today we are going to talk about the Rin Angiotensin elderone excess of the system right it is one of the very important physiological system which is doing lot of function but most important function is blood pressure regulation that how the system regulates your blood pressure so let's start first to understand its physiology right and to understand its physiology let's take an example that due to some reason if my blood pressure is going down for example I develop some Hemorrhage or bleeding I'm losing the blood out of my body then how this system is activated because the duty of the system is duty of raining inot tensin elderone system is to maintain my blood volume and to maintain my blood pressure volume and pressure in the vascular system should be regulated by this system it plays one of the very important role let's disturb the volume and pressure and see what what happens to the system example we take that there's a patient and he got in roadside accident and he is losing blood right of course now we'll discuss that how the system is activated let's suppose that this is the circulatory system of that patient right the organs which are going to play a role in this whole game is number one central nervous system which is responsible for sympathetic outflow we will talk about the kidney is that right rather drawing the full kidney we'll draw a nefron here right so I draw a small kidney here right then there's a role played by the liver we'll talk about that what is that role and then very important role is played by by pulmonary circulatory system and of course we will not forget the role which is played by adrenal cortex now let's start one by one what really happens that when your patient is bleeding let's suppose patient is losing the blood here naturally blood pressure is going down and blood volume is going down is that right many things will happen in the body one of the thing which will happen that if patient is bleeding and blood pressure goes down the blood flow to kidney will increase or decrease decrease the first thing we'll say this's reduced renal perfusion now whenever there is reduced renal perfusion right then veins from the kidney the veins from the kidney start bringing an enzyme in the blood this enzyme is released in blood from the kidney this enzyme is called renin what I have said that whenever blood pressure goes down kidneys start producing more renin and more renin come into blood but first of all we must study the kidney thoroughly that by reducing the blood pressure how kidne start producing renin right for this purpose I I will bring one nefron out and show the nefron The Operators which is supposed to release Rin one kidney has how many nephrons you know kidney have very specialized tube you are millionaire as far as nephrons are concerned in one kidney there are about 1.2 million nephrons but I will just bring out of this kidney one nefron out right let's suppose this is the nefron here and this nefron I'm going to draw outside to explain that how really this system work this is one epithelial tube or nephron from the kidney right and we'll see how normally this nefron works in relationship to blood supply let's suppose this is afront arterial which is bringing the blood to the nephron these are glomular capillar is and here is ephant arterial what is this this is eant arterial here it is eph front arterial right and here is your nefron now what really happens that we say that blood is patient is beding naturally blood coming to kidney is less so of course blood flow to this nefron is also less so eont arterial has poor blood flow now this is very interesting thing Nature has P put blood pressure measuring devices with every nefron what a Master System in the nature that nature has put blood pressure measuring device with every nefron so that every nephron knows how much blood is coming to it is it enough or not so Mr had you will tell me what is the blood pressure measuring device with every nephron anyone has idea about you have any idea every nefron has blood pressure measuring device if you have 2.5 million nephrons right now in your two kidness there are 2.5 million blood pressure measuring devices with every nefron let me tell you one thing you see what is this this was arrant arterial the the smooth these are the normal smooth muscles are eont arterial as eont arterial approaches the what is this glus right it smooth muscles become altered there are no more normal smooth muscles these are very specialized smooth muscles right and this group of very specialized smooth muscle which are present in the wall of eant nephron sorry eant arterial this is blood BL pressure measuring device these are the Barrow receptors it means nature consider blood flow to nephron extremely important that is why nature may may is the blood flow to every nefron right and this whole group it has been given a special name the name is called pin pin so what is pin pin are mod made of a special operatus which is made of what modified aant arteri smooth muscle which are able to measure the blood flow to nefron and whenever blood flow to nefron become less whenever the blood flow to nephron become less they start releasing runin into blood so it means they have double action one action is to measure the blood flow and second action is to release the renin it means they're acting like an endocrine gland because one group of cell releasing the hormone into blood and acting into some distant area so every nefron has small endocrine system with it am I clear this is a blood pressure measuring device whenever