Flashcards in L27 Deck (38)
What is the effect of venous dilation?
What diseases should you try to ↓preload for?
What is the effect of arterial dilation?
What is the reflex response to arterial dilation?
1. ↓BP - baroreceptor decreased firing - ↑sympa - ↑HR
What diseases do you want to ↓afterload for?
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
Ca-calmodulin couples these into a catalytically active enzyme
Where do you find eNOS - constitutively or transiently expressed?
Always there - varying levels of intracell Ca tell on/off
Where do you find nNOS - constitutively or transiently expressed?
Where do you find iNOS - constitutively or transiently expressed?
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
Interacts with existing NO --> bad molecules
Oxidized heme subunit of sGC = unresponsive to NO
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
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?
- Organic nitrates have little effect on resistance vessels
Nitroprusside or organic nitrates: release NO enzymatically and selectively in target cells
- Prusside releases NO non-enzymatically in circulation (stays intravascular)
What limits duration of nitroprusside
Accumulation of toxic thiocyanate
What limits duration of organic nitrates
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
SEs of organic nitrates
Headache - transient
3 types of organic nitrates
Do nitroglycerin or iso have longer t1/2
What are the forms of organic nitrates that you can form tolerance to?
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