L27 Flashcards
What is the effect of venous dilation?
↓preload
What diseases should you try to ↓preload for?
Pulmonary congestion
MI
What is the effect of arterial dilation?
↓afterload
What is the reflex response to arterial dilation?
- ↓BP - baroreceptor decreased firing - ↑sympa - ↑HR
2. ↑renin
What diseases do you want to ↓afterload for?
Weak pump
Poor organ perfusion - HTN
What is an endothelium specific product that mediates arterial smooth muscle relaxation?
Endothelial derived relaxing factor = EDRF
Aka not just ACh as previously thought
Describe the steps to NO production in endothelial cells
+ ACh, shear stress, other stimuli
↑Ca2+ –> calmodulin –> eNOS on
Arginine + O2 (eNOS) –> NO
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
What are the 2 parts of NOS enzymes
Oxidase domain
Reductase domain
Ca-calmodulin couples these into a catalytically active enzyme
Where do you find eNOS - constitutively or transiently expressed?
On endothelium
Always there - varying levels of intracell Ca tell on/off
Where do you find nNOS - constitutively or transiently expressed?
Neuronal
Always there
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
What does oxidation to do BH4 cofactor
BH4 -> BH2
How does BH2 change eNOS activity
Makes superoxide
Interacts with existing NO –> bad molecules
Oxidized heme subunit of sGC = unresponsive to NO
NO VASODILATION
What are NOS inhibitors? What are they predictors of?
ADMA - vasocontrictors
No eNOS - no dilation
Predictive CV morbidity
Normal situations that you’d activate iNOS
Bacterial infection
Get toxic levels NO locally to kill infection
What 2 things can NO become in circulation
NO3 = nitrate - stored in salivary glands NO2 = nitrite - reservoir in blood for hypoxia and acidosis
Nitroprusside or organic nitrates: relaxes veins, coronary arteries AND resistance vessels?
Prusside
- Organic nitrates have little effect on resistance vessels
Nitroprusside or organic nitrates: release NO enzymatically and selectively in target cells
Organic nitrates
- Prusside releases NO non-enzymatically in circulation (stays intravascular)
What limits duration of nitroprusside
Accumulation of toxic thiocyanate
What limits duration of organic nitrates
Tolerance
Disease to use organic nitrates
Angina - symptomatic relief
Acute HF - relieve pulmon congestion
What drug are organic nitrates combined with to reduce HR M&M
Hydralazine
SEs of organic nitrates
Headache - transient
Postural hypotension
3 types of organic nitrates
Nitroglycerin
Isosorbate dinitrate
Isosorbate mononitrate
Do nitroglycerin or iso have longer t1/2
Iso
What are the forms of organic nitrates that you can form tolerance to?
PO isos
Patch nitroglycerin
The long acting forms
What must you encorporate into organic nitrate use to avoid tolerance
8-12 hr free period every 24 hrs
What is the mechanism of organic nitrate tolerance? How do you resolve this?
Inactivate ALDH2 enzyme via oxidative stress
+ antioxidants - why + hydralazine
What is the fxn of ALDH2 enzyme
Takes organic nitrate –> NO
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)
1ary effect of organic nitrates
Venous > arterial dilation ↓preload = ↓LV DP ↓O2 demand ↑O2 supply via subendo perfusion = good for MI
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
Use of PDE5 I for CV diseases
Pulm HTN
What drugs can’t you prescribe viagra with?
PDE 5 I potentiate nitrovasodilators and should not be combined
What are sGC activators
Mimic NO at heme-free sGC
Use when tissue already suffered oxidative stress (can’t use nitrates)
What are sGC stimulators
Amplify response of reduced sGC to low level NO
= Riociguat
Does nitroprusside ↓preload or afterload?
Dilates resistance vessels = arterial dilation
↓afterload = FAST ↓BP
Ex: use if hear mitral regurg