your blood flow is coming less and there's less pressure on this operatus as soon as this operatus sense that blood flow is less or blood pressure is less it will start releasing which substance renin okay write it like this it is the renin so this is one way how renin is released by the special operators from the nephron now another mechanism is also there first understand normal normally what happen that when blood is moving through the glar capillaries there is some filtration done there is glomular filtrate am I clear now this GL filtrate normally has lot of sodium and many other substances of course the what are these These are the cells in the wall of nefron right now listen nephron has lot of cells in its wall now you see normally when there's normal blood flow then there's normal filtration and filtration normally is about 120 ml per minute in the all nefron this filtered material start going down but because it has a lot of sodium nephron cells take the sodium back to the body is that right about 70% of the sodium or 60 to 70% of the sodium which is filtered as it is moving through proximal convulated tubule it is reabsorbed back to the body we don't want to lose the sodium then sodium keeps on moving forward and about 25% of the sodium is reabsorbed here if 60 5% sodium if 100 unit of sodium go down 65 is reabsorbed here and 25 is reabsorbed here how much is left 15 I think your math is not okay 65 + 15 25 65 + 25 how much it become 90 it means normally out of the filtered sodium about 10% sodium comes here or this band This is the End of This is the beginning of distal convol tubule and end of the thick part of ascending limb of loop of Hy here Nature has put a very beautiful system there are some cells here which are very very slightly modified structure this group of cells here the nefron cells are somewhat modified these are tall these are dark looking and these cells love to taste the fluid here these cells are sensitive to they are sensitive to sodium they are sodium sensors what what is the function of these cells these are sodium sensing cells right now actually these are pressure sensing system and this is sodium sensing system this system together make a whole operatus now look aont arterial with pulin and this specialized group of cells from distal conol tub and it's Junction with the proximal part is that right this group of cell and this group of cell they make one specialized operators these acting as a bar receptors and these acting as a chemo receptors these are the bar receptors these are the chemo receptor they me the blood pressure they meor the sodium concentration is that right and they are held together by some connective tissue cells they held together by some yes connective tissue cells now I told you this blood pressure measuring device bar receptor group it is called vasen and this sodium sensing device which is present in every nefron it has a special name you know what is the name of this uh special group of cells which may the sodium thank God the researcher who found it he did not put his name on this actually in the beginning when researchers looked at the nephron structure they found this area was a little bit more dark as compared to the rest of the Nephron these group of cells are more dark so they just call it meula densa that there is some meu Mulin patch patch of cell which is looking very dense so this is called what is the name of this thing meula densa now pulin is from arrant arterial macular denit from distal convulated tubal this is vascular component this is nephron component this is pressure measuring device this is sodium measuring device and they are held together through connective tissue cells which are called lesses cell all this operators as a group all this operators as a group is present in every nefron it means every nefron has blood pressure measuring device as well as sodium meing system and as a group pin plus mulaa they have given a very special name to this and all of you know that name what is the name of the opetus what's the name of the opetus yeah J GL operatus have you heard of it so this is jxa glomular operatus just they call it a special operatus right just posed to glas justra glas with the glas there's a very special operators thank God they did not put a very complex name for it they just say they're special operators they never knew in the beginning what are its function now they know now let's go back to our anology we were saying that person is bleeding blood pressure is going down blood flow is going yes down so when blood flow is less bar receptors are activated in justra glus and the release renin meanwhile when your blood flow is less then glum filtration is more or less less of course if there's less blood coming right then filtration is also less now you think really with your own cortex that if filtration is very less listen listen if filtration is very less the fluid will move through this Lumen rapidly or slowly slow sure so whenever GFR is less luminal flow becomes slow when movement of the fluid through the Lumen become slow then what happen these cells which are working on this luminal fluid they have more chance to work or less chance to work less more my friend of course look if there are many mangoes going here attention Mr let's suppose there's water going and lot of mangoes going here and you are sitting here to catch the mangoes if flow is very fast you will miss the mangoes but if it is very very slowly coming you will catch every mango do you get it these cells work like you they are not catching mangos there they're