Block B - RAAS

Question 1

what kind of system is RAAS ?

Answer 1

The Renin angiotensin system (RAS) is a hormone system which regulates blood pressure and water ( fluid/electrolyte) balance in the body.

Question 2

when is RAAS activated and response ?

Answer 2

The Renin angiotensin system is activated by low sodium levels and sympathetic nerve stimulation , this will trigger the release of renin from the kidney, this is important in breaking down angiotensinogen from the liver into angiotensin I. Then the angiotensin I is converted to angiotensin II by the enzyme ACE found in the vascular endothelium. Angiotensin II is a potent vasoconstrictor and this stimulates the release of aldosterone from adrenal medulla in the kidneys to enhance sodium reabsorption. This is a cyclical effect and all the factors mentioned above leads to sodium retention.

Question 3

what will high RAAS activity lead to ?

Answer 3

High activity of RAS will result in high blood pressure.

Question 4

angiotensinogen ?

Answer 4

Angiotensinogen is the starting point for the renin angiotensin system, it is produced in the liver.

Question 5

broken down by into what

Answer 5

The angiotensinogen is broken down to the product angiotensin I by the enzyme renin released from the kidneys. Angiotensin –1 can then be broken down further into angiotensin II by the enzyme ACE (angiotensin converting enzyme) which is primarily found in capillaries of the lungs but can also be found in endothelial and kidney epithelial cells.

Question 6

what can angiotensin I be converted to angiotensin III by ?

Answer 6

Angiotensin 1 can also be converted to angiotensin III by the enzyme aminopeptidase.

Question 7

Ang1-7 ?

Answer 7

Ang 1-7 is biologically active compound and has counteractive actions to Ang II. It is produced from angiotensin II by the enzyme ACE2.

Question 8

Renin ?

Answer 8

Renin is secreted from the kidney and it’s release is controlled by blood pressure, NA+ and sympathetic nerves. Tissue renin is highly specific and it’s only substrate is angiotensinogen which is broken down into angiotensin I.

Question 9

circulating renin ?

Answer 9

Produced by the juxtaglomerular cells of the kidney and release is controlled by blood pressure, [Na+] and sympathetic nerve activity

Question 10

tissue renin ?

Answer 10

Found constitutively in various tissues of the body, components of the RAS found in heart, blood vessels and cardiovascular centres. Components produced locally or captured from circulation.

Question 11

regulation of renin by kidney ?

Answer 11

Renin release occurs from the kidney due to sympathetic nerve stimulation, the adrenaline released will act on the beta one receptors of the kidney triggering the release of renin. Furthermore, perfusion pressure is important in triggering renin release, low renal blood pressure will activate prostaglandins which trigger renin release from kidneys. Another contributing factor to renin release is low sodium levels in the kidney this activates prostaglandins which in turn trigger renin release.

Question 12

actions of Angiotensin II ?

Answer 12

The main effect of angiotensin II is that it is a potent vasoconstrictor and stimulator for aldosterone secretion. It has a direct effect on the kidney to cause Na+ and water retention (proximal tubular effect). This leads to raised blood volume and raised BP.

Question 13

feedback inhibiition ?

Answer 13

Feedback inhibition of renin secretion occurs and this increases sympathetic nerve activity. Furthermore, this stimulates secretion of Anti Diuretic Hormone which will also lead to increased blood pressure.

Question 14

AT1 receptors ?

Answer 14

Angiotensin II acts at AT I receptors, these receptors recognise both angiotensin II and angiotensin III but angiotensin II binds more readily. These receptors are activated during vasoconstriction and more chronically during cardiac hypertrophy

These receptors are GPCR which are coupled to phospholipase C, leading to an increase IP3 formation and intracellular concentration of calcium which increases smooth muscle cell contraction leading to vasoconstriction.

Question 15

chronic activation of AT1 receptors ?

Answer 15

Chronic activation of these receptors will lead to sustained activity which can lead to vascular remodelling and cardiac vascular remodelling which can put the person a risk for developing cardiovascular disease.

Question 16

immediate effect of AT1 receptors ?

Answer 16

The immediate effect of the ATI receptors is the binding of angiotensin II , the early / acute phase is the increase in IP3 levels leading to a rise in calcium levels and contraction of smooth muscle cells. The later/chronic effect is the sustained activation leading to changes in nuclear signalling , protein synthesis and vascular remodelling.

Question 17

AT2 receptors ?

Answer 17

AT2 receptors are more likely to bind angiotensin III , but can equally bind angiotensin II. These receptors once activated evoke effects that are opposite to those produced by stimulation of AT1 receptors. Thes lead to vasodilatation, antiproliferative effects and antithrombotic effects.

Question 18

At1 vs AT2 numbers ?

Answer 18

It is important to note that effects of AT1 receptors outweigh the effects of AT2 receptors and these are what drive the vasoconstriction and lead to hypertension

Question 19

substrates for ACE ?

