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Discuss the pathway of heart failure and neurohormonal activation

Poor ventricular function or Myocardial damage leads to insufficient SV, CO and tissue perfusion

--> Neurohormonal Activation:

1) Increased sympathetic

2) Vasoactive peptides like RAS, Vasopressin, Endothelin, Natriuretic

3) Inflamm mediators like PGs and cytokines

--> Vasoconstriction, Salt and water retention, hypertrophy/remodeling

--> Further ventricular dysfunction and heart failure 


Why are NSAIDs avoided in heart failure?

renal function depends on prostaglandin synthesis 


What triggers Renin release?

Decreased CO, volume, vascular resistance, BP leads to

decreased glomerular BP, decrease NaCl sensed at macular Densa and increased NE release

All act to increase Renin 


What is ACE and how does it work/what does it do?

What about ACE2?

ACE = cleaves AG1 to AG2 in the lungs

ACE2 = makes AG1-7 from excess AG2 and AG1-7 is a counter-regulatory peptide that acts as a dilator and reduces atherogenic effects 


What are the 3 different forms/classes of RAS inhibitors and some drugs within each category?

ACE-Inhibitors = Captopril, Enalapril, Lisinopril -"Prils"

Angiotensin Receptor Blockers (ARBs) = Losartan and Valsartan

Renin Inhibitors = anti-HTN not used in HR = Akiskiren


What are all the effects of Ag2?

1) Rapid Presser Response - vasoconstriction and enhanced sympathoadrenal activity

2) Slow Presser response - increase Aldosterone to increase Na reabsorption 

3) Alter CV structure by increasing TGF-Beta nd increasing Fibrosis

4) Hemodynamic alteration of CV structure - vascular and cardial hypertrophy and remodeling 


What is the relation of RAS to bradykining and Prostaglandins?

ACE converts AG1 to AG2

ACE also inactivates Bradykinin 

BRadykinin is a Potent endothelium dependent vasodilator that acts on the B2 receptor to release NO 


What are the adverse effects of ACE inhibitors?

Chronic Cough



What are the ACE-Inhibitors and the differences between them?

First Generation - Sulfhydryl

Captopril  - Sulfhydryl group, renal excretion (can lead to kidny dysfunction!), Short halflife

Second Generations: no sulfhydril 

Enalapril - no sulfhydryl (carboxyl instead), pro-drug convered and longer hlaf life, renal excretion (Can lead to kidney dysfunction!) 


Fosinopril - Prodrug with Bile exretion so less effects on kidney


What are the common adverse effects of Sulfhydryl drugs?

Dysguesia, skin rash, nephropathy, neutropenia 


What are the Mineralcorticoid receptor antagonists? Side effects? 

Sprinolactone and eplerenone

USed when increased Aldosterone which can cause volume overload, fibrosis, hypertrophy etc


Eplenerone - no side effects

Spironolactone - Gynecomastia and irregular menstrual periods 


What anti-HTN drugs raise serum K+? significance?

ACE inhibitors, Beta blockers, and MRA 

Careful for hyerkalemia leading to increased malaise, palpitations, weaness that can lead to sudden death!


What are the signaling pathways, tissue responses, expression and blockers for angiotensin receptor subtype AT1?

AT1 signal with increased phospholipase and tyrosine kinase, decreased Adenylyl cyclase;

AT1 cause vasoconstriction, aldosterone, Adrenergic potentiation, myocyte hypertrophy, vascular hypertrophy, and hyperplasia

See down-regulation in CHF

Blocked by ARBs -AT-1 selective!!!!! 


What are the signaling pathways, tissue responses, expression and blockers for angiotensin receptor subtype AT2? 

AT2 signal through Tyrosine phosphatase

AT2 cause vasodilation, antiproliferation and differentiation 

AT2 bad effects cause Plaque rupture and adverse vascular remodeling 

AT2 expressed only during development and increased in CHF



Differences between ACE-Inhib and ARBs?

ACE reduces AG2 and responses to BOTH AT1 and AT2 

ARB are antiogensin receptor blockers blocking AT1 response and so potentiation of AT2 response which could be bad in CAD bc could see plaque rupture 


Benefits of using ACE, ARB or Renin inhibitor?

Fall in BP that can be potentiated in combination with Diuretic 

regression of LVH and icnreased survival in CHF

Inhibition of vascular hyperplasia

Renal Function preserved in Diabetes!!! 


Adverse effects in using ACE, ARB, Renin inhib?

Dizziness and hypotension - potentiated with dehydration



Renal failure if Renal Artery Stenosis!!!




Explain compensated vs decompensated heart failure?

Compensated = adequate Na excretion from kidneys (ANP can balance RAS) 

Decompensated = RAS wining over ANP 


What are the A, B, and C types of Natriuretic peptides? Released from where to act on where and do what?

A-type released from stretch in Atria 

B-type released from Ventricular stretch

C-type released from vascular endothelium - ONLY acts Locally 


Supress RAS, Vasodilate to lower TPR, Incrase natriuresis and lose Na 


What is used as a biomarker for dysfunction in CHF?

Pro-BNP used to measure release of ANP and is cleavage product from propeptide to make Pro-BNP and BNP 


How do the natriuretic peptides work? what stops them?

activate guanylyl clcase A to convert GTP to cGMP and cause increased NA excretion, vasodilation, lusitropy etc 


Neprylisin is the endopeptidase that breaks them down