8. Vasodilators (2) Flashcards
What are the three mechanisms of renin secretion?
Detected by volume in central veins and baroreceptors in carotid arteries and aortic arch leading to disinhibition of renal sympathetic nerves
Pressure-sensitive granular cells also respond directly to localised fall in renal arterial pressure by secreting renin
Reduced GFR and delivery of sodium to the macula densa cells
What is the action of neuroendocrine RAAS in response to plasma volume?
See slide 6
What is the mechanism of action of aldosterone?
Steriod hormone
Regulates gene expression
See slide 7
What is vasopressin?
An anti-diuretic hormone
What is the mechanism of action of vasopressin?
See slide 8
What is the mechanism of action for controlling water permeability of collecting duct?
Vasopressin binds to G protein-coupled V2 receptors on basolateral membrane of prinicipal cells in collecting duct
Leads to migration of vescicles containing preformed water channels to apical membrane
AQP-2 channels released from vesicles and inserted into membrane, increasing water permeability
Channels of AQP -3/-4 already in basolateral membrane allow passage of water into hyperosmolar medullary intersitium
How does angiotensin II maintain glomerular filtration?
AngII contracts renal mesangium
AngII also contricts renal efferent arteriole
Where is the location of AT1 receptor subtype?
Blood vessels Heart Kidney Brain Lungs Liver Adrenal and pituary glands
What is the function of AT1 subtype?
Vasoconstriction Cardiac contractility Remodelling of heart and vessels Release of aldosterone and vasopressin Drinking/thirst noradrenaline release Negative feedback on renin release
Where is the location of AT2/
Mainly in brain
Reproductive tissue
Heart and foetal tissue
What is the function of the AT2 receptor?
Embryogenesis
Anti-proliferative effects
Vasodilation via bradykinin and nitric oxide release
Look
At slide 12
What are the actions of ACE inhibitors?
Peripheral vasodilation and decrease in BP
Decrease in aldosterone secretion
Decrease in sympathetic activation
Increase in bradykini/PG vasodilation
Decrease in angiotensin mediated generation of ROS
Decrease glomerular filtration rate
Decrease hypertension related remodelling
Give some examples of ACE inhibitors?
Cantopril
Enalapril
More common - longer duration Lisinopril Ramipril Perindopril Trandolapril
What are clinical uses of ACE inhibitors?
Hypertension
Post-MI especially if associated with ventricular dysfunction
In people at high risk of ischaemic heart disease
Heart Failure
Diabetic nephropathy (especially Type 1)
Progressive renal insufficiency
How does abnormal activity of RAAS contribute to development of hypertension?
Sodium retaining effects
Vasoconstrictor effects
Structural remodelling
Describe pathophysiology of systolic heart failure?
Reduced cardiac output and blood pressure trigger compensatory activation of RAAS to maintain tisue perfusion, promote remodelling
Progressively inadequate/deleterious
Frequent hospitalisation
Significant morbidity and mortality
What are the befenfits of RAAS blockade?
Reduce cardiac afterload Reduce cardiac preload enhance diuresis Regress LVH and risk of arrhythmias Reduce cardiac work and ischaemia Improve cardiac output Preserve potassium Reduce symptoms Slow progression, reduce frequency and severity of hospitalisation
What are adverse effects of ACEIs?
Dry cough and angiooedema Acute renal failure first dose hypotension hyperkalaemia Teratogenticity
What is angioedema?
Vascular reaction, localised oedema due to dilation and increased permeability of capillaries, development of giant wheel
What do ACE inhibitors interact with?
Diuretics
Potassium-sparing diuertics
Hypotensive agents
NSAIDS
What are the precautions for use of ACEI?
Low dose when starting - monitor BP and renal function
Avoid starting the drug in eastablished renovascular disease
Watch for K+ rising and avoid potassium supplements and K sparing diuretics
Probably contraindicated in severe aortic stenosis
DO NOT GIVE IF PREGNANCY PLANNED
What do ARBs do?
Antagonise effects of AngII at AT1 receptors
Do not prevent metabolism of vasodilator mediators such as bradykinin
Examples of ARBs?
Losartan
Irbesartan
Valsartan
Candesartan1
