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Language: en

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thank you very much mr chairman after these 
very nice talks you already know everything  

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about the key role of vasopressin regarding water 
homeostasis that's good because i will not talk  

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about that i will show you that vasopressin can 
also be a stress hormone and i will raise the  

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question can we prevent the detrimental impact of 
vasopressin as a stress hormone just by drinking?

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well amongst the hostile condition 
dryness is one of the worst,

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in life it induced negative water balance 
extracellular hypertonicity and then cell  

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shrinkage well if the hypertensity remain however 
after a few hours the cell will return to a normal  

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volume most of the time but there are still some 
impact like an increase in dna breaks an increase  

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in protein oxidation the recruitments of inducible 
protein like sjk 1 that is associated with a lot  

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of wrong effects and some metabolic changes like 
insulin resistance for example so when you are  

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exposed to a negative water balance and when whole 
plasma hospitality increase sharply we secrete avp  

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as we have already heard and on the right of this 
uh of this slide you can see that very quickly as  

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soon as plasma vasopressin is rising urine volume 
is decreasing because kidneys are absorbing a lot  

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of water but he's still excreting solutes as you 
can see here and urine concentration is rising up  

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very quickly very strongly that means that you 
can dissociate excretion of solute to a given  

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level and renal water saving regarding that one 
can consider avp as a kind of anti-stress hormone  

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anti-stress the stress being dehydration so it 
can prevent the stress of dehydration that's good  

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how does it work? we have seen that a 
few minutes ago some cells of our brain  

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especially the parthalamus are able to sense not 
or osmolality in itself but the osmotic gradient  

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and then translate that in actions and the 
actions are first a sharp proportional secretion  

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of avp in regard to plasma osmolality and 
if necessary after that you will have thirst  

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well let me distress for two slides avp dosage 
is a kind of nightmare for the biologist it's  

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quite unstable it links to platelets it can even 
link to the wall of the tube you have to extract  

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it and when you extract avp sometimes you damage 
it so the dosage of avp is not very easy for that  

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reason people have looked for a new marker for a 
surrogate marker of avp secretion that is easier  

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as a dosage well the answer is copeptin is a 
good of element, copeptin is a c-terminal peptide  

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of the pro-avp so this protein is made of 
avp and co-peptide it's produced one by one  

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copeptin has no binding a longer half-life it's 
stable in plasma and its dosage is really more  

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reliable this is the reason why in some of the 
slides you will not see anymore the dosage of avp  

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but the dosage of copeptin but get in mind in fact 
since it has no specific effect that when we are  

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saying that copeptin is rising well we are saying 
that avp secretion is rising there is no other way  

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to increase copeptin and even more interesting 
copeptin correlates better with osmolality  

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than avp as you can see the strength of 
the correlation is better with copeptin  

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due to the quality of this dosage so go back 
to the regulation of avp secretion we have  

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listened a lot of things about 
osmolality and we have also heard from  

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my colleague that volemia plays a role as you can 
see in this very nice and very old study there is  

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a stimulatory effect but it's not very sensitive 
however it's very very powerful to stimulate  

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avp secretion with hypovolemia you need something 
like a decrease of five percent of volemia 

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five percent that's a huge amount well which 
physiological condition can induce that  

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almost known on the contrary all the 
situations that are shock can induce  

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that whatever the mechanism septic shock 
hemorrhagic shock even cardiotomy shock  

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i mean all this kind of shock can induce a 
huge sharp and very strong increase in avp  

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secretion here is some example the red bar 
here corresponds to the normal value of  

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avp and copeptin here is the answer during the 
situation as you can see both avp and copeptin  

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in a similar way are increasing very strongly 
well something like two three four ten times  

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more than just when we are using avp for 
those three i mean for weather regulation  

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so in this circumstance that is a very aggressive 
circumstance what is the role of avp? probably not  

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only to save water i mean it's quite short well 
have a look to the receptor of avp we have three  

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receptors v2 receptors v1a and v1b the one with 
the highest affinity is v2 receptor is expressed  

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essentially in the kidney in the collecting duct 
and its role is to when activated is to induce  

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antidiuresis i mean to make the kidney setting 
water it also slightly act on sodium or absorption  