catching sodium there so when blood pressure become less glum filtrate become less luminal flow become less these cell extract extraordinary amount of sodium and by the time the fluid little fluid reaches here it is more than normal amount of sodium or less than normal amount of sodium less than normal amount of sodium then meula densa it love to taste sodium so whenever GFR is less then proxim B part of the nefron work on the slowly moving fluid extract too much sodium so less sodium reach to the sodium sensing device and whenever macular densa Feld there's less sodium coming it becomes Super Active it is activated when there's less sodium reaching here and it releases some nitric oxide is released by it and prostag glands are released by it and they activate these pulasan cells mular densa request this that please listen to us there's very little sodium coming here there's something wrong with GFR probably blood is not coming well so please release more renin so renin release become further augmented so now renin has been released under two influences under pressure change and under sodium change so every glomas has gal operators operators consist of blood pressure measuring device and operators consist of sodium sensing device blood pressure meing device is derived from the eant arterial smooth muscle sodium meing device is a derivative of nefron cells together they make justl operatus when ever blood flow is less to the kidney right this operatus releases excessive Rainin in the blood now what this renin should do renin should correct the balance bring the patient out of tragedy what was the tragedy blood pressure was going down and blood volume was going down Now function of renin is to bring the blood pressure back as well as blood volume up so that patient does not die for example patient has lost one lit of blood that somehow blood pressure should be maintained and somehow blood volume should be maintained we will talk about how renin does it but before that we will talk about one more Factor what is that that is that whenever your blood pressure go down whenever your blood pressure goes down let's suppose here is your heart so what really happens what is that what is this coted system as coted body what is the function of sorry coted sinus not coted body this is this is what I'm saying is coted sinus coted sinus is other blood pressure measuring device bar it also has bar receptor when patient is bleeding the blood flow to hair will be more or less less so whenever blood flow become less this koted system is also activated and to special neurons they report to the central nervous system that blood pressure is falling they report to the central of system that blood pressure is falling in the central of system right okay let's forget about this part of the diagram and concentrate only on this this is going into peritubular capillaries and then it collect back as Venus and okay connected here this was renal arterial flow and this is renal Venus flow Venus blood going back right and arterial blood let's come back I was saying as soon as blood pressure goes down koted sinus through the sinus nerves right this is through the Vegas V uh ninth nerve glossop frenal nerve right this is messages given to the central nervous system system that blood pressure is going down as soon as central nervous system senses that blood pressure is going down it will stimulate the sympathetic outflow through visot Center in the medala so from the medala fibers will come down neuronal connections will come down and stimulate what thing out stimulate sympathetic outflow this sympathetic outflow which is going out suppose these are pre ganic sympathetic neurons and here are post ganic sympathetic neurons I will not go to detail of all sympathetic fibers right now we are concerned only with those sympathetic fibers which are coming to GTR glomular operatus these are sympathetic neurons which are coming to GTR glomular operatus actually as soon as blood pressure start going down with the motor cental stimulated lot of sympathetic outflow come some of the sympathetic Fiber come to justl operatus and what they will release there they will release neurons will release neurons will release norepinephrine right and these cells have receptor for norepinephrine these are beta one adrenergic receptor what are these receptors beta 1 adrenergic I receptor you must know there are beta 1 adonic receptor present on gatas because beta blocker block them also and help us in hypertension management so the beta one adonic receptors present over here so sympathetic outflow stimulate these beta 1 receptors and when beta 1 receptors are stimulated here more release of Rin according to Mr had speculations more release of Ranon so how many mechanis are there to release the renin from here number one two local and one systemic intrarenal mechanism is low blood pressure in the E arterial and low sodium concentration to the ma densa both of them release renin these two are intar renal mechanism of release of renin extra renal mechanism of release of renin is most important sympathetic fibers connected with that is that right so we see this G operatus can measure the pressure directly can meure the sodium concent directly and in every emergency whenever sympathetic nervous system will fire renin will come now what this renin will do let's see what this renin is going to do this renin is going to the general circulation from the renin will go to the general circulation now renin has come to the systemic circulation right through the renal vein what renin will do