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.

v  Blood vessels have the ability to expand and contract to allow more or less blood to flow through them.

v  Hormones and various other mechanisms cause mediators to be produced in the endothelium of the arterioles (and other vessels) which change the vascular tone.

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.

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+ à Nitric oxide, prostacyclin and do not increase intracellular Ca2+ à 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.

Ø  Used to decrease blood pressure but not used in angina as low cardiac output can lead to reflux tachycardia.

Phenylalkylamine – Vermapil & Gallomapil

Ø  Selective for myocardium, reduces myocardial oxygen demand. Used to treat angina. Not a potent vasodilator.

Benzothiazepine – Diltiazem

Ø  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

v  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.

v  Newer drugs such as esmolol and atenolol target only β1 receptors.

Nitric Oxide

v  Blood vessel/endothelium stimulated by hormone/impulse.

v  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

v  Nitric oxide converted to cyclic GMP by s.guanylyl cyclase.

v  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 cyclo-oxygenase (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 cyclo-oxygenase 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 cyclo-oxygenase 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.

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.