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CVS > L10: Potential antihypertensive targets in vascular smooth muscle > Flashcards

L10: Potential antihypertensive targets in vascular smooth muscle Flashcards

1
Q

What is BP?

What is cardiac output?

A

Blood pressure = Cardiac Output x systemic resistance

ardiac output = Stroke volume x heart rate

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2
Q

Examples of Adrenorecpeotr agonists and their effects on vasculature

A

Isoprenaline = beta adrenoreceptor (stimulate cardiomyocytes & pacemaker cells + relaxes arteries) agonist – no/little change in mean BP, HR increases

NA acts preferentially on the alpha adrenoceptors – causes constriction of blood vessels, HR increases slightly then decreases, BP goes up (due to increase in systematic resistance)

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3
Q

Why bother treating high bp?

A
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4
Q

Overview of the RAAS

A

-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

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5
Q

Examples of renin antagonists

A

Aliskiren (a.k.a Tekturna) – renin antagonist:
- >causes reduction in the negative feedback induced by ACEis or ARBs
-> this rises Renin
-> Renin has other effects upon stimulating the RAAS:
1. Ang 1-7 – have biological effects + can interconvert
2. Chymase can create Ang II

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6
Q

RAAS in the brain

A

APA + APN important

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7
Q

Angiotensin I & II receptor affinity

A
  • exhibit similar affinity for AT1 and AT2 receptors.

-They also have a similar affinity for a non-AT1, non-AT2 angiotensin-binding site

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8
Q

How does the brain RAS (renin-angiotensin system) control BP?

A
  • 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) in the brain stem
  • inhibition of the baroreflex at the level of the nucleus of the solitary tract (NTS) – leads to vagal stimulation
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9
Q

Example of an inhibitor of APA + APN

A

EC33 high affinity for APA, lower affinity for APN

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10
Q

Effect of EC33 in the brain

A

EC33 has a high affinity for APA and blocks it

  • Central administration of EC33 blocked the pressor effect of intracerebroventricular Ang II in hypertensive rats.
  • BUT high intravenous (outside of brain) dose of EC33 did not change BP in hypertensive rats.

= Suggests that Ang II converted to AngIII in the brain

  • Intracerebroventricular infusion of APA significantly increases BP.
  • Intracerebroventricular infusion of APN (converts Ang III into Ang IIII) in hypertensive rats decreases BP
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11
Q

Drug that inhibits APA + clinical trial information of the drug

A

= Pro-drug RB150,

Crosses the intestinal, hepatic, and blood-brain barriers
–> cleaved into 2x EC33 molecules (inhibits APA - conversion of Ang II into Ang III)

Reduces BP

  • Phase II showed higher the basal daytime ambulatory SBP, the greater the firibastat-induced BP-lowering effect – in people that had higher blood pressure, there was a greater reduction in BP
  • Agrees with experimental models of hypertension where firibastat(RB150) acted as an antihypertensive agent and not as a hypotensive agent (didn’t reduce BP but prevented it from increasing)
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12
Q

Is the brain RAS involved in hypertension + give examples of RAAS modulators

A
  • Growing evidence confirms involvement of brain RAS in development of hypertension. Targeting this system with novel agents, such as APA inhibitor prodrug RB150/firibastat, has shown to be effective.
  • (Neuroagents) Oral NI956/QGC006 treatment in hypertensive DOCA-salt rats
    1. reduced brain APA hyperactivity and
    2. BP for 10 hours after a single dose
    4. Decreased plasma AVP
  • At a dose ten times less than RB150.
  • NI956/QGC006 has been identified as a best-in-class centrally acting APA inhibitor
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13
Q

What is present on a smooth muscle cell?

A

Contraction due to influx of Ca through VDCC

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14
Q

State ion channels on smooth muscle cells in vasculature?

A

CaV1.2; 3.1/3.2

Kv1.2; Kv2; Kv7

KIR (inward rectifying)

KCa (Ca activated k ion channel)

Mixed cation channels

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15
Q

What do Ca and K channels do?

A

Ca: become more open as membrane potential become less active

K: oppose Ca channels

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16
Q

When + why do VDCC open?