here I I told you renin is an enzyme right and every enzyme work on special type of substrate it will also work on some special type of substrate before we go for that you know liver has a lot of hepatocytes hepatocytes produce a lot of protein normally you know they produce albumins and globulins Alpha globin beta globulins but not gamma globins because gamma globulins are immunoglobulins antibodies which come from plasma cells B cells but but most of the proteins other than the gammaglobulins most not all but most of the proteins are produced by liver cells liver cell produce one very special type of protein normally and this protein is called angio Tenino enens cinogen right Inogen okay I will write it in small way this is angiotensinogen right from where it is coming it is coming from liver and it is not coming only during crisis it is produced by the liver all the time right now all of you have in your blood injur enogen but as soon as renin come it will work on enot enogen it will work on angiotensinogen and convert the angiotensinogen into enot tensin one it is enot tensin one so what is the function of renin renin is an enzyme which can convert angiotensinogen into ensin one is that right now all of you know it that when inot tensin one passes through the lungs it convert into inot tensin two that is a crust of understanding now that inot tensin one when it is passing through the lungs convert into angiotensin two it means in the lungs there should be some enzyme which convert Angiotensin one into angiotensin two and that enzyme is called Angiotensin converting enzyme again when Angiotensin one passes through the lungs it convert into OT tensin two angot tensin two right when angot tensin passes through the lungs it converts into ensin 2 this is large protein molecule it is decapeptide I mean 10 amino acid then there's enzyme in the lung which break down to more amino acid and this product is octapeptide only eight amino acids I want to know one thing ensin converting enzyme on which so many drugs work ensin converting enzyme are present in which part of the lung are they present in bronchioles are they present in aluli are they present in capillaries are they present where where in the lung angot tensin converting enzyme is present all of you know there are many drugs which inhibit that enzyme we must know where is that enzyme yes we talked to abas no idea Jamie same yesah maybe you are with the majority or you will try to guess something in the lungs everyone has heard there's enzyme called inot tensin converting enzyme have you heard of it or not Mah you have heard of it where exactly it is present no idea no idea Jamie just guess it wild guess you don't want to even guess maybe it is present on the plur yes any wild guess I'll be Li what do you think yeah P pumos sites okay write it down on the book and put a very big cross on this you know why if it is present in aluli then tell me one thing it means your blood has to pass through aluli Al blood flow system or air flow system the air pockets or blood pocket yes cap Al no the Alvi are air pockets and Pulmonary capillaries are attached with them but pulmonary capillaries are not Alvi themselves right so one thing is sure alil should not have the enzyme otherwise there there will be tragedy blood has to jump into Alvi so that ensin one should convert into inot tensin 2 okay let me explain actually here is Alvi let's suppose this is Airway and these are suppose alular system these are air pockets of course blood should not enter there is that right actually you know on the endothelial cells what are these endothelial cells of pulmonary capillary beds on the endothelial cells there's a unique enzyme expressed this enzyme is expressed on the surface of endothelial cells that is why this enzyme is called Ecto enzyme because this is not intracellular enzyme the cell is expressed on the surface of endothelial cells right not released into blood but now they believe that not only pulmonary blood uh capillaries have capacity to convert utens one into two even some other capillary beds can also do this function but for your level you just remember that in the pulmonary capillary endothelial lining they are expressing enzyme called what is the name of these enzymes you know they are very angry because you don't remember where they are you look at their expression right these are which enzymes inot tensin converting enzyme what they are doing actually they are responsible to convert inot tensin one into inot tensin two this is a function of these enzymes these are the function of these enzymes which are called enot tensin converting enzymes that they convert enot tensin one andot tensin to and when we talk about the drugs like captopril anoil asoil or other ensin converting enzyme Inhibitors those drugs basically bind with these proteins and block their function when we say there are whole group of drugs called Angiotensin converting enzyme inhibitor what are the function of those drugs these drugs are B basically bind with these enzymes and blocking their action every doctor knows that these enzyme are converting inot tensin one into inot tensin two but some good doctors know they do also one more function what is the second function of this enzymes there's another product in the blood which is called bready kin there's another product in the blood which is called bready kin brein is broken down by these enzymes brein you know look at it because it is inactivated bready kin inactivation [Music] inactivation brinin is visator and inot tensin 2 is viso constrictor so what