Potential Antihypertensive Targets In Vascular Smooth Muscle

Question 1

Blood pressure = (2)

Answer 1

Cardiac Output x systemic resistance

Question 2

Cardiac output = (2)

Answer 2

Stroke volume x heart rate

Question 3

Why bother? (4)

Answer 3

Increased risk of stroke, heart failure and coronaryartery disease

29% of global deaths = Cardiovascular disease

In 2008 CVD = 50, 000 premature deaths

=£30 Billion financial burden

Question 4

Newer anti-hypertensives (3)

Answer 4

*RAAS modulation
*Na /Ca2+ exchange blockers
*Rho Kinase

Question 5

Theoretical Anti-hypertensives (3)

Answer 5

*K+ channels
*Cl channels
*Remodelling

Question 6

Overview of the renin-angiotensin-aldosterone system (RAAS)

Question 7

Renin antagonists (6)

Answer 7

Aliskiren (a.k.a Tekturna)

ACEis or ARBs reduce the negative feedback
Renin rises
Other components of the RAAS can have effects
Ang 1-7
Chymase can create Ang II

Question 8

Brain AngIII (2)

Answer 8

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

Question 9

The brain RAS controls BP via (3)

Answer 9

(1) increase in vasopressin release from the posterior pituitary into the bloodstream

(2) activation of sympathetic premotor neuron activity at the
level of the rostral ventrolateral medulla (RVLM)

(3) inhibition of the baroreflex at the level of the nucleus of the
solitary tract (NTS) = vasodilation

Question 10

EC33 study in brain of rats (6)

Answer 10

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.
=
Ang II converted to AngIII

Intracerebroventricular infusion of APA significantly increases BP.

Intracerebroventricular infusion of APN in SHR rats decreases BP
Brain AngIII

Question 11

Pro-drug RB150 (4)

Answer 11

-Crosses the intestinal,
hepatic, and blood-brain barriers

-RB150 (a.k.a FIRIBASTAT) – Phase III clinical trials.

Phase II showed higher the basal daytime ambulatory SBP, the
greater the firibastat-induced BP-lowering effect.

Agrees with experimental models of hypertension where firibastat acted as an antihypertensive agent and not as a hypotensive agent

Question 12

What does this show us about Brain RAS? (3)

Answer 12

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.

Oral NI956/QGC006 treatment in hypertensive DOCA-salt rats:
-reduced brain APA hyperactivity and
-BP for 10 hours after a single dose
-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