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v1a receptor is very exciting you can find 
it almost everywhere you can find it in small  

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muscle cells in blood vessels on platelets in the 
liver and on the kidney and even in the adrenal  

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gland when you activate with v1a receptor you 
have a lot of effects that are not related to  

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water homeostasis for example you have here a 
vasoconstriction a platelet activation you have  

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an increased glycolysis and then an increase 
of glycemia and you also have a recruitment  

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of self-saving hormones raining aldosterone 
and finding natural resistance is decreasing  

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well to finish v1b receptor it is mostly 
expressed both in the anterior hypophases  

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and in the pancreas in Langerhan's islands 
of the pancreas well in the hypophysis it's  

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stimulating acth secretion in correlation with 
crf and acth stimulation in turn stimulates  

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secretion adrenal secretion of cortisol this is 
typically a stress hormone you already know that  

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and v1b receptor in the pancreas will modulate 
both insulin and glucagon secretion in order to  

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tend to raise blood glucose so if you take all 
these effects they are not related only to water  

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re-absorption and to water homeostasis 
there is this is cardiovascular effect  

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and metabolic effects get that in mind 
and now have a look to what is stress  

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well the stress syndrome was defined 80 years 
ago by Hans Selye in Canada and at the end of  

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his paper in nature he wrote well stress 
syndrome represents a generalized effort  

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of the organism to adapt itself to new 
conditions i must say that in this paper  

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he was essentially describing very knuckles event 
like surgery in animals and things like that  

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years later the concept of stressor was more 
defined especially thanks to the work of McEwen  

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and they decided that a stressor can be something 
larger for example there are some psychosocial  

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stressor pain fear and so on biogenic and 
well they are not only inner cross event but  

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experience that are challenging emotionally 
and physiologically that means a lot of things  

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can be a stressor and not only pain and fear 
you have here two kinds of stressor in mice  

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well the answer to a stress syndrome is the 
fight and flight response this is a normal  

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response that involves crf acth cortisol 
and catecholamines classically however  

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if you look to the action well stress hormone
adapts body by affecting cardiovascular energy  

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producing an immune system remember the effect 
of v1a and v1b receptor they largely interfere  

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with cardiovascular function and with energy 
producing by increasing glucose and according  

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to the work of Axelrod one can consider that 
avp and even ocytocine are a second level of 

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stress hormones then the question is well how can 
we summarize that well this this figure is trying  

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to summarize that at very low concentration avp 
is the hormone of water homeostasis and it rather  

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prevents stress at high concentration especially 
during hypovolemia well it's a stress hormone  

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that increases cortisol glycemia and sodium 
retention and vasoconstriction however the  

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question is are only osmolality and volemia 
involved in the regulation of avp secretion  

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the answer is no if you stand upright you will 
increase if you sit down you will decrease it  

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if you for example you smoke a cigarette you will 
increase avp by twice if you have some pain some  

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fear some nausea some vomiting if you look to the 
human menstrual cycle it influence avp secretion  

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if you change the thyroid status it will change 
the answer of avp secretion and well finally  

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a lot of things are able and depression for 
example are able to stimulate avp secretion  

00:10:25.120 --> 00:10:29.680
well when you go to what we are saying to our 
students usually you have vasopressin in the  

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middle and the two classical way of regulation 
osmolality and hypovolemia well osmolality is  

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usually linked to renal water saving and 
hypovolemia to a kind of stress adaptation  

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well but what are you doing with that all these 
are stressors that can modulate avp secretion  

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independently of osmolality and of hypovolemia 
and when you look carefully there are a lot  

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of things in everyday life i mean look 
sympathetic activity smoking nausea fever  

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and fear depression we have seen that diabetes 
uncontrollable hypertension sepsis and so on  

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so well the usual shame is 
probably a little bit short

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the remaining question is well what 
is the link between renal water saving  

00:11:21.040 --> 00:11:29.440
and stress adaptation? can we consider that 
preventing our body from dehydration with avp  

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could be a kind of stress? 
or stressor should i say  

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well go to a study published a few years ago by 
Danone this is a hypop study they took 95 patients  

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no patients but healthy people within these 95, 
71 were either low drinkers or high drinkers  