is the function of this enzyme these enzymes break down the vasodilators and produce vsoc Constructor of course when blood blood vessels will constrict blood pressure will go up am I clear now so again let's recap up to this patient was actively bleeding right it will take some time renal profusion is reduced then in your your what is this blood pressure sensitive cells release renin plus macular Dena senses low sodium coming here a sign of low GFR that also forces the cell to release renin moreover following blood pressure activate the sympathetic outflow and sympathetic fibers coming to the gal operatus further release of renin this renin is an enzyme which come into General circulation and break down the angiotensinogen into enot one and when otens one is passing through the mainly when it is passing through the pulmonary circulation then otens converting enzymes which are normally expressed on the endotherial cells of pulmonary circulation they convert enot tensin one into inot tensin 2 so they produce very powerful visoc Constructor and of course these enzymes are very active very intelligent while they're producing visoc Constructor they don't forget to inactivate the viso dilators like brinin now we have the inot tensin 2 in our circulation now we have to see what inot tensin 2 will do in the body what what it should do it should bring the blood pressure up and blood volume up that was the problem now so now we see how inot tensin 2 is going to achieve its function let's come to the actions of angot tensent to First we'll talk about the classical action number one Ango tension to okay I will draw here circulatory system in a little little detail the left heart and these are the arterials from the aorta these are the arterials and here is your right heart this is the Venus system and of course in between these arterial venous system there are what are these capillary beds I hope you must know Blood come from arterial side passes through the capillary beds and then it is drained to the Venus side right this is right heart and that is left heart and of course you will not forget to draw that there must be lung over there that this is your pulmonary circulation and blood gets oxygenated over there and then it comes to to the left atrium and of course here is your what is this air spaces clear now we'll see first of all what is the action of inot tensin 2 on this system because pressure and volume is falling into the system first of all inut tensin 2 has receptors on the arteri smooth muscle what are these arteri smooth muscle inot tensin two receptors are present on arteri smooth muscle plus inot tensin 2 receptors are also present on the venular smooth muscle so they are also present over here right now what really happens number one angot tensin 2 will work on what is this Venus smooth muscle when angot tensin 2 act on the angot tensin 2 receptors on Venus smooth muscles veins construct when veins will construct can blood remain pool into vein no most of our blood is accumul normally present in the veins veins contain about 70% of total blood volume that is why we call them the vascular component with highest capacity or simply veins are called capacit vessels so inot tensin 2 will constrict the veins when veins are squeezing pressure in veins will go up and blood will Rush towards where where the blood is going to the heart and then to the eventually left heart so under venoc construction blood going to the left heart is less or more when you squeeze the wiin Venus return to the heart is increased now when blood flow increases to the left heart it mean cardiac fing is more so Venus return Veno construction lead to increase Venus return that lead to increase cardiac fing increase cardiac feeling lead to increase and diastolic volume and increased end diastolic pressure at the end of the diast volume and pressure is more in The ventricle so ventricle is stretched and according to Frank Starling law more you stretch the ventricle more IT contract Frank Starling law is stated that within physiological limit more you stretch the myocard cell more they contract of course within physiological limit don't rupture them right now so whenever Venus return is more and diastolic volume is more we say that preload on the heart is more and whenever preload on the heart is more preload is the amount of blood in the ventricle on which it has to produce contraction is that right so whenever there's more blood accumulated here more it is stretch more IT contract so stroke volume will become more so that will lead to increase stroke volume that will lead to increase stroke volume and of course when stroke volume is more then what is there increase cardiac output and when there is increased cardiac output that will lead to increase in systolic blood pressure that was the point we wanted to reach you know our systolic blood pressure was falling as well as diastolic blood pressure was falling when your bleeding was going on for example bleeding was from here so blood pressure was falling so by Veno construction and increasing the Venus return to the heart and increasing the indolic volume and of course increasing the contractility and increasing the stroke volume resulting into increased cardiac output eventually increases systolic blood pressure because systolic blood pressure mainly depends on cardiac output am I clear during the syst blood pressure will go up meanwhile angot tensin 2 will also work on what is this arterial smooth muscle and arterials will constract now if arterials will become very narrow during the Cy even lot of