Pharmacology - Vasoconstrictors/dialators Flashcards
An increase in Total Peripharal Resistance (TPR) will occur due to what?
Vasoconstriction
In the contraction of blood vessels, how are GPCRs involved?
Ga(q) –> Stimulates PLC, which causes an increase in Ca2+ release from the SR
This causes MLCK to phosphorylate MLC –> causing contraction
Ga(i) –> Inhibits PLC
How do Calcium Channel Blockers (CCBs) work?
They block L-type Voltage-Activated Ca2+ channels (L-VACCs)
There are 2 different forms of these…
Cav1.2a –> Cardiac Muscle
Cav1.2b –> Smooth Muscle
This allows for a degree of selectivity
What is ‘Calcium Sensitisation’?
Where intracellular process causes inhibitory responses on MLCP (which itself causes relaxation), and so less calcium is needed to be present to causes contraction of muscles and blood vessels
What is Endothelin-1 (ET-1)?
And how is it made?
A molecule that increases BP when bound to specific receptors (ET A/B) on smooth muscle
So ET A antagonists can be used to treat hypertension
Stimulates vasodialation factors (eg, NO) when bound to ET B receptors in endothelium
Its made via various enzymes such as Furin and Endothelin-Converting Enzyme (ECE) in endothelial cells
What causes the relaxation of smooth muscle?
Opening of K+ channels –> causes hyperpolarisation, which is like a negative feedback to L-type VACCs
SERCA2 uptakes Ca2+ back into the SR
Nitric Oxide and ANPs cause more cGMP to be produced, causing Protein Kinase G to stimulate MLCP (relaxation)
The binding of agonists to Gs GPCRs will cause Protein Kinase A to inhibit MCLK (inhibiting contraction)
How is eNOS activated?
And what are the effects?
An agonists binds to a GPCR in an endothelial cell, causing an increase in Ca2+. This causes calmodulin (linked with Ca2+) to activate eNOS, which stimulates the production of NO
NO then activates soluble Guanylyl Cyclase (sGC) in the smooth muscle, increasing cGMP levels…. causing Protein Kinase G to stimulate MLCP (relaxation)
What is Asymmetric dimethylarginine (ADMA)?
An endogenous NOS inhibitor –> So decreases the amount of natural NO that we produce
Present in higher levels in people suffering from hypercholesterimia, hypertension, kidney faliure etc…
It is a marker of endothelial dysfunction and a risk factor for CVD
Why do men like selective PDE5 inhibitors?
Because they prevent cGMP breakdown, and so less PKG…. so less relaxation occurs….
Allowing them to get erections!
Eg, sildenafil (viagra)
Explain the synthesis of Prostnoids
Calcium stimulates cPLA2, which forms Arachidonic acid
COX-1 converts this to PGG2 –> PGH2
Thromboxane Synthase converts PGH2 –> TXA2 (in platelets)
PGD Synthase converts PGH2 –> PGD2 (in mast cells)
Prostacyclin Synthase converts PGH2 –> PGI2 (in endothelial cells)
What is Endothelial-derived Hyperpolarising Factor (EDHF)?
An independent cellular pathway that causes vasodialation via hyperpolarisation of smooth muscle cells
Usually caused by K+ channel opening
What are the 3 different isoforms of Nitric Oxide Synthase?
Endothelial (eNOS) –> Constitutively expressed and dependent on calcium
Will cause vasodialation in blood vessels and reduce aggregation of platelets
Neuronal (nNOS) –> Used in neurotransmission, gastric emptying and erections
Inducible (iNOS) –> Calcium independent
Used in host defence, often activated by LPS