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and low drinkers were having a fluid intake below 
1.2 liter per day and high drinkers were having a  

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fluid intake between two and four liters all were 
perfectly healthy they were the same size, age and  

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so on and they checked for the main difference 
between. well surprisingly plasma osmolality was  

00:12:08.880 --> 00:12:15.200
almost no different one million of differences 
almost nothing however avp was higher in the low  

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drinkers than in the high drinkers close to 0.6 
pmol and more surprisingly for us but we should  

00:12:22.720 --> 00:12:29.040
have guessed that in fact cortisol was increased 
in the low drinker first morning cortisol was  

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increased by 20 percent this is significant then 
what is the impact of this cortisol we don't know  

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but however this is already a kind of v1b effect 
and it can correspond to a stress recruitment  

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of the action of avp despite the fact that they 
are not dehydrated they are just saving water so  

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in fact the question is the question of threshold 
between the good and the bad action of avp because  

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in fact it's not a sequential but a continuous 
effect you have every day a lot of stressors  

00:13:01.120 --> 00:13:09.040
that stimulate or inhibit avp on the top of
osmolality however the real question is that  

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we know from the work of Axelrod that all the 
hormones involved in stress are detrimental  

00:13:17.120 --> 00:13:23.040
when recruited in a prolonged way so what is the 
clinical impact of recruiting avp as a stress  

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hormone is there any chronic impact well it seems 
that there could be some impact thanks to the work  

00:13:31.040 --> 00:13:38.000
of the team of professor Olle Melander we have the 
clear notion that there is a relationship between  

00:13:38.560 --> 00:13:46.640
copeptin so let us say avp and the risk to 
develop metabolic syndrome the higher is copeptin 

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the higher is the prevalence of the 
component of metabolic syndrome hypertension  

00:13:52.400 --> 00:13:58.400
increased crp body mass index and so on and so on 
they were even able to show clearly a relationship  

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between avp, copeptin and fasting blood glucose 
and fasting insulin we are talking about type  

00:14:06.800 --> 00:14:13.520
2 diabetes indeed more recently they were able to 
show that there is an independent that copeptin is  

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an independent predictor of diabetic heart disease 
and death so really it seemed that there is  

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an impact of avp on metabolic and cardiovascular 
system what about the kidney now well we know  

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for no more than 30 years that there could be 
an interaction between avp and ckd progression  

00:14:35.040 --> 00:14:40.640
most of the results are coming from the classical 
five-six nephrectomy model in mice or in let's say  

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rodent and well this bonkey was among the first 
to show that increasing fluid intake in this model  

00:14:48.400 --> 00:14:54.160
we delay the increase in avp the increase in 
proteinuria and the decrease in renal function  

00:14:54.160 --> 00:15:00.080
so it's protective another work should have shown 
that increasing water intake also protects from  

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interstitial fibrosis is a k point in this model 
and decreased tgf beta production that is a pro  

00:15:06.640 --> 00:15:17.200
fibrotic hormone and v1a blockade v1a not v2 
but v1a blockade by an antagonist is able if  

00:15:17.200 --> 00:15:22.400
given very early in this model to prevent 
the worsening of the chronic kidney disease  

00:15:22.960 --> 00:15:28.240
so clearly there are experimental evidence the 
main problem is that what is the anthropomorphic  

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relevance because a marine is not exactly a 
man a marine is living all his life with a high  

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component of water saving not it's not really 
the same case in humans so is there any link with  

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human pathology the answer is probably yes thanks 
to the very nice work of the team of bill clark  

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they have published a study based on a prospective 
court on more than two thousand people where  

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they check 24 hours urine within seven years at 
least three times and what they're able to show  

00:16:03.200 --> 00:16:09.840
is that when you consider urine volume at baseline 
urine volume is a surrogate marker of fluid intake  

00:16:09.840 --> 00:16:15.120
let me say that the more you drink the more you 
will extract urine so this is a quite good marker  

00:16:15.120 --> 00:16:23.680
of fluid intake so the relationship was the higher 
was urine volume the lower was a decrease in renal  

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function during the survey and the lower was urine 
volume the higher was the risk to have a higher  

