CRIT5003 MODULE 3.3.

Andrew Couch

ANTIHYPERTENSIVE OVERVIEW AND CLASSIFICATION

CONTROL OF BLOOD PRESSURE:
Components of Vascular system:
Aorta elastic; storage of energy (potential in systole, kinetic in diastole)
Arteries low resistance, some storage of energy
Arterioles a major contributor to TPR, control flow of blood to particular organs
at any given time
Capillaries thin walled; exchange of water and substances; slow rate of flow
Veins high capacitance; low resistance
Role of Arterioles:
-

Smooth muscle rich tonic contraction

Resistance is proportional to the radius ^4 ( thus a small change in radius =
significant change to resistance Hagen-Poiseulles Law)
Smooth muscle tone: controlled by SNS by:
o Direct innervation nerve endings that will activate alpha (contraction)
and B2 receptors (dilatation)
o Circulating hormones (angiotensin II, adrenaline, vasopressin)
o Autoregulation of flow (metabolic > myogenic activity)

Pressure (drop/ change) = flow x resistance:

Remember: (ohms law)

Under ideal laminar flow conditions, in which

vascular resistance is independent of flow
and pressure, the relationship between
pressure, flow and resistance can be depicted as
shown in the figure to the right. Because flow
and resistance are reciprocally related, an increase
in resistance decreases flow at any given P. Also,
at any given flow along a blood vessel or across a
heart valve, an increase in resistance increases the P.
Changes in resistance are the primary means by which blood flow is regulated
within organs because control mechanisms in the body generally maintain
arterial and venous blood pressures within a narrow range. However, changes in
perfusion pressure, when they occur, will affect flow.

CRIT5003 MODULE 3.3.A

Andrew Couch

The above relationship also indicates that there is a linear and proportionate
relationship between flow and perfusion pressure. This linear relationship,
however, is not followed when pathological conditions lead to turbulent flow,
because turbulence decreases the flow at any given perfusion pressure.
Furthermore, the pulsatile nature of flow in large arteries also alters this
relationship so that greater pressures are required for a given flow. In other
words, pulsatility, like turbulence, increases resistance to flow.

As depicted above, the vascular tree is divided into segments, and flow is equal
in each segment. The resistance in each segment determines the pressure drop.
Thus if we increase arteriolar resistance, we should note an increase in arterial
pressure, and a decrease in capillary pressure.
Thus resistance in the arterioles is very important. It determines:
-

Arterial blood pressure

Differential flow to organs
Capillary pressure in each organ (eg kidneys GFR)
o Therefore increasing the capillary pressure in the kidneys increases
GFR.

CONTROL OF BLOOD PRESSURE

CENTRAL CONTROL:
Sensor: Baroreceptor (carotid body and aortic body wall stretch)
Effector: Vasomotor Centre (VMC) portion of medulla oblongata that regulates
BP
-

Sympathetic
o Systemic resistance
o HR/ contractility
o Venous return
o Renin secretion (via B1 receptors on JG cells in kidney)
Parasympathetic

CRIT5003 MODULE 3.3.A

Andrew Couch

CRIT5003 MODULE 3.3.A

Andrew Couch

REVISION: Arterial Baroreceptors: location and stimulus-response

The single most important reflex that maintains arterial blood pressure in the
short term.
Stretch receptors
Location:
Carotid Sinus (a swelling at the origin of the internal carotid artery)
- contains a relatively high degree of elastic tissue and less smooth muscle
(carotid sinus will stretch more than other vessels)
- innervated by a branch of the glossopharyngeal nerve (IXth)
Aortic Arch aortic baroreceptors
- innervated by vagal nerve (Xth)
Baroreceptors are stimulated by both the rate of change of pressure (in pulsatile
pressure the pressue increases rapidly during the systolic phase), and the mean
arterial pressure.
Refer to pic below:

The baroreceptors work by:

A decreased arterial pressure results in DECREASED baroreceptor firing rate
which results in:
1) Increased sympathetic vasomotor activity
2) Increased sympathetic cardiac activity
3) Decreased vagal cardiac activity
NB: The baroreceptor reflex changes in arterial pressure are PREDOMINATELY
secondary to total peripheral resistance as opposed to cardiac output
changes.

