Vasoactive drugs Flashcards
Describe the physiologic process that can generate endogenous nitric oxide.
*Generated from the oxidation of the guanidine group of arginine (L-arginine –> L-citrulline)
(Exposure to bacterial LPS result in the generation of NO in the macrophage.)
Name the pharmacological actions of NO.
- Smooth m relaxation
- Decreased (white) cell adhesion
- Decreased E-selectin on endothelial surface
- Inflammatory response
- Neurotransmitter
- Platelet inhibitor
What is the physiological purpose of NO release in the bv following injury?
NO counteracts the vasoconstriction process
What enzymes can synthesize NO?
Identify the isoforms of the enzymes responsible for the synthesis of nitric oxide.
Nitic oxide synthase
- NOS-1, neuronal NOS, or nNOS
- NOS-2, inducible NOS, or iNOS
- NOS-3, endothelial NOS, or eNOS
What cels possess NOS-2?
Inducible iNOS
- Macrophages, smooth m. cells
Which of the NOS isoforms have a calcium requirement?
NOS-1 (neuronal) and NOS-3 (endothelial) only
What are 2 ways by which NO is deactivated?
- Heme
- Free radicals superoxide
Name 4 inhibitors of NO.
- L-arginine Derivatives (L-NMMA, L-NAME)
- Inhibitors of nitric oxide synthase synthesis
- Inhibitor of binding of arginine to NOs
- Scavengers of NO
Excess production of NO results in the generation of ______________, which is toxic to cells. Thus, NO inhibitors may be helpful in the treatment of sepsis related disorders.
Peroxynitrite
What is the MoA of N-monomethyl-L-arginine? (L-NMMA)
(not that important)
NO inhibitor
Competitive inhibitor–binds arginine binding sites in NOS
What is the MoA of N-nitro-L-arginine methyl ester? (L-NAME)
(not that important)
NO inhibitor
Competitive inhibitor, binds arginine binding site in NOS
Is L-NMMA selective or non-selective?
What about L-NAME?
(not that important)
Non-selective
Non-selective
7-nitroindazole: MoA?
Is it selective or nonselective?
(not that important)
NO inhibitor. Competitive inhibitor–binds both tetrahydrobiopteran and arginine binding sites in NOS
Partially selective for NOS-1
BBS-2: MoA?
Selective or non-selective?
(not that important)
NO inhibitor: Inhibits iNOS dimerization
Also weakly inhibits eNOS and nNOS
Hemaglobin: MoA?
NO scavenger
*What are the effects of NO within the cell?
Activates GC –> cGMP
- Also generates several reactive nitrogen derivatives by interacting w/ O2 and superoxide radicals.
- These oxides of nitrogen are highly reactive and unstable, interact with numerous proteins, lipids, nucleic acids and metabolize.
Compare and contrast the beneficial and toxic effects of nitric oxide.
- The beneficial effects include smooth muscle relaxation, vasodilation, immune regulation, anesthetic and anti-athlerosclerotic responses.
- The pathologic responses include free radical formation, nitrosation and irritant effects.
How could decreasing NO affect BP?
Increase BP
How is NO related to reperfusion?
lNO has been shown to protect against ischemic and reperfusion injury.
How is NO level altered in shock?
NO levels increased, markedly
Septic shock:
Bacterial infection and LPS B activate _________, resulting in hypotension, shock and possible death. This effect is reversed by NO inhibitors such as the L-NMMA.
iNOS (NOS-2)
How does atherosclerosis affect NO?
What vascular effects does this lead to?
Impairs NO formation
results in vascular defects and increased cellular proliferation
_____________ and _____________ are useful in the treatment of atherosclerotic disorders.
L-arginine and nitric oxide donors
Explain in detail how NO affects platelets.
NO is a potent inhibitor of platelet adhesion, activation, aggregation, & regulates the release of 5-HT, growth factors, and TXA from platelets.
Platelets contain constitutive and inducible NOS’s