00:16:29.680 --> 00:16:34.560
rapid renal decline as shown in this figure 
as you can see the old ratio was almost  

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1.52 i mean people having a low urine 
volume have a higher risk to present  

00:16:42.320 --> 00:16:49.840
a mild to moderate renal decline 
or even a rapid renal decline  

00:16:51.520 --> 00:16:58.160
so from observation to action there is a small gap 
and they they decided to fill it with the wit's  

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study, wit's study is water intake trial and until 
now we just have pilot trial results but it's  

00:17:04.560 --> 00:17:11.600
already very exciting so they took stage 3 ckd 
people having a renal function between 30 and 60  

00:17:11.600 --> 00:17:16.640
milliliter per minute and they asked them to 
increase their fluid intake loosely by one liter  

00:17:17.200 --> 00:17:24.400
and what happened well for six weeks they did it 
very well they increased their fluid intake by 0.7  

00:17:24.400 --> 00:17:29.520
liter and not surprisingly because at this level 
of renal function the capability of dilution is  

00:17:29.520 --> 00:17:35.840
still very good there are there was absolutely no 
change in plasma osmolality and natremia so it's  

00:17:35.840 --> 00:17:42.320
possible it's safe but more exciting when you look 
carefully to the results provided in their study  

00:17:42.880 --> 00:17:48.080
there is absolutely no evidence that their 
patients were dehydrated at baseline it's the  

00:17:48.080 --> 00:17:54.480
same thing in melander paper there is absolutely 
no evidence that patients are dehydrated  

00:17:54.480 --> 00:18:01.120
they have higher copeptin but they are not 
dehydrated look to copeptin in in the wit's study  

00:18:02.160 --> 00:18:08.720
well you know just by increasing by 0.7 liters 
they were able to decrease the copeptin by  

00:18:08.720 --> 00:18:14.640
something like one third so it's pretty well 
it works despite people who are not dehydrated

00:18:16.960 --> 00:18:24.160
so to try to summarize that in two slides here 
you have what one can guess the normal avp  

00:18:24.160 --> 00:18:30.640
concentration in your body on the left if you are 
healthy most of this avp is related to osmotic  

00:18:32.160 --> 00:18:37.520
regulation but there is always a path that 
is a stressor induced like because you are  

00:18:37.520 --> 00:18:44.960
standing upright you are smoking and so on we have 
clearly identified some disease or pre-diseases  

00:18:44.960 --> 00:18:52.080
that are associated with a higher level of avp or 
copeptin well one can guess that in these people  

00:18:52.080 --> 00:18:58.640
that are not dehydrated the increase in avp is 
probably non-osmotic or non-osmotically driven  

00:18:59.840 --> 00:19:06.080
if you add some water it appears that you can 
adjust whatever the mechanism you can adjust  

00:19:06.080 --> 00:19:12.000
avp secretion you can reduce it and then if you 
believe that vasopressin in itself is detrimental  

00:19:12.000 --> 00:19:19.440
as a stress hormone you get it you can protect 
your patient so to finish with this slide i like  

00:19:19.440 --> 00:19:25.520
this this zen analogy the finger pointing at the 
moon if one show you the moon don't look at the  

00:19:25.520 --> 00:19:34.080
finger until now we were pretty convinced that avp 
was related to renal water saving that avp could  

00:19:34.080 --> 00:19:40.480
be detrimental and that finally when you think 
about that well the paradigm was you have to drink  

00:19:40.480 --> 00:19:46.640
to prevent dehydration and when people are sick 
you find they should be dehydrated they have too  

00:19:46.640 --> 00:19:54.000
much avp and if you hydrate them well they will 
have less avp but it it's not a problem because a  

00:19:54.000 --> 00:20:00.480
part of this avp is stress-related it's a stress 
response and the problem is well just make them  

00:20:00.480 --> 00:20:06.080
drinking whatever the mechanism of the increase 
of avp you will suppress avp and if you believe  

00:20:06.080 --> 00:20:11.200
that avp is detrimental then you will protect 
your patient the only remaining question is  

00:20:11.200 --> 00:20:19.680
how much should they drink i do not 
have the answer i'm sorry yet thank you