A

= open more with depolarisation

May be due to :
- Cation (Ca) influx
- or Anion (e.g. GABA-A or glycerine receptor) efflux

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17
Q

Significance of Cl ions in smooth muscle contraction + MOA

A

SMC ACTIVELY accumulate Chloride ions via:
1. NK2Cl transporter
2. Cl- / HCO3 exchanger

Also found in renal tubules + targets for diuretics

When transporters inhibited -> arteries become less contractile

– vasoconstrictor binds to its receptor -> opens Cl channels -> allows Cl efflux, = depolarisation -> Ca channels open -> Ca infflux

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18
Q

Types of chloride channels

A

Different Cl ions opened by different mechanisms

Agonist-gated: e.g. Glycine/GABA-A receptors

Voltage-gated: opened by depolarisation (found in skeletal muscles)

Calcium-gated: opened by a rise in intracellular calcium

Mechano-sensitive: opened by membrane stretch

Cyclic nucleotide gated: opened by direct binding of cyclic AMP

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19
Q

How are Ca activated Cl channels encoded + how do they work i.e. how does vasoconstriction occurs?

A

= encoded by ANO1

Vasoconstrictor activates phospholipase C -> liberates Ca -> activate ANO1 Cl channel -> Cl efflux + membrane depolarisation -> VGCC open -> Ca influx + blood vessels CONSTRICT

ANO1 gene present in the left anterior descending artery and pulmonary artery – in smooth muscles and cardiomyocytes

20
Q

What is the significance of ANO1/TMEM16A?

A
  • Increases BP

Target for hypertension

21
Q

What are the effects of TMEM16A/ANO1 blockers?

A

Anti-contractile

22
Q

Vascular smooth muscle cell K channels

A
  • Inward-rectifying channels
  • Ca activated K channels
  • Some affected by ATP blocks
  • Voltage sensitive K channels (kv1.2/1.5/2.1/2.2/7): open by depolarisation
23
Q

Kv1 + Kv2 expression in hypertension?

A

Can go UP + DOWN

either as compensatory effect or causal effect

24
Q

What do K channels do?

A

Brake cellular excitability because:

K efflux -> membrane hyperpolarisation -> reduces chances of Ca channels opening -> less Ca influx = less cross bridge formation through reduced MLCK activation = RELAXED smooth muscle cell

25
Q

KCNQ family of encoded channels

A

Genes: KCNQ1, 2, 3, 4 & 5 encode for:
Kv7.1, 7.2, 7.3, 7.4 & 7.5 proteins
- All form tetrameric voltage-gated potassium channels.

  • Kv7.1 contributes to late repolarising phase of cardiac action potential
  • V0.5 ~ -40 mV

Modifiers:
- KCNE gene products
- PIP2 levels
- Pharmacological agents

26
Q

Which KCNQ is abundant in various arteries?

A

KCNQ1
KCNQ4
KCNQ5

27
Q

Agents that modulate Kv7 channels

A

Retigabine
- Activates Kv7 channels
– enhances Kv7; keeps them open for longer
-> Promotes membrane hyperpolarisation
- developed as anti-convulsant
- causes human MA to relax

Kv7 blockers:
Narrow blood vessels/contracts them
Reverses the relaxation by Kv7 enhancers

28
Q

What is the importance of pressure in cerebral arteries?

A

Myogenic response:
Higher the pressure = more they contract against it

29
Q
A

There’s endogenous dilators that work through Kv7 channels – when Kv7channels are KO’d the endogenous relaxants don’t work, these are:

  • B-adrenoceptor agonist
  • Adenosine
  • CGRP
  • ANP
  • Perivascular fat derived molecules
  • Kv7 activators as anti-hypertensives / enhance receptor-mediated dilatation
30
Q

Summary

A
  • Kv7.4 activity is downregulated in hypertension -> impairs response of Kv7 activators work = harder to target as antihypertensive

kv7.4 contribute to rating membrane potential in arterial SMC and important for receptor mediated vasodilatation, so is this a cause of hypertension?

31
Q

How is Ca involved in muscle relaxation?

A

Must be removed for the muscles to relax – can be done through:
- SERCA (uptake in Ca store in cell)
- Na/Ca exchanger – pump out the Ca from cell

32
Q

What are Na/Ca exchangers

A

Plasma membrane transporter
3 genes (NCX1-3)
NCX2 /3 = brain and skeletal muscle
VSM = NCX1.3 and 1.7 predominantly
Bidirectional exchanger
Regulated by membrane potential
Affected by Na and Ca gradients

33
Q

Na/Ca changer when [Na] high intracellular

A

Ca comes in (instead of 3Na in + 1Ca out when normal [Na] )-> arterial contraction

34
Q

Are Na/Ca exchangers good pharmacological targets?

