L9. Local and Hormonal Mediators Flashcards Preview

02. Cardiovascular > L9. Local and Hormonal Mediators > Flashcards

Flashcards in L9. Local and Hormonal Mediators Deck (23):

What are autocoids?

Autocoids are locally acing mediators, chemical messengers signalling between neighbouring cells


What are some common characteristics of local mediators?

Labile and rapidly metabolised or diluted out of their active range. For this reason their site of action is very close in proximity to their site of release


Where is histamine found?

In granules of mast cells mainly (found in the mucosal tissues) and in smaller amounts in basophils (in the blood)


What stimuli induces histamine release?

Antigen, IgE recognition
Complement fragments
physical stimuli
cytokines and chemokines


What is the typical response upon histamine binding to its receptors? What is the triple response to histamine?

Typically it is the allergic, inflammatory reaction
1. Reddening: vasodilation
2. Oedmea: by increase in vascular permeability
3. Flare: by spread (anti-dromic) through sensory nerves


What are the histamine receptors, the type and where are they located?

Histamine receptors are GPCRs
H1: in blood vessels and sensory nerves, bronchi, GIT, CNS
H2: vascular epithelium, mucosal beds of the nose and stomach, CNS
H3: presynaptic nerves, GIT, nasal mucosa, CNS
H4: Eosinophils, mast cells, basophils


What are the anti-histamines used for?

Anti-histamines target the H1 receptors and are useful in treating hay fever, atopic dermatitis, anaphylaxis and angioedmea, motion sickness.
Not useful in asthma.


What are different generations of the anti-histamines? Give Examples

Sedative: enters the CNS
Non-sedative: not entering the CNS but CVS affects (rare ventricular arrhythmia so recalled)
Newer non-sedative: have reduced risks of cardiac effects and don't enter the CNS
Eg. Citrizine, loratidine


What are the H2 receptor antagonists? How do they work and what are some examples

Regulate stomach acid secretions (revolutionary in treatment of peptic ulcers)- block parietal cell H2
Eg. Cimetidine and Ranitidine


What is bradykinin? What does it mediate?

A very potent vasodilator
Activates endothelial cells and permeability
Stimulates sensory endings (pain)
Can contract the uterus, gut and modulate gut and airway secretions


What is the process of bradykinin synthesis?

The kinin-kallikrein system:
Prekallikrein is activated by factor XII (upon bleeding) and forming Kallkrein. This activates high molecular weight kininogen into bradykinin


What is the stimulus that leads to the generation of bradykinin?

Bradykinin is generated after plasma exudation occurs during inflammation (the stimulus)


How is bradykinin degraded?

Kininase (Angiotensin Converting Enzyme) cleaves bradykinin


What are the bradykinin receptors, what kind are they and where are they located?

B1 and B2, both are GPCRs
B1: expressed only as a result of tissue injury, and may play a role in chronic pain. Also has a role in inflammation- recruits neutrophil via the chemokine CXCL5 production. Also on endothelial cells
B2: Ubiquitously and constitutively expressed in tissues


What is the pathogenesis of Hereditary Angiooedema in terms of bradykinin?

Caused by a deficiency of C1esterase inhibitors or SERPIN (Serine Protease INhibitors)
They normally inhibit kallikrin and the bradykinin breakdown pathway.

Lack of the inhibitor = over activity of bradykinin = too much oedema


What is the vascular reactivity conundrum?

There was a disparity about the action of ACh on vascular endothelium as either a vasodilator of vasoconstrictor in the in vitro setting.
Found that stimulation with Ach led to either increased constriction or a decreased constriction

Reason being the helical strip vs. the transverse ring and the fact that the endothelium is a dynamic entitiy


What is meant by vascular tone in terms of the vascular reactivity conundrum?

When treating with ACh on the transverse ring (intact) endothelium, it caused vasodilation, but only to a point and then it started to vasodilate. This is likely because a vascular tone created by the endothelium is then overcome by the higher concentrations of ACh


What is EDRF or NO?

Endothelium Derived Relaxing Factor, which was later found to be Nitric Oxide
A vasoactive factor that caused the relaxation of the vessels


How is NO production mediated?

It is receptor dependent: ACh or bradykinin bind to receptors on endothelial cells leading to increases in intracelllular calcium: stimulates the activity of NOS which convert arginine into NO which free diffuses out of the cell into the underlying smooth muscle


What are the three isoforms of Nitric oxide synthases?

nNOS (nerves, epithelial cells)
iNOS (inducible, macrophages and smooth muscle cells)
eNOS (endothelial cells)


How does Nitric oxide induce vasodilation?

Activates guanylate cyclase: stimulates the production of cGMP and this leads to vascular smooth muscle relaxation.


What are some NOS inhibitors?

L-arginine analogs: produce a vasoconstriction which demonstrates that NO has a homeostatic role (there is a basal release of NO that is lost upon inhibitor treatment)


What are the physiological roles of NO?

Flow dependent vasodilation
Inhibition of platelet adhesion and aggregation