6- Blood Vessel Order Function And Specialisation If Cels In The Cns Flashcards
Describe the properties of NO in the endothelium
Molecule: NO Precursor: L arginine (diet) Enzyme:endothelial nitric oxide synthase (eNos) Role of endothelial cell: source of ENOS VSMC receptor: - VSMC: glucanyl cyclase 2nd messenger: GTP to cGMP Effects on VSMC: relaxation Effects on platelets: inhibition
Describe the properties of prostacyclins in the endothelium
Molecule: PG12 Precursor: PGH2 Enzyme: PG12 synthase Role of endothelial cell: source of PGH2 VSMC receptor: IP1 VSMC: adenyl cyclase 2nd messenger: ATP to cAMP Effects on VSMC: relaxation Effects on platelets: inhibition
Describe the properties of thromboxane A2
Molecule: TXA2 Precursor: PGH2 Enzyme: thromboxane synthase Role of endothelial cell: source of PGH2 VSMC receptor: TP1 VSMC: phospholipase C (PLC) 2nd messenger: PIP2 to IP3 Effects on VSMC: contraction Effects on platelets: activation
Describe the properties of endothelin 1
Molecule: ET1
Precursor: big endothelin
Enzyme: [ECE) endothelin converting enzyme
Role of endothelial cell: precursor source and enzyme source
VSMC receptor: ETA and ETB
VSMC: phospholipase C
2nd messenger: PIP2 to IP3
Effects on VSMC: contraction/ relaxation
Effects on platelets: none
Describe the properties of angiotensin 2
Molecule: AG2 Precursor: AG1 Enzyme: ACE - angiotensin converting enzyme Role of endothelial cell: ACE expressed on membrane VSMC receptor: AT1 VSMC: phospholipase C 2nd messenger: PIP2 to IP3 Effects on VSMC: contraction Effects on platelets: none
Renin-angiotensin-aldosterone system (RAAS): recall the organisation and role of the RAAS, and synthesis pathway of angiotensin II
Renin from kidneys activates angiotensinogen from liver to form Ang I, which is converted to Ang II by ACE on pulmonary and renal endothelial cells. Ang II stimulates vasoconstriction (and water reabsorption!)
recall the structure and function of the vascular endothelium, and recall its role in inflammation
The vascular endothelium is one cell thick
•The vascular endothelial has five key roles, including local regulation of vascular tone, local control of thrombosis, absorption/excretion, as a barrier from blood-borne pathogens, and control of vessel growth
•Secretes vasoactive compounds: NO, PGI2 predominantly vasodilate; TXA2, Ang-II and ET-1 predominantly vasoconstrict
•Damage to the endothelium leads to local inflammation
Vascular endothelium drugs: recall the mechanism of action of drugs including aspirin
Aspirin causes irreversible inhibition of
the COX enzymes
COX1 - inactivation
COX2 - switches its function (to generating protective lipids)
• If you reduce the conversion of arachidonic acid to PGH2 then you reduce the amounts of prostacyclin and thromboxane
• Reducing thromboxane is good but aspirin also decreases the production of prostacyclin
• However, with low-dose aspirin, Prostacyclin levels will decrease slightly and then remain relatively high whereas thromboxane levels continue to fall
• This is because thromboxane is predominantly produced in the platelets
• Platelets DO NOT HAVE A NUCLEUS so they can’t generate more mRNA to produce new proteins to build the enzyme again
• So if we continue to take low-dose aspirin, we get a decrease in thromboxane but maintenance of prostacyclin
What are the functions of vascular endothelium
“Vascular tone management – the endothelium produces, translates and allows to pass an array of biochemicals capable of regulating vascular smooth muscle tone.
Thrombostasis – the endothelium secretes antithrombotic molecules to prevent clot formation or molecules from adhering to the luminal vessel wall.
Absorption and secretion – the endothelium contains many channels to facilitate the transport of molecules into and out of the blood vessels.
Barrier – the endothelium largely prevents microorganisms and other harmful molecules from passing into the interstitial compartment.
Growth – the endothelium is capable of regulating local angiogenesis and vascular cell proliferation
Describe arachnidonic acid
“Arachidonic acid is a phospholipid-derived acid that enters two separate pathways. The more important (in terms of this course) is the prostaglandin pathway which is catalysed by cyclooxygenase (COX) enzymes, which convert it into PGH2, the prostaglandin precursor. From there, it can be converted to thromboxane A2 (TXA2) which is a platelet-promoting, pro-atherogenic vasoconstrictor (i.e. it is not a health-promoting molecule). In the presence of prostacyclin synthase PGH2 can be converted into PGI2 (prostacyclin), which, unlike TXA2 is a health-promoting biochemical. The alternative route for arachidonic acid is the leukotriene family.
Name 5 roles of angiotensin 2
“binding to smooth muscle cells to cause vasoconstriction;
accentuating the sympathetic response to noradrenaline;
increased sodium reabsorption in the proximal tubule (increasing water reabsorption);
triggering release of aldosterone (which itself promotes sodium (and water) reabsorption); and,
stimulating the release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary gland, which increases water reabsorption in the collecting ducts of the kidneys.
Describe the mechanism of action of calcium channel blockers
“Since Ca2+ influx facilitates the cross-bridge cycling associated with muscle contraction, the goal of Ca2+ channel blockers (CCBs) is to inhibit voltage-gated Ca2+ channels which impedes the influx of Ca2+ that is associated with vasoconstriction. Typically, suffixed with –dipine (e.g. Amlodipine).
Describe the mechanism of ace inhibitors
If we inhibit ACE then not only do we inhibit the conversion of Angiotensin I to Angiotensin II
• But we also inhibit the breakdown of bradykinin
• By decreasing the breakdown of bradykinin, it stimulates relaxation because bradykinin has a vasodilatory effect
What is mechanism of viagra
cGMP is converted to GMP by Phosphodiesterase (PDES)
• GMP is metabolically inactive with regards to this pathway
• Viagra is a phosphodiesterase inhibitor
