NO and Nitrovasodilators

Question 1

What main factor gets released by endothelium to cause vasodilation and maintain fluidity/flow?

Answer 1

NO (aka EDRF - endothelium derived relaxing factor)

Question 2

What stimuli cause release of EDRF?

Answer 2

Laminar fluid flow (shear stress)
Factors released by aggregating platelets (e.g., ADP, serotonin)
Inflammatory mediators (e.g., histamine, bradykinin)

Question 3

What are the steps of production of NO?

Answer 3

ACh binds to receptors on endothelial cell, activating Ca2+ currents
Calcium binds to calmodulin and activates endothelial nitric oxide synthase (eNOS)
eNOS converts arginine + oxygen –> citrulline + NO

Question 4

How does NO cause vasodilation of vessels?

Answer 4

NO diffuses into smooth muscle cell and activates guanylyl cyclase by binding to the iron in its heme group
Guanylyl cyclase causes increase in cGMP
cGMP causes smooth muscle relaxation, and thus vasodilation

Question 5

What are the NOS inhibitors?

Answer 5

Methylated versions of arginine

L-NMA, tilarginine - monomethylated
ADMA - dimethylated

Question 6

Which NOS inhibitor can be present at inhibitory concentrations and is predictive of CV morbidity?

Answer 6

ADMA

Question 7

How does bacterial infection trigger septic shock?

Answer 7

LPS released by bacterial endotoxins causes release of TNF from host cells
TNF triggers nuclear factors and production of iNOS (inducible)
iNOS produces large amounts of NO
The NO is harmful to bacteria but also to the host

Question 8

What are the 3 subtypes of nitric oxide synthase?

Answer 8

iNOS
eNOS
nNOS

Question 9

Which NOS is active at ambient levels of Calcium and which require a calcium signal to activate them?

Answer 9

iNOS - active at ambient levels

eNOS and nNOS - require signal

Question 10

How does NOS get uncoupled and what occurs?

Answer 10

Oxidase domain of NOS gets uncoupled from reductase domain

NO is no longer formed, instead produces superoxide (a cytotoxic ROS)

Question 11

What occurs at higher concentrations of NO?

Answer 11

Cell death and apoptosis

Question 12

What are the major nitrovasodilators used?

Answer 12

Organic nitrates:
- Glyceryl trinitrate
- Isosorbide dinitrate
- Isosorbide mononitrate
Nitroprusside

Question 13

What vessels does nitroprusside effect?

Answer 13

Veins, coronary arteries, and resistance vessels

Question 14

What vessels do organic nitrates effect?

Answer 14

Venous, coronary arteries, biliary, esophageal smooth muscle, but little effect on resistance vessels

Question 15

When is nitroprusside given?

Answer 15

Hypertensive emergencies

Question 16

What limits the duration that nitroprusside can be given?

Answer 16

Toxic accumulation of thiocyanate

Question 17

What limits the duration that organic nitrates can be given?

Answer 17

Development of tolerance

Question 18

When is organic nitrate given?

Answer 18

To provide sympatomatic relief, prophylaxis and increased exercise tolerance in angina pectoris
- No demonstrated effect on CAD progression and mortality, purely symptomatic relief

Reduce pulmonary congestion (dyspnea) in acute heart failure

Question 19

What are potential adverse effects of organic nitrates?

Answer 19

Headache
Postural hypotension
Tolerance

Question 20

Which organic nitrate has the shortest half life?

Answer 20

Glyceryl trinitrate

Question 21

Do the metabolites of glyceryl trinitrate have any effect?

Answer 21

No

Question 22

What are the metabolites of isosorbide dinitrate and are they active?

Answer 22

isosorbide mononitrates

Active

Question 23

Does isosorbide dinitrate have a shorter or longer half life than isosorbide mononitrate?

Answer 23

Shorter

Question 24

What is the mechanism by which organic nitrate tolerance occurs?

Answer 24

Mitochondrial aldehyde dehydrogenase (ALDH2) is responsible for the bioactivation of glyceryl trinitrate
ALDH2 has two sulfhydryls, one of which gets nitrosylated by nitroglycerine
Then get formation of disulfide bond, resulting in oxidized ALDH2 and release of nitrite
Mitochondria convert nitrite to free NO

Accumulation of oxidized ALDH2 is responsible for organic nitrate tolerance and oxidative stress
Takes time for reduction of enzyme back to active state

Question 25

In what population is there a loss of glyceryl trinitrate efficiency?

Answer 25

G-to-A loss of function polymorphism in ALDH2, common in East asians

Question 26

What other symptoms is the ALDH2 polymorphism associated with?

Answer 26

Alcohol intolerance
(acetalydehyde increases --> flush, nausea, palpitations)

Question 27

What effects do organic nitrates have on veins and how does this relate to myocardial O2 supply and demand?

Answer 27

Venodilation –> decreased preload
Decreased wall tension = decreased O2 demand
Increased subendocardial perfusion = increased O2 supply

Question 28

What effects do organic nitrates have on coronary arteries and how does this relate to myocardial O2 supply and demand?

Answer 28

Coronary artery dilation

Increased perfusion = increased O2 supply

Question 29

What effects do organic nitrates have on TPR and how does this relate to myocardial O2 supply and demand?

Answer 29

Reduced TPR (effect small)
Decreased afterload = decreased O2 demand

Question 30

Why is the selective vasodilation provided by organic nitrates beneficial, especially in the setting of myocardial ischemia? (remember, organic nitrates have no effect on resistance vessels)

Answer 30

Venodilation along with lowering left ventricular diastolic pressure (decreased preload) allows more blood flow to be diverted to the vulnerable region

Question 31

What happens if selective arteriolar dilating agent is used in the setting of myocardiac ischemia?

Answer 31

Will dilate vessels in nonischemic area and divert flow away from the hypoxic area

Question 32

Why should nitrovasodilators and PDE5 inhibitors not be combined?

Answer 32

Both will increase cGMP levels, causing extreme potentiation of vasodilator effects, enhancing the parasympathetic erectile response