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Adv Pharm 1 > Smooth Muscle (pt 4/4) Nitric Oxide > Flashcards

Smooth Muscle (pt 4/4) Nitric Oxide Flashcards

1
Q

What is the difference between N2O and NO2?

A

N2O = Nitrous Oxide (anesthetic gas)
NO2 = Toxic Pulmonary Irritant

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2
Q

What is Nitric Oxide?

A

-A highly reactive gaseous signaling molecule
-Readily diffuses across cell membranes
-Endogenous to the human body
-Potent Vasodilator
-Platelet Inhibitor
-Immune Regulator
-Neurotransmitter
-Exogenous NO and NO-releasing compounds used in pharmacology (Nitrates, nitrites, nitroprusside, nitroglycerin)
-A naturally occurring environmental pollutant
-The major bioactive component of Endothelial-Derived Relaxing Factor (EDRF)
-Acts on vascular smooth muscle → relaxation

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3
Q

A gas that can diffuse through cell membranes.
-Triggers biochemical reactions
-Dissipates rapidly
-Synthesized & released by normal endothelium
-Regulated by endothelial ICF Ca++
↑ cytosol Ca++ ⇒ NO production
-Synthesis induced by increased stress

A

Nitric Oxide

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4
Q

Increased cytosol Ca++ causes what?

A

Nitric Oxide Production

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5
Q

What substances lead to increased cytosol Ca++ (leading to increased Nitric Oxide)?

A

Ach
Bradykinin
Catecholamines
Substance P
ADP

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6
Q

What is the MOA of Nitric Oxide?

A

-Vasodilation via guanylyl cyclase activation (↑cGMP)
-Inhibits platelet aggregation (Anti-thrombotic effect)
-Inhibits platelet derived vasoconstrictive substances
-Produced in leukocytes, fibroblasts, & vascular smooth muscle

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7
Q

The synthesis of Nitric Oxide is made by 1 of 3 enzymes that are expressed in a wide variety of cell types. What are the 3 enzymes?

A

nNOS (NOS-1)
iNOS (NOS-2)
eNOS (NOS-3)

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8
Q

What is nNOS (NOS-1)?

A

nNOS (NOS-1) – neuronal
Triggered by ↑ intracellular Ca2+

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9
Q

What is iNOS (NOS-2)?

A

-inducible or macrophage
-Triggered by inflammatory mediators
-Has constitutive activity

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10
Q

What is eNOS (NOS-3)?

A

eNOS (NOS-3) – endothelial
Triggered by ↑ intracellular Ca2+

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11
Q

NO mediates its effects by ______ modification of proteins.

A

covalent

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12
Q

How does Nitric Oxide interact with metals (Metalloproteins)?

A

-NO interacts with metals especially Heme
-NO binds to the heme of sGC (primary target)
-Synthesizes GTP to cGMP to activate Protein Kinase G (PKG)
-Reduce Ca2+ levels in blood vessels
-Decreases vascular tone
-Decreases vascular smooth muscle contraction
-Mechanism contributes to cytotoxic effects r/t NO overproduction
-NO inhibits the heme of heme-containing CYP450 enzymes
-Major cause of inflammatory liver disease

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13
Q

How does Nitric Oxide overproduction contribute to inflammatory liver disease?

A

Nitric Oxide binds to heme, synthesizing GTP to cGMP and activating Protein Kinase G (PKG).
-NO Inhibits the heme of heme-containing CYP450 enzymes
-Major cause of inflammatory liver dz

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14
Q

How does Nitric Oxide interact with Thiols?

A

-Compounds containing a carbon bonded sulfur + hydrogen group
-NO + (-SH) = nitrosothiol
-Found endogenously in the amino acid cysteine
-Unknown physiologic role

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15
Q

What is Tyrosine Nitration?

A

-NO undergoes both oxidation and reduction reactions
-NO reacts very efficiently to superoxide
-Superoxide = O2- (a free radical; Synthesized by many cellular enzymes)
-NO + (O2-) = OONO- (Peroxynitrite – highly reactive oxidizing agent that causes DNA damage, Nitration of tyrosine, and Oxidation of cysteine to disulfides or sulfur oxides)
-Reaction is mitigated by glutathion
-NO synthesis is increased in many inflammatory and degenerative diseases (Shown by Increasing Peroxynitrite levels and Increased tyrosine nitration = irreversible protein modification (Activate or inhibit protein function) )
-(+) Detection of tyrosine in tissues is a sign of oxidative stress
-Accumulation of toxins, peroxides and free radicals

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16
Q

What is Superoxide (O2-)?

A

A free radical synthesized by many cellular enzymes.

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17
Q

Nitric Oxide + Superoxide (O2-) = ?

A

Peroxynitrite (OONO-): a very highly reactive oxidizing agent.

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18
Q

What are the effects of Peroxynitrite (OONO-)?

A

-DNA damage
-Nitration of tyrosine
-Oxidation of cysteine to disulfides or sulfur oxides

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19
Q

What mitigates the reaction of Nitric Oxide + Superoxide to Peroxynitrite?

