8. Intro to Cardiovascular Pharmacology

Question 1

How does the nervous system control circulation?

Answer 1

The heart is innervated by both sympathetic and parasympathetic limbs of the autonomic nervous system
All the blood vessels are innervated primarily by the sympathetic nervous system
Whenever blood pressure (BP) increases, there is a decrease in heart rate and cardiac contractility via baroreceptor mediated reflex decrease in HR

BP=CO x TPR
CO=HR x SV

Question 2

What are the 5 things the release of norepinephrine from sympathetic nerve endings leads to?

Answer 2

1. Vasoconstriction of resistance type arterioles (⬆️TPR, ⬆️BP, ⬆️afterload)
2. Reabsorption of tissue fluid as a result of a decrease in capillary resistance
3. ⬆️venoconstriction- capillary vesicles (⬆️venous return, ⬆️preload)
4. Release of renin and increase in renin-angiotensin II- aldosterone activity (indirect- ⬆️blood volume, ⬆️plasma Na+)
5. Increase in HR and cardiac contractility (β adrenergic effect)

Question 3

What does increase sympathetic drive lead to?

Answer 3

Increased activation of β1 receptor mediated renin release from the renal juxta glomerular cells that promotes angiotensin II (Ang II) generation (potent endogenous vasoconstriction)

Question 4

What is angiotensin II (Ang II)?

Answer 4

Potent endogenous vasoconstrictor
Stimulated aldosterone release from the adrenal cortex to promote increased blood volume and elevated plasma Na+

⬆️vasoconstriction, ⬆️blood volume, ⬆️plasma Na+ = ⬆️BP (cause for hypertension)

Slide 6 CV pharm

Question 5

What is the renin-angiotensin-aldosterone system (RAAS or RAS)?
What happens with high and low BP?

Answer 5

In physiological condition, when BP, blood volume, plasma Na+ FALL, there is ⬆️renal sympathetic drive that leads to β1-R mediated RENIN release
⬆️Ang II-ALDO to ⬆️BP

When BP is normal or high, less sympathetic drive & reduced renin release
When BP falls, there is increased sympathetic drive and increased renin release, renin promotes Ang II production, Ang II promotes sympathetic activation, vasoconstriction, and aldosterone production to enhance blood volume and BP

Slide 7 CV pharm

Question 6

Study the pathway of liver to control of blood pressure through Ang II on slide 8-9 CV pharm

Answer 6

Okay

Question 7

What does renal β1-R stimulation promote?

Answer 7

Renin release

β1 R-blockade promotes ⬇️renin production ⬇️blood pressure

Slide 9 CV pharm

Question 8

What does a FALL in blood volume, blood pressure (BP), and plasma Na+ lead to?

Answer 8

Activates reflex increase in sympathetic drive
⬆️norepinephrine
Kidney JG cells
Renin
Liver (angiotensin)
Angiotensin I
Angiotensin II - ADR complex - aldosterone - ⬆️Na+⬆️BV
Angiotensin II - VSMC - Vasoconstriction - ⬆️BP⬆️TPR

Slide 10 CV pharm

Question 9

What does atenolol do?

Answer 9

β1 blocker (they inhibit renin release)
⬇️CO

⬇️RAS- ⬇️afterload- ⬇️TPR ⬇️BP

⬇️RAS- ⬇️preload- ⬇️venous return

⬇️RAS- ⬇️Na+ & blood volume

Slide 10 CV pharm

Question 10

What is aliskiren, enalapril, losartan, spironolactone, and eplerenone?

Answer 10

Aliskiren- renin inhibitor - ⬇️BP

Enalapril- ACE inhibitor (work on the Ang II level) - ⬇️BP

Losartan- AT1-R [Ang II] blocker (ARB) (blocks Ang II induced vasoconstriction & aldoster) - ⬇️BP

Spironolactone- K+ sparing diuretic - ⬇️BP

Eplerenone- K+ sparing diuretic - ⬇️BP

Slide 10-11 CV pharm

Question 11

What are the 4 things that occur when angiotensin II is decreased?

Answer 11

Ang II converting enzyme (ACE) inhibitors decrease renin-induced Ang II formation, this leads to decreased aldosterone release from adrenal cortex (decrease blood volume and Na)

1. Decreased output of sympathetic nervous system
2. Increased vasodilation of vascular smooth muscle
3. Decreased aldosterone production which leads to decreased retention of sodium and water
4. Increased levels of bradykinin

All contribute to decreased blood pressure

Question 12

What is the vasopressin system?

Arginine vasopressin AVP

Answer 12

Vasopressin (or antidiuretic hormone ADH) is released from the posterior pituitary gland
Plays major role in the reabsorption of water from the collecting ducts in the kidneys
Restored plasma volume
Also powerful vasoconstrictor agent in pharmacological doses

⬆️AVP ⬆️BV ⬆️CO ⬆️BP

Question 13

What is the atrial natriuretic peptide (ANP)?

Answer 13

ANP is released from atria in response to plasma volume expansion
Exerts both natriuretic [excretion if Na+ along with water and vasodilatory effects]

Question 14

Activation of sympathetic nervous system leads to what ultimately?

Answer 14

Increase TPR (vasoconstriction)
Reabsorption of tissue fluid
Decrease vascular capacitance

ACTIVATION OF RAAS OR RAS

Question 15

Where do ACh (acetylcholine) and BK (bradykinin) act on?

Answer 15

Act on endothelial cell (EC) to cause endothelium dependant smooth muscle cell relaxation via nitric oxide (NO) release

Slide 15 CV pharm

Question 16

Where do sodium nitroprusside (SNP) and nitrovasodilators (nitrates, hydralazine) act on?

Answer 16

SNP and nitrovasodilators act directly on smooth muscle cell and cause endothelium-independent relaxation

They mimic and act like nitric oxide (NO) but have no NO moiety in their structures that activate sGC

Slide 15 CV pharm

Question 17

What do NO, prostacyclin (PGI2), and EDHF do?

Answer 17

NO, PGI2, and EDHF release from endothelial cell and cause endothelium-dependant vasodilation of adjacent VSMC
Also decreases blood pressure

Slide 16 CV pharm

Question 18

What does endothelin-1 (ET-1) do?

Answer 18

ET-1 is secreted from endothelial cell and acts on ETa and ETb receptors
Both ETa and ETb receptors are contributing to pulmonary hypertension

ET-1 promotes vasoconstriction in vascular smooth muscle and increase blood pressure via activation of vascular ETa & ETb receptors

ETb bound ET-1 is internalized and degraded in the lungs & kidney

ET-1 is a 21 amino acid peptide
ET-1 releases NO

Question 19

What is bosentan?
What is ambrisentan?
What is macitentan?

Answer 19

Bosentan is a non-selective endothelin (ETa/b) antagonist

Ambrisentan is a selective ETa antagonist

Macitentan is a non-selective ETa/b antagonist
Blocks both ETa and ETb receptors
Better effectiveness in management of pulmonary hypertension than ambrisentan because lower degree of adverse effects

ET-1 antagonists are useful in treatment of pulmonary hypertension
Not efficacious in overcoming essential HT