CRIT5003 MODULE 3.3.A

Andrew Couch

RENAL CONTROL:
Renin
Renin release is stimulated by 2 mechanisms:
1. Sympathetic beta-1 adrenergic receptor stimulation in JG apparatus
2. Decreased renal arteriole pressure
Angiotensin II
Works by three mechanisms:
1. Vascular smooth muscle vasoconstriction
2. Increased aldosterone secretions
3. Increases sympathetic nerve ending noradrenaline
Aldosterone Na+ and H20 retention
Summary:

Red = increased
Purple = decreased
HYPERTENSION:
Essential (primary) Hypertension (80-95%)
Secondary Hypertension (5-20%)

CRIT5003 MODULE 3.3.A

-

Andrew Couch

Renal artery stenosis

Chronic kidney disease
Primary hyperaldosteronism (Conns adrenal adenoma; bilateral idiopathic
adrenal hyperplasia; congenital adrenal hyperplasia)
OSA
Thyroid disease
Phaeochromocytoma

Pathogenesis of HTN
Resetting of baroreceptor and renin response to maintain a higher blood pressure
When we initially commence patients on anti-hypertensive therapy, there is
generally a counteraction by compensatory receptors by baroreceptors and the
renin system:
Compensatory Reaction:
-

Na+/ H20 retention

o We see this with sympatholytics (NOT B-Blockers though)
o Also seen with vasodilators eg CCBs (amlodipine)
Peripheral oedema
Tachycardia
o Noted with alpha-1 blockers and directvasodilators
Eg prazosin and amlodipine

We can minimize these counteractive responses by utilisation of:

-

ACE Inhibitors, A2RBs and diuretics

Beta Blockers (inhibit tachycardia)

VASCULAR SMOOTH MUSCLE

Remember vascular smooth muscle is under tonic contraction. This contraction
occurs via actin and myosin coupling as in skeletal muscle (although it is not
organised into bands). This contraction is a result of increased intracellular
Ca2+.
Initiation:
-

Humoral (noradrenaline, angiotensin II, vasopression etc)

Mechanical (myogenic response)
o When the smooth muscle contracts secondary to passive stretch
likely L-type ca2+ mediated
Electrical (direct SNS innervation)

VASCULAR SMOOTH MUSCLE (VSM) INNERVATION FACTORS (stimulatory &

inhibitory):

CRIT5003 MODULE 3.3.A

VSM contraction
the following
-

Andrew Couch

generally works by
mechanism:

Stimulation of
L-type voltage
gated Ca2+
channels results in
increased IC
Ca2+ ions
This is further
contributed to by
release of Ca2+ ions from SR
Ca++ then binds calmodulin which interacts with myosin light chain
kinase (MLCK)
o Calmodulin is a calcium-binding messenger protein expressed in all
eukaryotic cells
With consumption of an ATP molecule, this phosphorylates Myosin
light chain
This results in actin-myosin interaction and subsequent contraction of VSM.

Myosin Light Chain

Phosphatase (MLCP)
results in
dephosphorylation of
MLC and hence
relaxation

When Potassium
channels open,
hyperpolarization of
the cell occurs. This
results in decreased
Ca2+ flow through
the L-type calcium
channels. Again this

CRIT5003 MODULE 3.3.A

Andrew Couch

IMPORTANT: REMEMBER that

in smooth muscle cells, an
INCREASE in cAMP =
DECREASED vasodilation and
vice versa. (B2 & a2
respectively)
THIS IS THE OPPOSITE to
Cardiac contractile and nodal
cells, where an INCREASE in
In reference
cAMP
resultsto
in the
INCREASED
above
diagram:
contraction, & increased HR
respectively
Alpha-2:
Remember alpha-2 receptors are classically located on vascular pre-junctional
terminals where is INHIBITS the further release of noradrenaline in a form of
negative feedback. However, there are a few post-synaptic A-2 receptors, which
work as follows:
Via an inhibitory G-protein decreased cAMP increased Myosin Light Chain
Kinase
therefore increases contraction
Alpha-1:
Norepinephrine released from sympathetic nerve terminals act on a1, which are
coupled to Gq receptors (coupled to PLC); this results in release of IC Ca2+
stores with resulting vasoconstriction
Phospholipase C activation splits membrane-bound phospholipid into DAG
(remains membrane bound) and IP3 IP3 moves into cytosol and stimulates
release of Ca2+ from SR increased contraction
Also works to decrease the inhibitory enzyme myosin light chain
phosphatase (MLCP)
Beta-2:
Circulating epinephrine from adrenal medulla (or exogenous) acts on B-2
receptors in the blood vessels (and bronchial smooth muscle) leading to reduced
inward Ca2+ current, with a reduction in myosin/ actin interaction
vasodilatation.
Remember that both B-1 and B-2 receptors are coupled to GstimulatoryPCR
and thus both activate adenylyl cyclase to increase production of cAMP
from ATP. HOWEVER, B1 receptors then result in increased IC Ca2+ and

