volume regulation.

Slide 6

The paradigms of that system is that sodium retention always takes place in the extracellular space and because it exerts osmotic activity it will inevitably lead to water retention and extracellular volume expansion and that means that we have to maintain our total body sodium content within very close limits to prevent hydropic decompensation.

Slide 7

So the superstar of that regulatory system is the kidney. I think we just live in a kind of nephrocentic area in terms of salt sensitivity and our understanding of blood pressure increases with salt. Now, if we say it with Claude Bernard once again, he was always sure that we should first of all have a look at the facts and then have a look at the theories or the paradigms even if these ideas are supported by great names and are generally accepted.

Slide 8

In terms of the paradigms I’ve just shown you a few moments ago I think we should just check them in terms of sodium retention and fluid control, so once again what is the paradigm on sodium content? It must be very narrow because of the osmotic activity of the water to maintain the extracellular volume because sodium retention is there and the total body sodium control and the extracellular volume control is the task of the kidneys.

Slide 9

Now, I will control these paradigms by facts from well first a Startling long-term balance study in humans and this was done by Martina Heer in Cologne. So what she did is that she fed healthy students a 220, a 440 or a 660 mmol sodium diet and what you see is that within 3 weeks these subjects accumulated about 1800 mmol of sodium.

Slide 10

So, if we come back to our concept if we accumulate about 1500 mmol of sodium and the sodium load was accumulated in the extracellular space, we would expect a volume retention of 10L and here’s the body weight. So there was water free retention, the sodium was somehow swallowed inside the body and the question now is where is that salt? You can solve that by transferring this experimental evidence to an animal experimental approach because what you need now is a chemical analysis of the sodium potassium and water content in different tissues. This was done here in the DOCA-salt model so here you see the total body sodium content versus the total body water content and each dot represents a rat and these rats well only had low salt versus high salt and you see that the total body sodium content is maintained and all rats move on the trodden pad of isosmolality, so there’s water retention. If you expected a 100% increase of the total body sodium content, we would expect an 80% water content as just indicated with the rat point over there.

Slide 11

So if we induce sodium retention with DOCA which activates the mineralocorticoid receptor, we find tremendous sodium accumulation so the sodium content is increased for about 100% in some individual rats but we have no water retention. So, that is clear experimental evidence for water free sodium retention.

Slide 12

Now the question is where is the salt? A tremendous load of the salt is in the muscle with DOCA. We have an increase of the intracellular muscle sodium content up to 40-50 mmol/L and this is balanced by a corresponding potassium loss, so what happens is that the sodium moves inside the cells, sodium retention is not automatically in the extracellular space in this case and the same amount of potassium together with water is excreted.

Slide 13

So this is osmotically neutral sodium potassium exchange, a translocalisation of sodium from the extracellular to the intracellular volume. You have more sodium, less potassium and the water volume is maintained constantly despite sodium retention.

Slide 14

The other thing is if you have a look at the skin and compare the interstitial sodium concentration with the blood concentration, also the same is true for potassium, you find that the sodium load somehow has escaped isosmolality about 170 versus 135 and this escape is not balanced by a corresponding potassium loss.

Slide 15

What has happened here is that the extracellular matrix in the skin has exchanged and this seems to be a mechanism of the glycosaminoglycans. They are negatively charged due to the sulphatation grade and if you feed them high salt, you have more negative charge density in the extracellular matrix and what happens is osmotically inactive sodium storage. So you have negative charge density, sodium ions leave their completely hydrated space and this is the setting of osmotically inactive sodium storage. So we have two mechanisms for water free sodium retention. Osmotically inactive sodium storage in the skin and osmotically neutral sodium potassium exchange in the muscle.

Slide 16

So does that have something to do with blood pressure? First the paradigm was that the sodium content has to maintain constantly narrow, so it’s variable and the water retention is not always isosmolol. Sodium retention is not only in the extracellular space but also in the intracellular volume and there’s a renal and extrarenal control of total body sodium and extracellular volume.

Slide 17

So, does this novel component of sodium redistribution have an impact on blood pressure regulation? This just briefly summarises the guiding concept of blood pressure.

Slide 18

So where we have, for example, with DOCA sodium retention, a slight increase of the total body sodium content, a very slight increase of the extracellular volume and this is modulated by the vascular resistance and increases blood pressure. Now this blood pressure increase and the associated natriuresis overrides the DOCA effect and you have a maintenance of the extracellular volume at the price of an increased blood pressure. But this concept also relies on the fact that total body sodium inevitably increases the extracellular volume. So, we will just think a little bit about this new regulatory alternative which has not been considered until now.

