Pharacology - Nitric Oxide & endothelial dsfunction

Question 0

L-arginine ————> X & X
X & X & X

Xs = ?

Answer 0

L-arginine ————–> L-citruline & NO

NO synthase & NADPH & O2

Question 1

What is the substrate used for the biosynthesis of NO?

Answer 1

L-arginine

Question 2

Role of NO in

Cardiovascuar system?
Immunesystem?
Nervous system?

Answer 2

Cardiovascular system - vasodilation by smoothmuscle relaxation
Immunesystem - elimination of pathogen by macrophages, leukocytes & neutrophils
Nervous system - neurotransmitter

Question 3

Name four functions of NO in epithelial cells?

Answer 3

1 epithelium dependent vasodilation
2 prevention of adhesion of leukocytes and platelets to endotheliu
3 prevention of platelet aggregation
4 production of NO in epithelial cells prevent smooth muscle cell proliferation

Question 4

endothelium-dependent vasodilation, mechanism?

Answer 4

e.g. bradykinin/ACh/stress-induced Ca influx activates eNOS which synthesizes NO. NO binds with smooth muscle cell guanylyl cyclase —-> increased cGMP. Elevated cGMP levels dephosphorylate MLC and intervene in the binding of Myosin-Actin, thereby producing smooth muscle relaxation.

Question 5

What are the most important physiologial effects on CV system by administering NO?

Answer 5

vasodilation of veins > large arteries&raquo_space; arterioles

= decreased preload, redistribution of coronary flow to ischemic areas

Question 6

What is a major adavantge of administering NO-mimetics rather than arteriolar vasodilators in coronary disease?

Answer 6

It does not cause coronary steal phenomenon.

Question 7

NO contraindication?

Answer 7

right-sided heart failure

Question 8

Three situations where giving organic nitrates and molsidomine are indicated?

Answer 8

stable angina, variant angina(pain relief)
MI(before hospitilization)
pulmonary edema(with high blood pressure)

Question 9

Two situations where giving sodium nitroprusside(I.V.) is indicated?

Answer 9

1 hypertensive crisis(also dilates arterioles)

2 heart insufficiency(w/high blood pressure)

Question 10

Name five factors with the propensity to cause endothelial injury?

Answer 10

1 disturbed blood flow
2 inflammatory cytokines
3 oxidized lipoproteins
4 Advanced Glycosylation End products
5 Homocysteine

Question 11

Describe the effects of endothelial injury on the

vascular system(diameter)?
smooth muscle cells?
Leukocyte recruitment?

Answer 11

1 Vascular system - decreased PGI2 and EDRF = vasospasm(low diam.)
2 SMooth muscle cell - expression of GF and mitogens = increased SMC proliferation, migration & ECM product.
3 Leukocyte recruitment - elevated chemoattractants and Leukocyte adhesion molecules

Question 12

NOS cofactors?

Answer 12

FMN, FAD, NADPH, BH4 - tetrahydrobiopterin

Question 13

Name four drugs that may reverse edothelial dysfunction

Answer 13

1 statins
2 ACE-inhibitors
3 new Ca-blockers
4 new Beta-blockers

Question 14

Sildenafil, mechanism of action?

Answer 14

Binds and inactivates phosphodiesterase 5, which usually degrades cGMP.

Question 15

Two conditions where sildenafil and tadalafil are used?

Answer 15

Male sexul dysfunction

Pulmonary hypertension

Question 16

Nitrates - sildenafil contrindications?

Answer 16

Nitrates are contraindicated within 24 hours after sildenafil administration, due to risk for hypotonia

Question 17

Three ways by which L-arginine/NO pathway is inhibited?

Answer 17

1 Glucocorticoids inhibit biosynthesis of inducible NOS
2 Synthetic arginine analogues compete with L-arginine
3 Endogenous NOS inhibitors PIN & ADMA

Question 18

Three actions of CO as signaling molecule?

Answer 18

1 Vasodilation
2 Inhibition of inflammation
3 Inhibition of apoptosis

Question 19

Superoxide anion + NO = ?

Answer 19

Peroxynitrate(ROS). Increased levels are seen in people with dysfunctional endothelium.

Question 20

Three NOS isoenzymes are?

Answer 20

1 cNOS - constitutively NOS1
2 iNOS - inducible NOS2
3 eNOS - endotelial NOS3