A

Glutathione

20
Q

NO synthesis is ________ in many inflammatory and degenerative diseases.

A

Increased

21
Q

Increased Nitric Oxide synthesis in inflammatory and degenerative diseases leads to ?

A

-Increasing Peroxynitrite levels
-Increased tyrosine nitration = irreversible protein modification (Activate or inhibit protein function).

22
Q

What is a sign of oxidative stress?

A

(+) Detection of tyrosine in tissues
Accumulation of toxins, peroxides and free radicals

23
Q

Endogenous vasodilators (Acetylcholine or bradykinen) activate NO synthesis in the luminal endothelial cells, leading to ?

A

Endogenous vasodilators (Acetylcholine or bradykinen) activate NO synthesis in the luminal endothelial cells, leading to calcium efflux from the endoplasmic reticulum into the cytoplasm

24
Q

Increased Calcium into the cytoplasm causes Ca to bind to _____, which activates _______, resulting in ____ synthesis from _______.

A

Calcium binds to calmodulin (CaM), which activates NO synthase (eNOS), resulting in NO synthesis from L-arginine.

25
Q

NO diffuses into smooth muscle cells, where it activates ________ and _____ synthesis from ______.

A

NO diffuses into smooth muscle cells where it activates soluble guanylyl cyclase and cGMP synthesis from guanosine triphosphate (GTP).

26
Q

cGMP binds to and activates ______, resulting in an overall reduction in calcium influx and _______ of calcium-dependent muscle contraction.

A

cGMP binds to and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx and inhibition of calcium-dependent muscle contraction.

27
Q

PKG can also block _____ that lead to muscle contraction.

A

PKG can also block other pathways that lead to muscle contraction.

28
Q

cGMP signaling is terminated by ______, which convert cGMP to ______.

A

cGMP signaling is terminated by phosphodiesterases, which convert cGMP to GMP.

29
Q

What is the primary approach to decreasing Nitric Oxide generation in cells?

A

NOS Inhibitors.

30
Q

What is the structure of NOS Inhibitors?

A

Structure = Arginine analogues
Bind to the NOS arginine-binding site

31
Q

NOS’s are structurally _____, so most meds are non-selective.

A

NOS’s are structurally similar so most meds are non-selective

32
Q

nNOS Inhibition is useful in what disorders?

A

nNOS Inhibition – useful in neurodegenerative disorders

33
Q

iNOS inhibition is useful in what disorders?

A

iNOS Inhibition – useful in sepsis and inflammatory disorders

34
Q

Concurrent eNOS inhibition impairs what?

A

Concurrent eNOS inhibition impairs hemostatic signaling.
-Vasoconstriction
-Ischemic damage

35
Q

NOS selective drugs are ?

A

Under investigation.

36
Q

What is the MOA of Nitric Oxide donors?

A

Metabolized to release Nitric Oxide and elicit smooth muscle relaxation.

37
Q

Explain the effects of Organic Nitrates.

A

-Ex: Nitroglycerin is metabolized to NO, promoting venous dilation.

Arterial & venous dilation with less effects on platelet aggregation.
-Exhibit tolerance during continuous administration

38
Q

Explain the effects of Organic Nitrites.

A

Arterial vasodilators but abused for euphoric effects.
-Require metabolic activation to elicit vasorelaxation
-Arterial vasodilators
-Do not exhibit tolerance

39
Q

What is the example drug of the Organic Nitrites?

A

Ex: Inhaled Amyl Nitrite

40
Q

What are the effects of Sodium Nitroprusside (Nipride)?

A

Arterial & venous dilation and used to rapidly reduce arterial HTN.
-Dilates arterioles and venules
-Used for rapid pressure reduction in arterial hypertension
-Breaks down to cyanide and NO in the presence of light and via chemical/enzymatic mechanisms

41
Q

What are the effects of NO Inhalation?

A

Reduces PA pressures & improves perfusion of ventilated lung areas.
-Used in the Tx of: Pulmonary HTN, Acute Hypoxia, and CPR.
-Ex: Compressed Gas

42
Q

What reaction can occur with the use of Compressed Gas for NO Inhalation?

A

-Can react with O2=NO2
-Pulmonary irritant = decreased lung function
-Can induce the formation of methemoglobin

43
Q

What is the example drug of the PDE Inhibitors?

A

Sildenafil

44
Q

What are the intended and adverse effects of the PDE Inhibitors?

A

Slows the degradation of cGMP & prolong NO effects.
-Risk for Hypotension, blindness with surgery & anesthesia (ischemic optic neuropathy)

45
Q

Why should you give Newborns with hypoxic respiratory failure due to pulmonary hypertension Inhaled Nitric Oxide?

A

Because it dilates the pulmonary vessels.
↓ Peripheral Vascular Resistance
↓ PA Pressures
↓ V/Q Mismatch due to dilation of lung tissue with better ventilation

46
Q

Does Extracorporeal membrane oxygenation (ECMO) effect pulmonary pressures?

A

No

Adv Pharm 1 (28 decks)

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