Drugs on VSM Flashcards
List the vasoconstrictor agents used on patients.
- Noradrenaline: released from sympathetic nerves – acting at α1-adrenoceptors on VSMCs
- Adrenaline: Released from adrenal medulla – at high enough concentrations will act α1-adrenoceptors. Also, remember that most vascular beds do not contain many β2-adrenoceptors
- Angiotensin II: Formed from RAAS, acting on AT1 receptors on VSMCs (potent)
- Vasopressin (ADH): Released from posterior pituitary, acting on V1-receptors on VSMCs
- Endothelin-1: Released from the endothelium acts on ETA receptors on VSMCs
Vasoconstrictors increase vascular tone by activating
the same G-protein-coupled pathway in VSMCs . What is this pathway and how does it lead to vasoconstriction?
It is the Gq/11 coupled pathway. This converts PIP2 into DAG and IP3 using PLC. The DAG is used to increase membrane excitability and causes depolarisation, this leads to the activation of vgCC’s increasing the intracellular concentration of Ca2+. The IP3 binds to ryanodine receptors located on the SR and this increases the release of calcium ions from the intracellular calcium storage. The calcium binds to calmodulin in the cell and forms the Ca-Calmodulin complex which in turn binds to MLCK, activating it. The activated MLCK phosphorylates the Myosin Light Chain and this leads to cross bridge cycling and therefore contraction.
List some vasodilator agents.
- Adrenaline: Acting at β2-adrenoceptors found in some vascular beds, e.g. skeletal muscle, coronary.
- Nitric Oxide (NO): Synthesised in endothelium, released and acts of VSMCs (also prevents platelet aggregation).
- Prostacyclin (PGI2): Released from endothelium, acts on VSMCs to activate PKA pathway to produce vasodilatation (also inhibits platelet aggregation).
- Inflammatory mediators, e.g. Histamine, Bradykinin, PGE2, Sub P: Act on endothelium to produce NO which produces vasodilatation.
How can metabolic hyperaemia be caused in a patient?
- K+ ions (vasodilator): Released from endothelium, neurones, skeletal/cardiac muscle contraction, produces hyperpolarisation of VSMCs, vasodilatation, correlates metablic activity of tissue to blood flow (metabolic hyperaemia).
- Adenosine, acidosis, hypoxia: metabolic hyperaemia.
Excess production of vasoconstrictor agents is often associated with what?
With excess vasoconstriction and vascular disease – hypertension, heart failure.
Excess production of vasodilator agents is often associated with what?
Excess systemic vasodilatation, dangerous drop in blood pressure, poor blood flow, end organ damage – e.g. In sepsis.
Vasodilators decrease vascular tone by lowering the intracellular concentration of calcium ions. Give examples of how this can be done.
Anything that blocks the receptors on VSMC’s will cause dilatation. Another way is to drive calcium back to its stores or out of the cell. This can be done by increasing the activity of Calcium ATPase (SERCA). Something else that could be done is producing hyperpolarisation. This makes the cell more negative inside and will mean the vgCC’s will not open and there is no calcium influx. Last thing that can be done is blocking the voltage gated Calcium Channels (vgCC’s).
Stimulation of Beta2-adrenoceptors on VSMCs produces relaxation. How?
Beta2-adrenoceptor (linked to Gs GPCR) stimulation PKA activity from stimulation of adenylyl cyclase.
- Ca ATPase (SERCA) – increase uptake into SR (stores)/exclusion from cell. Lowers calcium levels inside cells.
- K channel activity (make them open more often) hyperpolarisation VGCCs
- MLCK (due to less activation of calcium calmodulin complex).
- PKA also inhibits MLCK, directly.
What are the 2 things which control vascular tone?
Tonic sympathetic activity (constriction) + NO release (dilation)
Summarise how NO is produced in the endothelium.
Agonist (such as bradykinin, Sub P) bind to Gq/11 receptor on endothelial cell. This causes the formation of DAG and IP3 by the PLC pathway. The IP3 causes intracellular release of Ca2+ ions from the ER and the DAG phosphorylates non voltage gated Calcium channels leading to a Ca2+ influx. The Ca2+ binds to calmodulin and is used with PI3 kinase and eNOS to produce NO.
How does NO cause vasoconstriction in the vessel?
NO produces relaxation by activating PKG (through Guanylyl cyclase and cGMP) and directly activating K channels (hyperpolarisation) this means less vgCC’s are activated. PKG has same effect as PKA. NO is targeted clinically and is therefore very important.
List some drug targets used to prevent excess vasoconstriction.
- Angiotensin receptor blockers, Alpha 1 inhibitors: These will prevent activation of these receptors and therefore pathway doesn’t exist.
- Nitrates: Produce more NO which activates PKG. Produces vasodilatation.
- Potassium channel openers cause hyperpolarisation. Inhibits vgCC’s.
List some of the clinically used vasoactive drugs which have a direct action on VSMC’s.
VGCC blockers (CCB) e.g. Amlodipine
Block influx of Ca2+ to reduce contraction – hypertension, angina.
Nitrates e.g. Glyceryl trinitrate (GTN)
NO donors, PKG-mediated vasorelaxations – angina, pulmonary oedema.
1-adrenoceptor antagonists e.g. Prazosin
Competitive receptor antagonists – drug-resistance hypertension.
Angiotensin II receptor antagonists (ARB) e.g. Losartan
Block AT1 receptors to reduce vasoconstriction – hypertension, heart failure.
PDE5 inhibitors e.g. Viagra
Blocks cGMP breakdown in corpus cavernosum in penis – erectile dysfunction.
K Channel Openers e.g. Nicorandil
Hyperpolarisation, less VGCC activation/Ca influx, vasodilatation, angina.
Name a vasoactive drug which has a non-direct action on VSMC’s.
Angiotensin-converting enzyme inhibitors (ACEi) e.g. Enalapril
Block production Ang II from Ang I, hypertension, heart failure.