A

Spontaneously hypertensive rats
= Higher level of NCX protein and mRNA in aorta

Patients with idiopathic pulmonary arterial hypertension
= Higher level of NCX protein and mRNA

Overexpression of NCX1
= Development of hypertension after high salt intake

Reduced expression of NCX
= reduced increase in arterial tension + reduced radioactive Ca uptake in Na-free conditions
= resistance to salt-induced hypertension

THUS the following were developed

NCX inhibitors (eg SEA0400, KB-R7943)
= Lowers BP in salt or ouabain-sensitive hypertensive mice
= Reduce ouabain-induced vasoconstriction

NCX inhibitors have mixed effects as found in heart too but for them to work, NAX must work in reverse mode.

35
Q

Na+ source of rise in Na within VSMs?

A
  1. Non-selective cation channels (TRPs) – membrane channels
  2. Voltage-dependent Sodium channels – membrane channels
  3. ENaC (epithelial sodium channels)
  4. Na / K ATPase – membrane potential is maintained by these as they restore the ionic balance after action potentials

NaCX has interactions with the Na/K ATPase – 2 proteins that utilise the movement of Na ions

36
Q

Details about Na/K ATPase

A
  • Different isoforms
  • Knockouts: poor survival but tend to be more sensitive to vasoconstrictors
  • Blocked by:
    1. Ouabain
    2. cardiac glycosides (digoxin)
    3. cardiotonic steroids (endogenous oubain, bufalin, marinobufagenin)
    4. Cardiotonic Steroids = increased in salt-dependent hypertensive models
    These drugs produce contractions
37
Q

Other than NAX, state a second target VSM

A
  1. GPCR activated by vasoconstrictor (Gq coupled)
  2. Receptor tyrosine kinases (as well as some GPCRs) affect exchange factors on RhoA
  3. RhoA leads to the activation of ROCK
  4. ROCK inhibits 2 regulators of myosin light chain phosphatase
  5. Myosin doesn’t get dephosphorylated – we still get cross bridge formation
  6. Long level of contraction at a low level of calcium

= rho Kinase inhibitors

38
Q

Rho Kinase Inhibitors

A
39
Q

What are the 2 new anti-hypertensive drugs in development?

A
  1. NAX inhibitors
  2. Rhao kinase inhibitors
40
Q

ROCK-induced contraction of VSMs?

A

Vasoactive agents bind to their respective GPCRs -> release of RhoA from guanine nucleotide dissociation inhibitor (GDI). RhoA translocates to the membrane. Mechanisms involving RhoA activation also involve transactivation of receptor tyrosine kinases (RTKs). GEFs promote exchange of Guanosine diphosphate (GDP) to Guanosine triphosphate (GTP), activating the RhoA-ROCK pathway. Activated ROCK renders MLCP inactive by phosphorylation of CPI-17 and/or zipper-interacting protein (ZIPK), facilitating MLC20 phosphorylation and vascular contraction. Increased Ca2+may directly activate ROCK through phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-dependent pathways.

41
Q

Potential targets for anti-hypertensive treatment?

A

Kv7 channels
ANO1 Cl channels

42
Q

IS arterial tone only due to VSMCs?

A

VSMs influenced by endothelium + chemicals released from fat surrounding the vessels

Endothelial release NO

In obese people, the adipocytes become inflamed and there’s different vasomodulatroy chemicals released

43
Q

Does endothelial regulation differ between conduit + resistant arteries; are they only NO making factories?

A
  • No, not only NO making, they are complex and can differ
  • NO and hydroperoxide in the conduit arteries produced = relaxation of arteries
  • Low resistance GAP junctions in the resistance arteries – electrical activity passing from endo cells to SMCs
  • Ca/K channels in resistance arteries – produce endothelial hyperpolarisation that can affects VSM
44
Q

What does high nitrate intake via beetroot juice lead to? And how?

A

Low BP

How:
1. Nitrate goes into bowels and absorbed by kidney,
2. excreted
3.Nitrate that gets to salivary glands gets converted by bacteria into nitrite,
4. nitrite degrades and releases NO
5. = relaxes blood vessels

45
Q

Other than arteries in hypertensive patients being more constricted and less reposnsive to endogenous vasodilators, what else happens to them?

A

-They are remodelled.

Vessels change:
- become thicker,
- collagen deposition and
- smooth muscle proliferation

CVS (5 decks)

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