With the aid of pharmacological and molecular biological techniques the a-adrenoceptor subtypes were determined. a-adrenoceptors exist on peripheral sympathetic nerve terminals and are divided into two subtypes a1, and a2. These subtypes were at first classified by their anatomical location; a1 is found mostly postsynaptically, whilst a2 although typically sited presynaptically, can also occur postsynaptically. These initial subtypes were further divided into a1a, a1b, and a1d; and a2a, a2b, a2c, and a2d. This knowledge has led to the development of selective agonists and antagonists for each subtype.
a-Adrenoceptor Location and Function:
a1-adrenoceptors: are found in both the central and peripheral nervous system.
-In the Central Nervous System they are found mostly postsynaptically and have an excitatory function.
-Peripherally they are responsible for contraction and are situated on vascular and on non-vascular smooth muscle. a1-adrenoceptors on vascular smooth muscle are located intrasynaptically and function in response to neurotransmitter release.
For non-vascular smooth muscle they can be found on the liver, where they cause hepatic glycogenolysis and potassium release. On the heart they mediate a positive inotropic effect. Cause relaxation of GI smooth muscle and decrease salivary secretion.
a2-adrenoceptors: are found in both the central and peripheral nervous system. They are found both pre- and postsynaptically and serve to produce inhibitory functions.
-Presynaptic a2 receptors inhibit the release of noradrenaline and thus serve as an important receptor in the negative feedback control of noradrenaline release.
-Postsynaptic a2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of these receptors causes platelet aggregation, and blood vessel constriction.
All a-adrenoceptors use G-proteins as their transduction mechanism. Differences occur in the type of G-protein the receptors are coupled to. a1-adrenoceptors are coupled through the Gp/Gq mechanism, whereas a2-adrenoceptors are coupled through Gi/Go. Gp/Gq activates phospholipase C that phosphorylates phosphatidyl inositol to produce inositol triphosphate, and diacylglycerol. These compounds act as second messengers and cause release of calcium from intracellular stores in the sarcoplasmic reticulum, and activation of calcium channels respectively. They produce their effects by the release of calcium. The a2-adrenoceptor G-protein, Gi/Go, has been shown to be negatively coupled to adenylate cyclase and so reduces the formation of cyclic AMP which leads to a decreased influx of calcium during the action potential - the ion responsible for transmitter release. Therefore lowered levels of calcium will correspondingly lead to a decrease in transmitter release
The clinical uses of adrenergic compounds are vast. The treatment of many medical conditions can be attributed to the action of drugs acting on adrenergic receptors. a- adrenoceptor ligands can be used in the treatment of hypertension. Drugs such as indoramin and prazosin are a1-adrenoceptor antagonists and have antihypertensive effects, as is clonidine an a2 adrenoceptor agonist. a1-adrenoceptor antagonists are also employed in the control of benign prostatic hypertrophy. However there can be cardiovascular side effects associated with a1 block. a2-adrenoceptor agonists such as clonidine are often used as an adjunct to general anaesthetics.
Characterisation of a-adrenoceptors:
|Agonist Potency Order||A=NA>>ISO||A=NA>>ISO|
|Second Messengers and Effectors||PLC activation via Gp/q causes inc. [Ca2+]i||dec. cAMP via Gi/o causes dec. [Ca2+]i|
|Physiological Effect||Smooth muscle contraction||Inhibition
of transmitter release
Link to IUPHAR nomenclature: alpha-1 table or alpha-2 table