Download Cardiovascular 9 – Blood Vessel Order, function and

Cardio 9 – Blood Vessel Order, Function and Specialisation
Anil Chopra
1. Appreciate the metabolic function of the endothelium as a generator of
hormones that regulate vascular and cardiac smooth muscle form and function
and blood element reactivity.
 Blood vessels have the ability to expand and contract to allow more or less
blood to flow through them.
 Hormones and various other mechanisms cause mediators to be produced in
the endothelium of the arterioles (and other vessels) which change the vascular
tone.
Regulation of Vascular
Function
Adventiti
a
Medi
a
Cell
s
SM
C
E
C
+
±
N
E
-
NO
+
±
-
Blood
Intim
a
±
±
ET-1
±
PGI2
±
Ad/NA
Ang II
Peptides
ADH
5-HT
TXA2
Endotoxin
Insulin
Glucose
Shear
Stress
Ca
p
2. Describe ways in which endothelium can be stimulated. How does this result
in the release of hormones.
Different chemicals that travel in the blood can stimulate the endothelium to release
different hormones. These can either cause an increase in blood vessel (mainly
arteriolar) vasodilation (caused by Nitric Oxide NO & Prostacyclin PGI2) or
vasoconstriction (caused by Endothelin-1 ET1, Thromboxane TXA2, and Angiotensin
II).
3 & 4. Describe:
 Renin-angiotensin system
 How calcium channel blockers work
 How adrenergic hormones affect heart and vasculature
 How low-dose aspirin works
 How β1 antagonists work (β-blockers)
 How nitro vasodilators work
 How ACE inhibitors work
 The side effect of the drugs
The Renin-Angiotensin System
Renin is produced in the kidney. It converts angiotensinogen to angiotensin I in the
blood. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin
II. Angiotensin II causes vasoconstriction and degrades bradykinin.
Decrease in Blood
Pressure
Renin
Angiotensinogen
Angiotensin
Converting Enzyme
Angiotensin I
ACE also degrades
bradykinin (acts on β1
receptors to release
vasodilators)
Angiotensin II
Vasoconstriction
Acts on ATI receptors to
directly stimulate
vasoconstriction; also
causes renal salt absorption
ACE Inhibitors
Such as captoril. They reduce blood pressure by blocking the action of angiotensin
converting enzyme so no angiotensin II is produced and bradykinin is not broken
down.
Calcium Channel Blockers
Drugs that either decrease intracellular Ca2+  Nitric oxide, prostacyclin and do not
increase intracellular Ca2+  endothelin, angiotensin II, Thromboxane.
They decrease intracellular calcium levels by blocking the voltage gated calcium
channels in cardiac and blood vessel muscle. This means that upon stimulation, less
calcium flows into cells (negative inotropic effect) and so the muscles contract less. In
cardiac muscle, this results in a decrease in cardiac output by decreasing the heart rate
and stroke volume. In smooth muscle around vessels, this decreases total peripheral
resistance and so results in vasodilation.
Overall result is a decrease in blood pressure.
Dihydropyridine – (suffix “pine”) Amlodipine, Felodipine, Nicardipine.
 Used to decrease blood pressure but not used in angina as low cardiac output
can lead to reflux tachycardia.
Phenylalkylamine – Vermapil & Gallomapil
 Selective for myocardium, reduces myocardial oxygen demand. Used to treat
angina. Not a potent vasodilator.
Benzothiazepine – Diltiazem
 Somewhere between dihydropyridines and phenylalkylamines, depresses
cardiac muscle and vasodilates.
Affect of Adrenergic Hormones
Noradrenaline and adrenaline activate α and β receptors on smooth muscle and
cardiac muscle.
Noradrenaline and adrenaline effect:




α1 receptors on most arteries (phospholipase C) to cause vasoconstriction.
α2 receptors on postsynaptic nerves (cAMP) to cause nerve conduction.
β1 receptors on monocytes (cAMP) to increase cardiac output.
β2 receptors on skeletal muscle vessels (cAMP) to cause vasodilation.
β1 Antagonists
 Used to treat hypertension, tachycardia and cardiomyopathy. Some work by
blocking all β receptors (1 and 2). This results in a reduced heart rate and
reduced force of contraction. It also has side effects of vasodilation –
propanolol.
 Newer drugs such as esmolol and atenolol target only β1 receptors.
Nitric Oxide
 Blood vessel/endothelium stimulated by hormone/impulse.
 L-arginine converted to nitric oxide by nitric oxide synthases (NOS) – 3 types:
o NOS I/ nNOS in nerves
o NOS II/ iNOS in inflamed cells
o NOS III/ eNOS in endothelium
 Nitric oxide converted to cyclic GMP by s.guanylyl cyclase.
 cGMP causes vasodilation but is broken down quickly by phosphoesterases.
Nitrovasodilators
Used to treat angina e.g. nitroprusside
They can work by:
- donating nitric oxide (e.g. nitroglycerine)
- activating eNOS (e.g. endothelium dependent vasodilators)
- inhibiting phosphodiesterases. (e.g. Viagra) – increasing cGMP levels in cells.
Prostacyclin and Thromboxane
Prostaglandin is synthesised from arachidonic acid under the influence of cyclooxygenase (COX).
This is then acted on by:
-
Prostacyclin synthase in endothelial cells produces prostacyclin.
Prostacyclin acts on IP receptors and eventually causes vasodilation and
inhibition of platelets. Atherosclerosis is reduced.
-
Thromboxane synthase in platelets produces Thromboxane.
Thromboxane acts on TP receptors and causes vasoconstriction and
stimulation of platelets. Atherosclerosis is increased.
Low-Dose Aspirin
Aspirin is a non-steroidal anti-inflammatory drug.
It irreversibly inhibits cyclo-oxygenase. It works
as a cardio-protector to reduce the risk of a stroke
and atherosclerosis because even though cyclooxygenase inhibition will reduce the production
of both prostacyclin and Thromboxane; in cells
- In endothelial cells, cyclo-oxygenase can
be re-synthesised
- In platelets, there is no nucleus, so cyclooxygenase cannot be resynthesised.
Aspirin can inhibit cyclo-oxygenase 1 in platelets
but not cyclo-oxygenase 2 at inflammatory sites.
New NSAIDs are the sites for COX-2.
Effect of Aspirin
prostacyclin
thromboxane
Low dose - Aspirin
Endothelin -1
Endothelin 1 is a very potent vasoconstrictor. It is released at times of
pathophysiological insult. It acts on ETA and ETB receptors, on vessels and cardiac
monocytes. It results in vasoconstriction and increases force and rate of cardiac
contraction. It may also play a role in pulmonary hypertension.