Potential antihypertensive targets in vascular smooth muscles Flashcards
What affects blood pressure?
Cardiac Output x systemic resistance = blood pressure
What affects the cardiac outpit?
Stroke volume x heart rate = Cardiac output
What is isoprenaline?
Isoprenaline is a beta-adrenoreceptor (stimulate cardiomyocytes and pacemaker cells/relaxes arteries) agonist – has no/little change in blood pressure, heart rate to goes up
How does noradrenaline act?
NA acts preferentially on the alpha adrenoceptors – causes constriction of blood vessels, heart rate increases slightly then decreases, blood pressure goes up
Give an overview of the RAAS system
- Renin converts angiotensinogen into Angiotensin I
- ACE enzyme converts ANG I into ANG II whilst ACE 2 converts ANG I into ANG 1-9
- ANG II can bind to AT1/2
- ANG II is converted into ANG III by aminopeptidase A
- ANG III can also bind to AT1/2
Why do some antihypertensive target angiotensin II activity?
- Antihypertensives usually target angiotensin II activity – ACE is targeted or by blocking the receptors angiotensin II works on
- This affects peripheral resistance, sympathetic nervous discharge, aldosterone release
What do ANG II and ANG III have in similar?
Ang II and Ang III exhibit similar affinity for AT1 and AT2 receptors.
They also have a similar affinity for a non-AT1, non-AT2 angiotensin-binding site
How does the brain RAS (renin-angiotensin system) control BP
- increase in vasopressin release from the posterior pituitary into the bloodstream
- activation of sympathetic premotor neuron activity at the level of the rostral ventrolateral medulla (RVLM)
- inhibition of the baroreflex at the level of the nucleus of the solitary tract (NTS) – leads to vagal stimulation
What is EC33
Aminopeptidase A (APA) inhibitor - has a high affinity for APA and blocks it
What does central administration of EC33 and an intravenous dose of EC33 cause? and what does this tell us?
- Central administration of EC33 blocked the pressor effect of intracerebroventricular Ang II in SHR.
- BUT high intravenous dose of EC33 did not change BP in hypertensive rats.
- Suggests that Ang II converted to AngIII in the brain
What does intracerebroventricular infusion of APA and APN (aminopeptidase N; converts Ang III into Ang IV) do to blood pressure?
- Intracerebroventricular infusion of APA significantly increases BP.
- Intracerebroventricular infusion of APN (converts Ang III into Ang IIII) in SHR rats decreases BP
How is EC33 administered?
As a pro-drug RB150
- it crosses the intestinal, hepatic, and blood-brain barriers
- it then gets cleaved into 2 EC33 molecules (inhibits the conversion of Ang II into Ang III)
What is EC33 like as a drug?
- Has a good blood pressure reducing affect
- in people that had higher blood pressure, there was a greater reduction in BP
- Agrees with experimental models of hypertension where firibastat acted as an antihypertensive agent and not as a hypotensive agent (didn’t reduce BP but prevented it from increasing
What has new research regarding RAS and hypertension tells us?
Growing evidence confirms involvement of the brain RAS in the development of hypertension.
Targeting this system with novel agents, such as the first-in-class APA inhibitor prodrug RB150/firibastat, has been shown to be effective.
What ion channels are present on smooth muscle cells and what do they do?
Calcium channles and potassium channels:
- Ca channels become more open when the membrane potential become less active
- K channels oppose them
VDCCs open more with depolarisation
• Cation (Ca) influx
• Anion efflux
How do smooth muscle cells accumulate chloride ions?
Smooth muscle cells ACTIVELY accumulate Chloride ions:
• NK2Cl transporter
• Cl- / HCO3 exchanger
Also found in renal tubules and are targets for diuretics
What are the different mechanisms of chloride ions?
Different Cl ions opened by different mechanisms
- Agonist-gated: Glycine/GABA-A receptors
- Voltage-gated: opened by depolarisation (found in skeletal muscles)
- Calcium-gated: opened by a rise in calcium
- Mechano-sensitive: opened by membrane stretch
- Cyclic nucleotide gated: opened by direct binding of cyclic AMP
What happens when NK2Cl transporter and Cl- / HCO3 exchanger are inhibited?
When inhibited, arteries become less contractile – the vasoconstrictor opens Cl channels, allows Cl efflux, causes depolarisation which causes Ca channels to open, Ca influx
What are Ca-activated Cl channels encoded by?
Ca activated Cl channels encoded by ANO1
How does VGCC open?
Vasoconstrictor activates phospholipase C, liberates Ca, Ca will activate ANO1 Cl channel, Cl efflux and there will membrane depolarization. This will cause VGCC to open, Ca influx and blood vessels will constrict
Where is the ANO1 gene present?
ANO1 gene present in the left anterior descending artery and the pulmonary artery – in smooth muscles and cardiomyocytes
ANO1 plays a role in increasing BP and is a target for drugs that want to lower BP
What do TMEM16A/ANO1 blockers do?
TMEM16A/ANO1 blockers are anti-contractile:
In the presence of the blockers, there’s less contraction when a vessel contracting drug is introduced
What are the different types of vascular smooth muscle cell K channels?
There’s a lot of different K channels • Inward-rectifying channels • Ca activated K channels • Some affected by ATP blocks • Voltage sensitive K channels (kv1.2/1.5/2.1/7): open by depolarisation
What are voltage-sensitive (Kv) potassium channels like?
• Dominant expression
o Kv 1.2 & 1.5 (correolide sensitive, PSORA)
o Kv 2.1 & 2.2 (stromatoxin sensitive)
o Little evidence for Kv 3.x / 4.x = transient currents
- Assemble with various subunits (KCNE, KCHIPS, Kv9s)
- Kv1.x and 2.x shown to go down AND up in hypertension