blood come here can it easily move to that side no so even if heart is not pumping because after the cyly heart will undergo relaxation there'll be on set of dle during the DI of course aortic Val closes blood cannot go back the only choice for the blood during dle was that no blood coming during the dle here but whatever blood is pumped here that should rush to the capillary side and Venus side during the diay now if arterials are open too much most of blood will run forward and pressure in the dle will fall but if arterials are too narrow they're tight do you think blood which is present during the dle here can it easily move so blood will be retained gain on the arterial side and pressure in the arterial tree during the dly will be also increased and we say that diastolic blood pressure increase there's increase in diastolic blood pressure so that was our Target what was the Target that when we were losing the blood systolic and diastolic blood pressure were going down by increasing the Veno constriction and venos return we we increase the cardiac output and systolic blood pressure by increasing the arterial constriction we reduce the movement of blood from arterial side to the Venus side and blood which is strapped here even in during di it maintain the pressure up is it right but story is not yet over meanwhile in tensin 2 will also go to cells here and these cells in the outer what is this Zona GL Loa these are the cells and outer adrenal cortex these cells are called Zona glosa and what are the receptors here these cells also have receptors which are receptors for angot tensin 2 when ensin 2 work here what happens when inot tension two work over here these cells start releasing a substance called ELO sterone and tenson two will act on zagosa and lead to the release of elderone what this elderone will do this oston now let's see how oston work okay I will draw just one cell here this is one cell I enlarged and this cell is called principal cell principal cell the P cells in last part of nephron usually they are in second part half of the distal convol tubules and they're present in collecting tubules what are these cells principal cells actually this is let's suppose the nucleus of principal cell it has different genes here of course every nucleus has genes now listen what eloin will do this oston which is released by from where Zog it will come into circulation through the circulation it will reach to the P cells and what it will do this oston will come here let's suppose this is the elderone when elderone enter into this cell there it will find The receptors for elderone and let's suppose this is the receptor for elderone so this is a very special type of protein which act like a key and this key is operated by which which substance elderone this is elderone operated receptors what they do as soon as oston bind this protein rush to the nucleus and open the locks of the genes what is it is going to do open the locks of the genes when Gene number one is opened by this osone receptor complex Gene number one start making a special type of protein and that protein is planted into into basolateral membrane what is this basil size and lateral side of which cells principal cells so these special proteins are planted into basil lateral membrane under the direction of Elo sterone what these proteins are doing are they doing anything important or just Paras fashion yeah what these proteins are doing these are sodium potassium 0 PES okay they are present in every cell but in this kidney cell they present on basolateral membrane and not present on luminal membrane but under the direction of oston the concentration of sodium potassium 80 pages on the basolateral membrane has been increased so what really happens that these cells these are sodium potassium pump so they keep on throwing the sodium from the cell to extracellular environment so cells start throwing the sodium from its cytoplasm to the blood and at the same time J must be knowing they are accumulating in the cell what is this potassium these are sodium potassium pumps so it means under the influence of oston principal cell start throwing the sodium from their cytosole to the inum and start accumulating potassium so these cells become extremely poor in sodium and extremely rich in potassium under the directions of aldosterone mediated enhanced sodium potassium atpases then Gene number two is also activated by the same gene number two is also activated by the same receptor system elderone receptor when second Gene is stimulated this produces a product which will not not go to the basolateral membrane which will product will come and it will be planted into what is this luminal membrane the special protein which is product of the second Gene this protein fits into luminal side and what is this protein this is sodium channels these are not pump these are simply channels they let the sodium pass freely as sodium want to move now whatever little amount of sodium will come here if this cell is extremely poor in sodium sodium will rush in you know things move from high concentration to low concentration as soon as sodium come in through the pump it is thrown to the blood this is how sodium is reabsorbed under the direction of elderone that elderone first enhances the activity of the sodium potassium atpases so that cells keep on pushing too much sodium from the cell to the blood cells become extremely poor in sodium then sodium automatically start shifting from the what is this nephron Lumin to the cell and from the cell to the blood is that right so that sodium which