NO and Nitrovasodilators Flashcards
What main factor gets released by endothelium to cause vasodilation and maintain fluidity/flow?
NO (aka EDRF - endothelium derived relaxing factor)
What stimuli cause release of EDRF?
Laminar fluid flow (shear stress)
Factors released by aggregating platelets (e.g., ADP, serotonin)
Inflammatory mediators (e.g., histamine, bradykinin)
What are the steps of production of NO?
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
How does NO cause vasodilation of vessels?
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
What are the NOS inhibitors?
Methylated versions of arginine
L-NMA, tilarginine - monomethylated
ADMA - dimethylated
Which NOS inhibitor can be present at inhibitory concentrations and is predictive of CV morbidity?
ADMA
How does bacterial infection trigger septic shock?
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
What are the 3 subtypes of nitric oxide synthase?
iNOS
eNOS
nNOS
Which NOS is active at ambient levels of Calcium and which require a calcium signal to activate them?
iNOS - active at ambient levels
eNOS and nNOS - require signal
How does NOS get uncoupled and what occurs?
Oxidase domain of NOS gets uncoupled from reductase domain
NO is no longer formed, instead produces superoxide (a cytotoxic ROS)
What occurs at higher concentrations of NO?
Cell death and apoptosis
What are the major nitrovasodilators used?
Organic nitrates: - Glyceryl trinitrate - Isosorbide dinitrate - Isosorbide mononitrate Nitroprusside
What vessels does nitroprusside effect?
Veins, coronary arteries, and resistance vessels
What vessels do organic nitrates effect?
Venous, coronary arteries, biliary, esophageal smooth muscle, but little effect on resistance vessels
When is nitroprusside given?
Hypertensive emergencies
What limits the duration that nitroprusside can be given?
Toxic accumulation of thiocyanate
What limits the duration that organic nitrates can be given?
Development of tolerance
When is organic nitrate given?
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
What are potential adverse effects of organic nitrates?
Headache
Postural hypotension
Tolerance
Which organic nitrate has the shortest half life?
Glyceryl trinitrate
Do the metabolites of glyceryl trinitrate have any effect?
No
What are the metabolites of isosorbide dinitrate and are they active?
isosorbide mononitrates
Active
Does isosorbide dinitrate have a shorter or longer half life than isosorbide mononitrate?
Shorter
What is the mechanism by which organic nitrate tolerance occurs?
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
In what population is there a loss of glyceryl trinitrate efficiency?
G-to-A loss of function polymorphism in ALDH2, common in East asians
What other symptoms is the ALDH2 polymorphism associated with?
Alcohol intolerance (acetalydehyde increases --> flush, nausea, palpitations)
What effects do organic nitrates have on veins and how does this relate to myocardial O2 supply and demand?
Venodilation –> decreased preload
Decreased wall tension = decreased O2 demand
Increased subendocardial perfusion = increased O2 supply
What effects do organic nitrates have on coronary arteries and how does this relate to myocardial O2 supply and demand?
Coronary artery dilation
Increased perfusion = increased O2 supply
What effects do organic nitrates have on TPR and how does this relate to myocardial O2 supply and demand?
Reduced TPR (effect small) Decreased afterload = decreased O2 demand
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)
Venodilation along with lowering left ventricular diastolic pressure (decreased preload) allows more blood flow to be diverted to the vulnerable region
What happens if selective arteriolar dilating agent is used in the setting of myocardiac ischemia?
Will dilate vessels in nonischemic area and divert flow away from the hypoxic area
Why should nitrovasodilators and PDE5 inhibitors not be combined?
Both will increase cGMP levels, causing extreme potentiation of vasodilator effects, enhancing the parasympathetic erectile response
