22 NO and nitrovasodilators

Question 1

types of NO synthase

which are constitutive?

Answer 1

• *eNOS** - endothelium required
• *iNOS** - macrophages fighting bacteria

nNOS - produced in neural tissue

eNOS and nNOS are constitutively active but require calmodulin to be active

iNOS is active straight out da ER

Question 2

which are active agents?
inorganic nitrites
inorganic nitrates

organic nitrites

organic nitrates

Answer 2

“inorganic nitrates are inactive! NO3-

organic nitrates/nitrites, and inorganic nitrites are all active!
“

Question 3

organic nitrates

Answer 3

GTN/nitroglycerin

isosorbide dinitrate

isosorbide mononitrate

Question 4

NOS inhibitors

Answer 4

“L-NMMA

ADMA

endogenous products of arginine(competitively bind eNOS)
“

Question 5

amino acid producing NO

Answer 5

“arginine

arginine + O2 —-> citrulline + NO via eNOS
“

Question 6

indications for organic nitrates

Answer 6

• *angina pectoris** - prophylaxis, exercise tolerance, symptom relief
• *acute heart failure** - reduces pulmonary congestion

   combo w/hydralazine = good for heart failure too

Question 7

how does GTN tolerance develop?

how to prevent development?

Answer 7

ALDH2 inactivation –> reduces organic nitrates

causes oxidative stress once ALDH2 is inactivated

8-12hr nitrate free period each day to prevent tolerance

Question 8

effect of organic nitrates

Answer 8

• *venodilation** - less wall tension, more subendocardial perfusion
• *coronary dilation** - increased perfusion, resistance vessels unaffected

reduction in TPR(small) - decreased afterload, reflex tachycardia

Question 9

why are PDE5 inhibitors contraindicated with nitrovasodilators?

Answer 9

PDE5 usually regulates cGMP

cGMP is potentiated by NO

if NO potentiates cGMP AAAAND PDE5 is inhibited, there will be BIG PROBLEMS

Question 10

coronary steal

Answer 10

nitrovasodilators(nitroprusside) that open up resistance vessels in the heart end up diverting blood AWAY from ischemic areas

usually vessels supplying ischemic tissue are fully vasodilated, so if you dont mess with resistance vessels, ischemic tissue should get perfused if you open up the larger vessels above the resistance

Question 11

administration of organic nitrates

Answer 11

• *GTN** - sublingual, IV, buccal –> volatile!
• *isosorbide dinitrate** - sublingual, oral

isosorbide mononitrate - oral

Question 12

bioactivation of GTN

Answer 12

GTN is reduced by ALDH2 to NO2-

NO2- is converted by mitochondrial enzymes to NO

Question 13

amelioration of organic nitrate tolerance

Answer 13

antioxidants - folate, ascorbate