vascular endothelium Flashcards
(14 cards)
Nitric oxide
ACh binds to GPCR PLC migrates along membrane PLC converts PIP2 to IP3 IP3 triggers Ca2+ influx from ER Ca2+ upregulates eNOS eNOS converts L-arginine + O2 to L-citrulline + NO NO diffuses into VSMC and activates C GC converts GTP to cGMP cGMP upregulates PKG PKG activates potassium channels Membrane hyperpolarises Cell relaxes Vessel dilates
Prostacyclin
PG12 produced via COX1 (and COX 2) PG12 diffuses into VSMC PG12 binds to IP receptor Upregulation of adenylyl cyclase AC converts ATP to cAMP cAMP inhibits MLCK Reduced cross bridge cycling Cell relaxes Vessel dilates
Thromboxane A2
TXA2 diffuses through apical and basement membrane
TXA2 binds to TPbeta on VSMC
PLC migrates along membrane
PLC converts PIP2 to IP3
IP3 triggers Ca2+ influx from extracellular space and SER
Ca2+ upregulates myosin light chan kinase
VSMC contracts
Vessel constricts
TXA2 binds to TPalpha receptor on platelets
Platelet becomes active and produces more TXA2
Positive feedback potentiates response
Platelets aggregate
Angiotensin II can lead to 5 things
arteriolar vasoconstriction
sympathoexcitation
*these things increase vascular resistance
tubular sodium reabsorption
aldosterone secretion
ADH secretion
*these things increase water retention
together they increase blood pressure
how do you get from angiotensinogen to angiotensin II?
angiotensinogen to angiotensin I using renin
Angiotensin I to angiotensin II using ACE
how does angiotensin II work?
renin cleaves angiotensin to ang I ACE is expressed on endothelial cells in renal/pulmonary circulation Ang I cleaved to form An II by ACE An II diffuses across endothelium Ang II binds to AT1 receptor PLC migrates along membrane PLC converts PIP2 to IP3 IP3 triggers Ca2+ influx Ca2+ upregulates myosin light chain kinase Cell contracts (ACE metabolises bradykinin and NO mediated vasodilation is reduced) Vessel constricts
How does endothelin I work?
Endothelial cell nucleus produced Big endothelin 1
Endothelin converting enzyme converts zymogen to ET-1
ET-1 binds to ETZ and ETB receptors on VSMC
Receptors release PLC
PLC converts PIP2 to IP3
IP3 triggers Ca2+ influx
Cell contracts
Vessel constricts
BUT for vessel dilation: ET 1 binds to ETB on endothelial cell upregulated eNOS Increased NO production No diffuses into VSMC cell relaxes
what are ACE inhibitors for?
Angiotensin II receptors can be blocked.
§ ACE inhibitors can partially block production of angiotensin II (other pathways exist for production, hence, partially).
Beta blockers are for?
§ Beta-blockers stop renin release in the kidneys.
NSAIDs are for?
§ NSAIDs can increase renin release (unwanted effect).
pharmacology of ACE inhibition
Main product of the kinin system is an octapeptide called bradykinin
Bradykinin is a vasodilator which does pretty much the opposite of angiotensin II
ACE used to be called kininase II because one of the things it did was to break down bradykinin
If you block ACE then you’ll have less angiotensin II and more bradykinin
How does aspirin work?
Aspirin causes irreversible inhibition of the COX enzymes
NOTE: NSAIDs cause reversible inhibition of the COX enzymes
Aspirin has different effects on COX1 and COX2
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
When thinking of thromboxane, this effect 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 (also in the endothelial cells but mainly 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
issues with blocking VG calcium ion channels
Blocking Voltage-Gated Calcium Channels
There needs to be a way to block certain calcium channels without affecting the calcium channels in the heart
It just so happens that the affinity of the channel blocker to the channel is related to the MEMBRANE POTENTIAL OF TARGET CELLS
Smooth muscle cells have a higher membrane potential (more positive) than cardiomyocytes
why do people taking the same medicine have very different experiences?
drugs are not tissue specific
receptor expression and distribution varies between tissues
