RAAS

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Renin-Angiotensin-Aldosterone System (RAAS)

Supports SNA - boost NA release, stimulates aldosterone secretion and Na and water excretion

*renin controls how active the system is (produced by juxtaglomerular cells in the kidney)

Angiotensinogen - alpha globulin produced by liver

Angiotensin I - biologically inactive (converted by ACE to Angiotensin II)

Angiotensin II - *main active form* negative feedback to induce production of renin

Angiotensin receptors are bound and activated by angiotensin II G-protein coupled receptors

AT1 = cardiovascular effects

AT 2 = foetal development + growth

AT 3 = may be involved in control of aldosterone

ACE = membrane bound and found in endothelial cells, produced by lung and is found elsewhere in the body (important in managing vascular tone)

*Angiotensin II responsible for actions

Effects of angiotensin:

vasoconstriction

thirst - kidneys susceptible

sympathetic nervous system activation (increasing amount of NA released)

ADH release

Aldosterone release

Fluid and sodium retention

*increase effective circulating volume and blood pressure*

stimulate cell growth in heart and arteries, short term effects don't have much of an impact but sustained AT 2 - hyperplasia and hypertrophy, cardiac remodelling

Distribution of aldosterone receptors is restricted to certain sites - lots in kidney

Aldosterone:

steroid hormones - receptors are intracellular (mineral-corticoid)

increase Na channel proteins and increase Na/K ATPase pump - retain Na

Can cause vasoconstriction and endothelial dysfunction

Effect on CNS to stimulate SNS

If things go wrong and system becomes over-active = pathophysiology of heart failure

Mal-adaptive change - adapting to the system contributing to heart failure (can directly target RAAS and receptors)

Role of RAAS in disease:

heart failure

hypertension

acute MI

stroke

diabetic nephropathy

Pharmacological intervention in the RAAS:

direct renin inhibitors

ACE I

angiotensin receptor blockers

aldosterone antagonists

Inhibitors of Angiotensin II:

Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)

Angiotensin II receptor antagonists

prevent formation of AT2 by inhibiting ACE

ACE inhibitors - mechanism of action:

AT I moves into active site and binds at specific points and is converted to AT II = cleavage point breaks off 2 amino groups

Pharmacodynamic effects of ACE inhibitors:

modest, balanced vasodilators with important neuroendocrine modulatory effects

arteriolar and venodilation

decrease plasma aldosterone

enhanced sodium and water excretion

reduced oedema

AT2 - act to increase glomerular filtration - can result in hypertension in glomerulus which can cause renal damage

ACE counteracts this and reduces loss of nephrons

ACE inhibitors: pharmacodynamic effects:

improve clinical signs

improve quality of life

increase survival

Side effects:

hypotension

renal impairment

hyperkalaemia

risk of high K due to messing with Na re-absorption

Pharmacokinetics:

renal/hepatic elimination

food can decrease bioavailability

Angiotensin II receptor antagonists:

direct action at angiotensin II receptors

responsible for vast majority of cardiovascular effects

target receptors directly

block A2 formed by other routes

can result in decreased blood pressure and decreased proteinuria

hypotension, decrease red blood cell count

given orally and excreted unchanged in the faeces

*ACE I lead to decreased aldosterone - levels fall for a short period of time and then come back to normal - aldosterone escapes angiotensin system

Aldosterone antagonists block aldosterone = what you want to achieve in heart failure patient (in dogs adverse effects - reversible prostatic atrophy and in cats - skin reactions)