Cardiovascular Peptides and Drugs Self Study Flashcards
What are the effects of endothelin-1 on blood pressure?
It acts at ET-A and ET-B receptors.
ET-A receptors promote vasoconstriction
ET-B receptors promote both vasodilation and vasoconstriction
Net effect of ET-1 injection is transient hypotension followed by prolonged hypertension
How does ET1 modulate smooth muscle and cardiac muscle?
It is a potent mitogen, causing vascular remodelling and cardiac hypertrophy.
If we can block it, we can block lots of hypertension and remodeling conditions like atherosclerosis, MI, and coronary artery disease
What stimulates release of ET1?
In low sheer stress, vasoconstrictors like AT2, thrombin, and other cytokines increase its synthesis.
PGI2 and No decrease its synthesis
It is released by the vascular endothelium
What is the primary drug which is an endothelin inhibitor, its indication, and major untoward effect?
Bosentan, indicated for atrial pulmonary hypertension
-> think of boss man stan giving the “end of the line” slip for endothelin
Teratogenic and fatally hepatotoxic (think of the sweat spot on his shirt)
What are the important natriuretic peptides and what do they respond to / do?
ANP, BNP, and urodilatin
They respond to increased atrial stretch and are released by ventricular myocardium. They have natriuresis + diuresis + vasorelaxant effects
What tends to increase the release of natriuretic peptides?
Anything that increases blood volume overtime, like heart failure, chronic renal failure, primary aldosteronism, and vasoconstricting hormones (epinephrines, endothelins, vasopressin, etc)
What is BNP a good marker of?
Severity of heart failure
What are the physiological mechanisms behind natriuretic peptide action?
Interacts with ANP - guanylyl cyclase increasing cGMP
- Sodium and water loss via increased GFR
- Decreased proximal tubule sodium uptake
- Inhibition of RAA axis and ADH
- Direct decreasing of arterial blood pressure
How are the natriuretic peptides like ANP cleared?
Bind to receptors on endothelial cells, internalized and degraded. Also degraded by natural endopeptidase “NEPRILYSIN”
What are two natriuretic peptide drugs?
Nesiritide - recombinant BNP - it’s necessary to turn the tide!
Ularitide - recombinant urodilatin
What are nesiritide and ularitide indicated and what is their main untoward effect?
Indicated in decompensated heart failure, to reduce sympathetic tone, RAA, and reduce blood pressure to increase cardiac output
Main side effect is fatal renal failure
What is the drug which can inhibit neprilysin and what is it given with?
Sacubitril, given with valsartan, an AT1 receptor antagonist
-> approved for heart failure
Why is neprilysin an interesting Alzheimer’s target?
It is an endogenous endopeptidase which cleaves many substrates, including amyloid beta peptide.
It is the rate limiting step in beta-amyloid degradation -> upregulating it may be effective in treating Alzheimer’s