was about to be lost into urine is reabsorbed and you know who loves to follow sodium who loves to follow sodium I think it's water right so naturally sodium is reabsorbed along with that water is also reabsorbed and of course s is rich in potassium so third Gene is activated and third Gene make pottassium channels and potassium is more inside the cell or in the Lumen inside the cell even he knows good so what will happen pottassium will start leaking out so under the direction of what under the direction of elderone principal cells start reabsorbing sodium and water to the blood and start secreting the extra potassium into urine is that right now this salt and water this salt and water or you can say simply sodium and water which is retained in the blood they will decrease the blood volume or increase the blood volume so it's very easy if blood volume is increased if blood volume is increased then Venus return will yes increase so cardiac ventricular fillings will increase ventricular contractility will increase and systolic blood pressure will go up this is how elderone by retaining salt and water take the systolic blood pressure up another support to that ELO Angiotensin 2 has done this work through the ELO now Angiotensin do will ensin 2 will go to the central nervous system I think it's a long travel and it will work on receptors present in the hypothalamus andot tensin 2 will go and work with the receptors on hypothalamus and force some neurons in hypothalamus and they will activate action potential which will reach to the posterior pitor and from there what will come out don't tell me any funny thing what will come out from posterior P ADH don't tell me oxytocin that is not going to help the patient right now right so now otens 2 has made a long travel going to the hypothalamus stimulate which nucleus enens 2 ADH Su optic nuclei excellent super optic nuclei stimulated and eventually the super optic nucleus have the nerve endings and posterior pitutary still and from there ADH come into blood what ADH will do I will know not going to detail just trust me I'm right what ADH will do it will make the last part of the Nephron more permeable to water it will under the direction of ADH right the cells of last part of the Nephron become more permeable to water is that right and you know that last part of the Nephron is going to Meda of the kidney is that right and when this nefron is moving towards the med medular interum m interum is hyper smaller do you know that or not when I will teach you kidneys you will know that very clearly that mid interum is hyperm osity here is very high when this part of the nefron become water permeable here fluid is hypos smaller here fluid is hypers smaller water will move from hypos area it will be pulled to hyperosmolar area so water will Rush from where yes from the last part of the nefron from the Lumen water will rush through the cells to the interstitium so there will be increase water reabsorption so that water should not be lost into urine is that right and this water which is coming back it's too easy to understand this water will increase blood volume increase Venus return of course increase cardiac feeling increase contractility increase stroke volume increase cardiac output increase systolic blood pressure again we reach to the blood pressure it again reach the blood pressure is it right am I clear any other function of simp inot tensin 2 extremely important function of inot tensin 2 yet not mentioned is it is a super stimulator of sympathetic nervous system this is a super stimul lat of sympathetic nervous system so inot tensin two receptors are present even lot of component of sympathetic nervous system so what really happens look here central sympathetic outflow will increase number one then these cells in the ganglia sympathetic ganglia they are also stimulated First Central sympathetic outflow is stimulated then these gangas are stimulated then if this is the post ganglionic now ending and let's suppose this is the target tissue on which this nerve ending is ending this target tissue may be Venus smooth muscle this may be arterial or smooth muscle or this target tissue may be myocardium normally what happen that post King lanic sympathetic nerve endings release nor epinephrine nor epinephrine work on The receptors and once norepinephrine which is released and has done its action on the receptor it 80% of it is taken back by the nerve ending is that right this is normal physiology now what enot trans will do here enot tensin 2 has receptors here also it will stimulate the nerve ending in such a fashion the release of norepinephrine will be increased and reup of the norepinephrine will be reduced so amount of norepinephrine which is present in this area is reduced or increased if n ending is producing more neine if n ending under the direction of hensi 2 is releasing more norepinephrine and not recapturing it then amount of norrine present in the synapse is less or more it is more if you are releasing something more and not taking it back that that thing will be there less or more you know it so in this way norepinephrine will be more in this area and even Angiotensin 2 has receptors which increase the ex adrenergic receptor concentration on the target tissue so it means what inin 2 is doing it is increasing the whole parameters of sympathetic nervous system increasing the sympathetic Central sympathetic outflow increase increasing stimulation of sympathetic ganglion increase stimulation of sympathetic nerve ending increase responsiveness of Target tissue I'll see what will