Slide 19

So the question is does osmotically inactive sodium storage play a role? Because if we could buffer sodium, an osmotically inactive sodium reservoir, we would reduce the volume and the same is true for osmotically neutral sodium potassium exchange but this has been already considered as important because if you have an increase in the sodium content in the muscle cells, you have an increase in the calcium content and that would lead to vasoconstriction and therefore, increased blood pressure. Also in terms of high pulse osmolality we know that there’s a set pound for volume at the hypothalamus and it’s not only if we look at the work of Virginia Brooks and others, it’s not only the sodium, the volume but also sodium concentration osmolality which is measured and which determines the vascular resistance.

Slide 20

So if we have a look at DOCA-salt rats, they accumulate about 4 ml of sodium, the increase in total body water should be 27 ml but they only accumulated 5 ml, so they buffered a tremendous amount of volume and that should be beneficial for blood pressure control. If you ovariectomise these rats, the rats lose their osmotically inactive sodium storage capacity.

Slide 21

Now, virtually the same amount of sodium suddenly increases the extracellular volume for 10 ml instead of 5 ml. If you summarise this data where we have the same sodium content but different blood pressure values of 20 mmHg, we find that the difference is here 80% versus 67% so the buffer did not work but we also have an increased volume sensitivity.
So the question that remains and that is the last question is whether these 5ml or these 10ml of extracellular volume are important in terms of blood pressure regulation. I think the argument against it is if you feed these rats sodium chloride versus sodium bicarbonate. Because what happens if you give them sodium bicarbonate, is that you completely abolish the salt sensitivity in the rats.

Slide 22

So, the question is, is there less, or the same or even more sodium volume? The answer is the total body sodium content is increased and this is not balanced by potassium loss and there’s even more volume retention but blood pressure is higher.

Slide 23

So, summarising this novel or this alternative view in blood pressure regulation, we must say that sodium retention perhaps is less important than we believed and water retention also is less important than we believed and that osmotically inactive sodium storage or loss of this storage capacity may play a role in post-menopausal hypertension and that the redistribution of electrolytes or local hyperosmolality at the brain might play an important role.

Slide 24

So to end up I do not say the kidneys are not important but if you think about why salt increases blood pressure, we must just acknowledge that in experimental models of salt-sensitive hypertension extrarenal mechanisms are critically involved and blood pressure homeostasis and that volume homeostasis can be maintained despite massive sodium retention. But also that this redistribution of sodium and potassium content may critically increase vascular resistance. So what we should think of if we think about the blood pressure increases together with salt, we should not only think about the external sodium balance which is maintained by the kidneys but also we should consider sodium redistribution inside the body, sodium versus K and that is internal sodium balance or extrarenal regulation of the blood pressure response. So thanks a lot for your attention.

Slide 25

Chairman: Thank you. Presentation is open for discussion.

Question: A simple question. What cations does this sodium replace when it binds to the glycosaminoglycans in the skin?

Dr Titze: Well, do you mean osmotically inactive sodium storage?

Question: Yes.

Dr Titze: So, the sulphatation should be acids but we did not measure it. So if you dialyse them with sodium or potassium, it’s just a question of binding capacity. So there’s a replacement of cations and if you have a lot of sodium and you’re dialysed with potassium, it will just be replaced but most probably it is placed with protons.

Question: Is it possible that salt and blood pressure cause an effect that is very much dependent on genes like other diseases and conditions? Some people respond, other people don’t respond.

Dr Titze: Well, I didn’t have that much time. You see one very favourite model is the LIDELL mouse for salt-sensitive hypertension. That is clearly genetically determined because we have again a function mutation of the epithelial sodium channel. So everybody believes that they have an increase in extracellular volume and an increase in blood pressure but the sodium and water content in these mice is exactly the same. So sodium retention definitely depends on the sodium retention but what we can show that the transported self really does a job so you have an increased transport rate in the kidney. So what we should think about, if we think about genetic models is that well, a defect can be placed genetically and you have a problem with the sodium but then you have a regulatory cascade which maybe not dependent on the gene and I think it’s very important to understand this cascade as well.

Chairman: Last question.

Question: Can I ask about the time course of osmotically neutral sodium storage, for instance in a haemodialysis patient between one dialysis session and the next. Is ingested sodium stored in an osmotically neutral manner?

Dr Titze: So osmotically neutral means sodium potassium exchange and if we give them DOCA for example, we don’t have data in humans at the moment. This will be done this year I guess. So what happens in rats is first comes the sodium exchange and you find that within 2-3 days and osmotically inactive sodium storage first of all is dependent on growth. Young animals have a higher osmotically inactive sodium content and then if you induce it with the diet, it takes about 1 week to 14 days, so it’s a very slow process.

Chairman: Yes, last question.

Question: What about chloride?

Dr Titze: Well, in terms of the diet chloride leads to salt-sensitive hypertension but bicarbonate in contrast leads to even more sodium retention and even more water retention. So, we don’t know and I think Claude Bernard asking about the facts would have said, well it’s a nice story with the sodium and the potassium but what about the chlorides?

Chairman: Ok, thank you very much Doctor Titze for this exciting new finding of osmotically inactive sodium storage. We will now come to the next talk.