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Flashcards in L27 Deck (38):
1

What is the effect of venous dilation?

↓preload

2

What diseases should you try to ↓preload for?

Pulmonary congestion
MI

3

What is the effect of arterial dilation?

↓afterload

4

What is the reflex response to arterial dilation?

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

5

What diseases do you want to ↓afterload for?

Weak pump
Poor organ perfusion - HTN

6

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

Endothelial derived relaxing factor = EDRF
(Aka not just ACh as previously thought)

7

Describe the steps to NO production in endothelial cells

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

8

Describe how NO made in endothelium affects vasc smooth muscle

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

9

What are the 2 parts of NOS enzymes

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

10

Where do you find eNOS - constitutively or transiently expressed?

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

11

Where do you find nNOS - constitutively or transiently expressed?

Neuronal
Always there

12

Where do you find iNOS - constitutively or transiently expressed?

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

13

What does oxidation to do BH4 cofactor

BH4 -> BH2

14

How does BH2 change eNOS activity

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

15

What are NOS inhibitors? What are they predictors of?

ADMA - vasocontrictors
No eNOS - no dilation
Predictive CV morbidity

16

Normal situations that you'd activate iNOS

Bacterial infection
Get toxic levels NO locally to kill infection

17

What 2 things can NO become in circulation

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

18

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

Prusside
- Organic nitrates have little effect on resistance vessels

19

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

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

20

What limits duration of nitroprusside

Accumulation of toxic thiocyanate

21

What limits duration of organic nitrates

Tolerance

22

Disease to use organic nitrates

Angina - symptomatic relief
Acute HF - relieve pulmon congestion

23

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

Hydralazine

24

SEs of organic nitrates

Headache - transient
Postural hypotension

25

3 types of organic nitrates

Nitroglycerin
Isosorbate dinitrate
Isosorbate mononitrate

26

Do nitroglycerin or iso have longer t1/2

Iso

27

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

PO isos
Patch nitroglycerin
The long acting forms

28

What must you encorporate into organic nitrate use to avoid tolerance

8-12 hr free period every 24 hrs

29

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

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

30

What is the fxn of ALDH2 enzyme

Takes organic nitrate --> NO

31

What happens with LOF mutations to ALDH2

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

32

1ary effect of organic nitrates

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

33

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

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

34

Use of PDE5 I for CV diseases

Pulm HTN

35

What drugs can't you prescribe viagra with?

PDE 5 I potentiate nitrovasodilators and should not be combined

36

What are sGC activators

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

37

What are sGC stimulators

Amplify response of reduced sGC to low level NO
= Riociguat

38

Does nitroprusside ↓preload or afterload?

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