Answer 19

ACE has a number of substrates such as angiotensin I , bradykinin , enkephalins and substance P. Due to this , if a drug is nonspecific , certain side effects can occur due to the various substrates ACE acts on.

Question 20

what are captopril , enalapril , lisinopril , fosinopril and ramipril and effects ?

Answer 20

ACE inhibitors

inhibit the formation of angiotensin II by preventing the conversion of angiotensin I. There are some consequences of ACE inhibition such as a fall in circulating angiotensin II, and a reduced aldosterone secretion as angiotensin II levels have fallen will cause an increase in sodium and water excretion which decrease plasma volume and BP. Ultimately this leads to a reduction in the peripheral vascular resistance (PVR) and reduction in blood pressure. There is also a reduction in the sympathetic nerve activity which will also reduce PVR and BP.

Question 21

overall effect of ACE inhibitors ?

Answer 21

The overall effect of ACE inhibitors by reducing the aldosterone release, resulting in the knock on effects mentioned above will decrease blood pressure.

Question 22

consequences of ACE inhibitors ?

Answer 22

By inhibiting the ACE enzyme this will result in an increased renin release form the kidneys to increase the levels of angiotensin I, so that limited conversion to AngI-7 occurs via ACE2 enzyme or other routes.

There are increased levels of bradykinin, a substrate for ACE which causes vasodilation, anti-proliferation and antithrombotic actions. Angiotensin 1-7 acts on the Mas receptor which causes vasodilation anti-proliferation and antithrombotic actions.

Question 23

ACE inhibitors and hypertension >

Answer 23

ACE inhibitors are used for hypertension as they decrease blood pressure by reducing PVR. They cause the inhibition of bradykinin breakdown may play a role due to it’s vasodilatory properties. There is an increased formation of angiotensin 1-7 which opposes actions of Angiotensin II.

Question 24

diuretic effect of ACE inhibitors

Answer 24

The diuretic effect of ACE inhibitors helps to “unload” the heart to improve cardiac function. The local inhibition of ACE may directly prevent the development of hypertrophy due to the chronic AngII effects on cell function/growth

Question 25

effect of increased angiotensin 1-7 ?

Answer 25

has an opposite effect compared to AngII which has hypotensive actions to reduce blood pressure.

Question 26

side effects of ACE inhibitors ?

Answer 26

Adverse effects of ACE inhibit include hypotension and renal failure in certain patients . The most common effect is a cough which can be problematic in some patients (incidence can occur in up to 35% patients). The underlying cause is unclear but thought to be due to accumulation of bradykinin and substance P could contribute.

Other adverse effects include angio-oedema which occur in 0.1-0.68 % of patients, this is swelling of dermis/sub-cutaneous tissue. This is thought to be mediated by bradykinin and substance P (potent vasodilators causing vascular permeability and fluid leakage)

The adverse effects on foetus include renal failure, renal dysplasia, hypotension, pulmonary hypoplasia, oligohydramnios so they are not recommended to take during pregnancy.

Question 27

losartan , valsartan , irbesartan and candesartan and effects ?

Answer 27

Angiotensin receptor blocking drugs include losartan, valsartan, irbesartan and candesartan. These drugs block the ability of angiotensin II to bind to the receptors. These drugs to not prevent the formation of angiotensin II, instead they prevent the ability to bind and produce their effects, blocking vasoconstriction, aldosterone production and sodium retention.

Question 28

effects of AT1 receptor blockers ?

Answer 28

Broadly similar pharmacology to that of ACE inhibitors but they do not decrease angiotensin II levels and they do not a cause cough so are often used in patients who cannot tolerate the cough associated with ACE inhibitors

Question 29

aliskiren and effects ?

Answer 29

Renin inhibitors

hey effects are broadly similar in pharmacology to that of ACE inhibitors and effective in lowering BP which will reduce angiotensin I levels so they should not cause cough as are not influencing ACE activity and bradykinin production. A possible risk is the combination of aliskiren and ACE inhibitors/ARBs in patients with kidney impairment as this will increase hypotension and increase side effects in patients that are more at risk.

It remains to be established if they are as effective and as safe as ACE inhibitors , they are used but not as widely as ACE inhibitors and AgII receptor inhibitor.

Question 30

clinical uses of renin inhibitors ?

Answer 30

ACE Inhibitors and ARB’s used predominantly in hypertension but also heart Failure as they improve exercise tolerance and reduce mortality. Usually combined with a diuretic.

They can also be used in patients who have suffered a myocardial infarction , as they will have underlying hypertension. For treatment of HF, current BNF guidelines recommend an ACE inhibitor plus beta blocker to achieve improved left ventricular function in the heart and exercise tolerance. This is usually combined with a diuretic to help decrease the load on the heart.