CR2 EOY1S (+ 17 Qs at end) Flashcards
Name 3 sources of endogenous NO [4]
Endogenous NO is derived from:
- Endothelium
- Nerve fibres
- Skeletal Muscle
- Tunica intima
What are the 2 endogenous forms of NOS need to know? [2]
Where are each found? [2]
Are they Ca2+ dependent or independent? [2]
Nitric oxide synthase enzyme (NOS)
NOS type I: neuronal NOS, nNOS
- Found in central & peripheral neuronal cells and muscle
- Calcium dependent
NOS type III: endothelial NOS, eNOS
- Vascular endothelial cells
- Calcium dependent
Decsribe the structure of NOSs xx
NOS: oxidoreductase homodimer enzymes:
- Oxygenase domain: binding for NADPH, FMN & FAD
- Reductase domain: binding for BH4, heme and L’arginine (substrate
- Calmodulin binding site: in between reductase and oxidase domains
What happens to NOS if there is / isn’t BH4 present?
BH4 present: causes dimerisation and proper catalytic activity for NO formation
BH4 absence: causes monomer, becomes a superoxide
For the formation of NO using NOS, what substrates are essential? [3]
Which co-factors are essential? [5]
For the formation of NO using NOS, what substrates are essential? [3]
- L-arginine
- O2
- NADPH
Which co-factors are essential? [5]
- FAD
- FMN
- BH4
- haem
- calmodulin.
OXYGEN is essential for the synthesis. Because of the oxygen requirement, NO synthesis is inhibited in hypoxic tissue
Explain MoA of endothelial NO synthase creating NO
- Normally: eNOS associates with Caveolin 1 in caveolae (invaginations of plasma membrane) this inhibits calmodulin complex (CaM) binding to eNOS
- Shear stress promotes wall stretching, which promotes the dissociation of eNOS from caveolae
- This allows eNOS release into the cytoplasm and its activation (through binding of a Ca2+/ calmodulin (CaM) complex)
- M2-muscarinic acetylcholine receptor activation or other stimulation initiates an influx of Ca2+ that binds to calmodulin.
- eNOS dissociates from Cav1 and then combines to Ca/CaM.
- eNOS is activated leading to synthesis of NO.
[] shear stress favors the activation of eNOS by releasing endothelium-dependent agonists.
What are they? [4]
Increased shear stress favors the activation of eNOS by releasing endothelium-dependent agonists.
Agonists stimulated NO formation:
* Acetylcholine (M3muscarinic)
* Bradykinin
* Substance-P
* Adenosine
Where is nNOS found in the brain? [4]
In brain, nNOS is present in:
- autonomic nitrergic nerves: innervating cerebral arteries and arterioles
- brain neurons
- mature skeletal muscle
- present in on muscle sarcolemma attached to dystrophin
Explain MoA of NO evoking vasodilation
- NO activates guanylate cyclase (GC) in vascular smooth muscle
- This converts guanosine triphosphate to cyclic guanosine monophosphate cGMP
- cGMP acts through cGMP-dependent protein kinases (PKGs) to inactivate myosin.
- The net effect of raised cGMP is to inhibit contraction.
Explain how NO release, during exercise counteracts sympathetic NS xx
During exercise:
- Sympathetic nervous system produces a general vasoconstriction of arterioles in muscle during exercise (mediated by alpha-1 receptors). This tends to reduce local muscle blood flow
BUT
- During exercise the blood flow in active muscles increases over TEN FOLD.
- Due to release of NO AND adenosine and Ca2+ influx (linked to NO formation
Together:
- Vasodilation in active & vasoconstriction in inactive muscles effectively redistributes blood to the active muscles
Whats the craic why NO & fetal lungs when they take their first breath?
Baby takes his or her first breath: the increase in oxygen in the lungs stimulates the synthesis of nitric oxide in the pulmonary endothelium. Causes pulmonary vasodilation
Increased oxygen tension after birth upregulates the expression of eNOS and PKG, which act in concert with the maturational increase in sGC and PKG activities, to contribute to a low postnatal PVR
What causes persistent pulmonary hypertension of the newborn? [1]
- Too little NOS (or inhaled meconium prevents inhaled oxygen reaching the NOS): severe hypoxia
- causes raised pulmonary vascuclar resistance
How does erectile dysfunction occur? [3]
Name a drug class that reverses ED [1]
Endothelial dysfunction leading to smooth muscle cavernosal contraction causes erectile dysfunction (want relaxed cavernosal muscle to allow erection)
cGMP converted back to GTP by proteins known as phosphodiesterases.
Phosphodiesterase (PDE‐5) catalyzes the degradation of cGMP, facilitating smooth muscle contraction
PDE-5 Inhibitors like viagra stop this!
What can endothelial dysfunction be caused by? [4]
Consumptive processes that transform bioavailable NO into other species:
- Reactive oxygen species such as -O2 reacts readily with NO forming peroxynitrite (ONOO−)
- Uncoupling of NOS: BH4 insufficiency results in uncoupled NOS, which produces superoxide anions instead of NO
Deficiencies in production of NO in the endothelium:
- Reduced bioavailability of l-arginine o
- Presence of its inhibitor, asymmetric dimethyl-l-arginine (ADMA)
Name 3 viruses that can cause acute bronchitis [3]
Name 2 bacteria that can cause acute bronchitis [2]
Viruses: Adenovirus, coronavirus, parainfluenza, influenza & rhinovirus
Bacteria: Bordetella pertussis & Mycoplasma pneumonia
Describe the pathophysiology behind acute bronchitis (e.g. caused by respiratory synctial virus)
Epithelial cells: 1st line of defence
RSV: binds and invades mucosal lining via epithelial cells
Epithelial cells switch on immune response after recognised through Toll-like receptor (TLR)-3 and retinoic acid-inducible gene (RIG)-I-like receptors
Cellular infection triggers the release of early inflammatory mediators (e.g.interferons (IFNs) and tumour necrosis factor (TNF)-α) and chemokines (e.g.CXCL8 and CXCL11).
A) Innate: Macrophages and Neutrophils, e.g. PMN polymorphonuclear leukocytes cells recruited PMNs)
B) Acquired: Dendritic cell, triggering B and T cells: CD4, CD8 and primed T cells
How do you distinguish between community acquired pneumonia (CAP) and hospital acquired pneumonia? [1]
Hospital acquired pneumonia is distinguished between CAP by the fact that hospital acquired pneumonia that occurs >48 h after hospital admission & no incubation at time of admission
What is the most frequent causative agent of pneumonia? [1]
What is the second most frequent causative agent of pneumonia? [1]
Streptococcus pneumoniae= 50%
Haemophilus influenzae = 20%
Name the signs of pneumonia [4]
Name a complication that pneuomonia a risk factor for !!
Signs:
- Tachypnoea
- Tachycardia
- Hypoxia
- Hypotension
- Fever
- Confusion
Can lead to sepsis
What investigations would you undertake to ID if Ptx has pneumonia? 6
- CXR: look for consolidation
- PCR to ID pathogen causing infection
- Urea and electrolytes informs severity
- C reactive protein
- FBC
- Liver functon tests
How does CXR compare between acute bronchtits and pneumonia? [1]
Pneumonia: consolidation of the lung parenchyma
Acute bronchitis: appears normal
Why does obesity increase BP? [3]
- increased oxidative stress damages endothelium of BV: stiffer
- increased RAAS system
- increases sympathetic system
which all influence CVD and CKD, which themselves contribute to BP