CRIT5003 MODULE 3.3.A

Andrew Couch

increased myosin/actin interaction; B2 however results in decreased IC

Ca2+ and decreased myosin/actin interaction.
FURTHER REVISION:
Muscarinic 1 (similar to alpha 1) q
exocrine glands
-

GqPCR (Thus associated with PLC, IP3, DAG etc)

Muscarinic 2 (similar to alpha 2) inhibitory

cardiac tissue
-

GiPCR (Thus inhibits adenylyl cyclase, and reduces cAMP production)

Remember that Muscarinic 2 receptor agonism is also associated with a
GkPCR, and results in increased efflux of Potassium current resulting in
hyperpolarization

Muscarinic receptors: Gq Gi Gq Gi Gq (M1 M2 M3 M4 M5)

Nicotinic Receptors: (Ligand-gated channels)
Upon interaction with an agonist (eg Ach, nicotine etc), conformational change
occurs, and the channel opens, allowing positively charged ions to move through
it it is a non-selective cation channel. The movement of cations causes
a depolarization of the plasma membrane (which results in an excitatory
postsynaptic potential in neurons), but also by the activation of voltage-gated
ion channels.
TO SUMMARISE:
VSM CONTRACTION:
Increased Ca2+ source:
1. Extracellular (via L-type Ca2+ channel)
2. Intracellular stores from Sarcoplasmic reticulum (IP3 mediated)
VSM RELAXATION:
Inhibition of MLCK by increased cAMP (via B2 receptors)
Increased MLCP (from increased cGMP from increased Nitric Oxide)
Decreased Intracellular Ca2+
Hyperkalaemia
Increased re-uptake into SR stores (via B2 Gstimulatory effect)

CRIT5003 MODULE 3.3.A

IN VASCULAR SMOOTH MUSCLE:

Increased cAMP (Gs)
-

Beta 2 (adrenaline)
A2 (adenosine)
IP (PGI2) - IP = prostacyclin receptor

Decreased cAMP (Gi)

-

Alpha-2 (noradrenaline and adrenaline)

Activated Gq (thus increased IP3)

-

Alpha-1, Angiotensin1, Vasopressin, endothelin

Andrew Couch

CRIT5003 MODULE 3.3.A

Andrew Couch

Note that the endothelium plays an important role in vascular smooth muscle
tone. Relaxation associated with endothelium derived factors is often associated
with K+ channel related hyperpolarization.
-

Nitric Oxide
Prostacyclin (PGI2)

Chronic Hypertension is associated with abnormal K+ channels

CRIT5003 MODULE 3.3.A

Andrew Couch

ANTI-HYPERTENSIVE DRUGS
CLASSIFICATION:

Angiotensin related (ACEI, A2RBs)

Diuretics
Sympathoplegics
Calcium Channel Blockers
Vasodilators

CCBs can be considered as direct vasodilators, although they do also have

significant effects on the heart
Influence of choice for a particular agent is dependent on other comorbidities:
LVF ACE/A2RBs, thiazides, BBlockers
LVH ACEI/ A2RBs, dihydropyridines (reduces afterload)
MI - ACEI/ A2RBs, B-Blockers
Angina CCBs (although caution with dihydropyridines as reflex tachycardia can
worsen angina), Bblockers
Tachyarrhythmias non-dihydropyridines (narrow complex only Verapamil in
VT can cause VF!), B-Blockers
DM - ACEI/ A2RBs
Pregnancy dihydropyridines, some B-Blockers

SYMPATHOPLEGIA
-

Central/ vasomotor centre (eg alpha-2 agonist)

Sympathetic ganglia v effective but obselite dur to s/e
Alpha 1 blockers (prazosin)
Beta1 blockers
o Initial reduction in cardiac output (decreased HR & SV)
o Secondary reduction in vascular resistance (decreased renin/ AII)

ANGIOTENSIN ANTAGONISM
Ace inhibitors
Angiotensin receptor blockers

CRIT5003 MODULE 3.3.A

Andrew Couch

VASODILATORS:
-

L-type Ca2+ channel blockers

NO mediated (nitric oxide)
K+ channel openers (causes hyperpolarization)
D1 Dopamine receptor activation

DIURETICS
Initially diuretics lead to a decrease in ECF and blood volume. This obviously will
result in an initial direct effect of decreased blood pressure:
-

Decreased venous return, thus cardiac output

Increased systemic vascular resistance
o But the decreased cardiac output prevails and an reduction in BP
occurs

Over 6-8 weeks:

-

Cardiac output normalises

The mild decrease in blood volume remains
However, systemic vascular resistance decreases to below pretreatment levels
o Thus continued effect of decreased BP remains
o Mechanism not fully understood
?decreased neuronal activity, possibly due to decreased sodium
levels