happen with this look if sympathetic nervous system works more on the veins veins will construct when they will construct further more increase in Venus return know you must tell me more cardiac filling more contractility more cardiac output and more stroke volume sorry more increase in systolic blood pressure right this Veno construction meanwhile when sympathetic activities increased on the arterial more arterial construction and increasing diastolic blood pressure when sympathetic activity increase and releases more norepinephrine here more reles of renin whole system is Amplified is that right and then we should not forget something very important Ino tensin 2 has receptors on the central thirst system so when Ino tensin 2 work on the those group of neurons which control the feeling of thirst patient who is bleeding he will feel thirsty of course he will ask water and if you have it he will take the water and try to increase blood volume again that is helpful by all these means what angot tensin 2 I must say by all these means raining inot tensin elderone excess what it is doing it is trying to elevate the blood volume and blood pressure is that right am I clear to everyone no problem this is physiological functions of angot tensin 2 and elderone but one most important pathological function I did not tell you there are some diseases in which blood flow to kidneys chronically low for example if you have congestive cardiac failure if you have a cardiac failure heart has a very poor cardiac output for example I have very severe heart failure my systolic function or contac ility of The ventricle is very poor whatever the reason if my heart is a poor pump my blood flow to every organ is reduced including blood flow to kidneys reduced so all those patients in which heart feel as a pump cardiac output become less then blood flow even to the kidney is reduced and in these patient there's chronic activation of Rainin inot tensin oston Nexis you understand it in the same way who has person has cardiac failure of course is blood pressure also drops so sympathetic stimulation is also chronically activated so patient who have congestive cardiac failure right in them there's chronic sympathetic activation and there's chronic ran inot tensin aldosterone activity when inot tensin 2 level is chronically increased then something really very bad happen what happen if angot tensin 2 is chronically increased and ostero is chronically increased this chronically increased angot tensin 2 right and elderone will work on The myocardium and change the morphology of the heart this is something which is recently discovered but very very important the patient with congestive cardiac failure have chronic elevation of angot tensin 2 and elderone and they chronically work on the myocardial cell and fibroblast there the stimulate the Proto onco genes genes which are concerned with growth these all myocardial cells start producing growth factors if myocardial cells start producing growth factor and these growth factor which are produced by The myocardium work on the myocardial cells so myocardial cell undergo hypertrophy but this is not normal hypertrophy it is pathological hypertrophy at the same time myocardial cells and fibr blast start producing extra ount of connective tissue so myocardial cells become abnormal abnormally enlarged and in between the myocardial cell lot of fibrotic tissue and extracellular Matrix is deposited and these things under chronic influences these things under chronic influences lead to alteration in geometry of the heart chronically elevated elderone levels and chronically activated ensin 2 level in congestive cardiac failure lead to morphological changes in the heart what are these morphological changes myocardial cells undergo pathological hypertrophy and they undergo pathological production of extra cellular metrics and growth factors and many other alteration those all alterations in the lump lumpsum they are called cardiac remodeling so we can say that in congestive cardiac failure due to Chronic elevated elevation of otens 2 and elderone myocardium undergo Progressive pathological geometrical changes or we simply call it as Dr Ral said we simply call it myocardium is undergoing remodeling phenomenon this chronic remodeling of myocardium makes a myocardium more poor contract machinery and patient with congestive cardiac failure under the chronic influences of inot tensin 2 and elderone go under Progressive cardiac failure is it right in the same way chronically elevated enot tensin 2 and elderone also work on the smooth muscles of vessels and bring pathological changes in them so this is one of the most modern concept that if you allow the renin inutan and elderone excess to work pathologically high that will eventually disturb the whole efficient geometry of the heart as well as vasculopathies are produced is that right that is why any patient with congestive cardil at any stage it comes to you either at very early stage or late stage the most important drug is drug which inhibit the angot tensin converting enzyme so that Angiotensin 2 should not be produced and elderone should not be released or alternatively we use the drugs which block The receptors of angiotensin 2 so that Angiotensin 2 blocking receptor blocking drugs are also very effective and not only they change the preload and after load and blood volume but they also reduce the pathological Progressive geometrical changes in the heart they prevent the cardiac remodeling we'll discuss in detail what are these drugs and how they work in the next session