L27

Question 1

What is the effect of venous dilation?

Answer 1

↓preload

Question 2

What diseases should you try to ↓preload for?

Answer 2

Pulmonary congestion

MI

Question 3

What is the effect of arterial dilation?

Answer 3

↓afterload

Question 4

What is the reflex response to arterial dilation?

Answer 4

1. ↓BP - baroreceptor decreased firing - ↑sympa - ↑HR

2. ↑renin

Question 5

What diseases do you want to ↓afterload for?

Answer 5

Weak pump

Poor organ perfusion - HTN

Question 6

What is an endothelium specific product that mediates arterial smooth muscle relaxation?

Answer 6

Endothelial derived relaxing factor = EDRF

Aka not just ACh as previously thought

Question 7

Describe the steps to NO production in endothelial cells

Answer 7

+ ACh, shear stress, other stimuli
↑Ca2+ –> calmodulin –> eNOS on
Arginine + O2 (eNOS) –> NO

Question 8

Describe how NO made in endothelium affects vasc smooth muscle

Answer 8

Diffuses into v.s.m
Binds heme subunit of sGC = activate
GTP –> cGMP
↑cGMP = smooth muscle relaxation

Question 9

What are the 2 parts of NOS enzymes

Answer 9

Oxidase domain
Reductase domain
Ca-calmodulin couples these into a catalytically active enzyme

Question 10

Where do you find eNOS - constitutively or transiently expressed?

Answer 10

On endothelium

Always there - varying levels of intracell Ca tell on/off

Question 11

Where do you find nNOS - constitutively or transiently expressed?

Answer 11

Neuronal

Always there

Question 12

Where do you find iNOS - constitutively or transiently expressed?

Answer 12

Inducible
Need TF to activate expression - transiently expressed
When there, enough baseline Ca-calmodulin to activate enzyme immediately
Caution of cytotoxic NO levels

Question 13

What does oxidation to do BH4 cofactor

Answer 13

BH4 -> BH2

Question 14

How does BH2 change eNOS activity

Answer 14

Makes superoxide
Interacts with existing NO –> bad molecules
Oxidized heme subunit of sGC = unresponsive to NO
NO VASODILATION

Question 15

What are NOS inhibitors? What are they predictors of?

Answer 15

ADMA - vasocontrictors
No eNOS - no dilation
Predictive CV morbidity

Question 16

Normal situations that you’d activate iNOS

Answer 16

Bacterial infection

Get toxic levels NO locally to kill infection

Question 17

What 2 things can NO become in circulation

Answer 17

NO3 = nitrate - stored in salivary glands
NO2 = nitrite - reservoir in blood for hypoxia and acidosis

Question 18

Nitroprusside or organic nitrates: relaxes veins, coronary arteries AND resistance vessels?

Answer 18

Prusside

- Organic nitrates have little effect on resistance vessels

Question 19

Nitroprusside or organic nitrates: release NO enzymatically and selectively in target cells

Answer 19

Organic nitrates

- Prusside releases NO non-enzymatically in circulation (stays intravascular)

Question 20

What limits duration of nitroprusside

Answer 20

Accumulation of toxic thiocyanate

Question 21

What limits duration of organic nitrates

Answer 21

Tolerance

Question 22

Disease to use organic nitrates

Answer 22

Angina - symptomatic relief

Acute HF - relieve pulmon congestion

Question 23

What drug are organic nitrates combined with to reduce HR M&M

Answer 23

Hydralazine

Question 24

SEs of organic nitrates

Answer 24

Headache - transient

Postural hypotension

Question 25

3 types of organic nitrates

Answer 25

Nitroglycerin Isosorbate dinitrate Isosorbate mononitrate

Question 26

Do nitroglycerin or iso have longer t1/2

Answer 26

Iso

Question 27

What are the forms of organic nitrates that you can form tolerance to?

Answer 27

PO isos Patch nitroglycerin The long acting forms

Question 28

What must you encorporate into organic nitrate use to avoid tolerance

Answer 28

8-12 hr free period every 24 hrs

Question 29

What is the mechanism of organic nitrate tolerance? How do you resolve this?

Answer 29

Inactivate ALDH2 enzyme via oxidative stress | + antioxidants - why + hydralazine

Question 30

What is the fxn of ALDH2 enzyme

Answer 30

Takes organic nitrate --> NO

Question 31

What happens with LOF mutations to ALDH2

Answer 31

Less responsive to organic nitrates - more at risk for tolerance + coronary spasm LOF associate with alochol flushing syndrome (aldehyde build up)

Question 32

1ary effect of organic nitrates

Answer 32

``` Venous > arterial dilation ↓preload = ↓LV DP ↓O2 demand ↑O2 supply via subendo perfusion = good for MI ```

Question 33

Why is it good that organic nitrates do no dilate coronary resistance vessels?

Answer 33

Avoid coronary steal Vessels to damaged area are already dilated to allow BF there Dilating elsewhere will remove that compensation

Question 34

Use of PDE5 I for CV diseases

Answer 34

Pulm HTN

Question 35

What drugs can't you prescribe viagra with?

Answer 35

PDE 5 I potentiate nitrovasodilators and should not be combined

Question 36

What are sGC activators

Answer 36

Mimic NO at heme-free sGC | Use when tissue already suffered oxidative stress (can't use nitrates)

Question 37

What are sGC stimulators

Answer 37

Amplify response of reduced sGC to low level NO | = Riociguat

Question 38

Does nitroprusside ↓preload or afterload?

Answer 38

Dilates resistance vessels = arterial dilation ↓afterload = FAST ↓BP Ex: use if hear mitral regurg