Phenyethanolamine N-methylatransferase is found only in adrenal medulla therefore the conversion of noraldrenaline to adrenaline happens in adrenal medulla not neurons.
Storage of Noradrenaline:
Dopamine is transported into the synaptic vesicles by an amine transporter system that is also involved in the reuptake of pre-formed Noradrenaline.
This carrier system is blocked by "Reserpine" which is the oldest antihypertensive drug.
Depletion of the transmitter stores results. Synaptic vesicles contain dopamine or Noradrenaline plus adenosine triphosphate ATP and the β-hydroxylase.
In the adrenal medulla, Noradrenaline is methylated to yield adrenaline both are stored in the Chromaffin cells of adrenal gland.
Release of Noradrenaline:
An action potential arriving triggers the influx of Ca2+ ions into the cytoplasm of neurons causes vesicles to fuse with the cell membrane and expel their contents into the synaptic space.
This release is blocked by drugs as "Bretylium" which is also an antihypertensive agent.
Another drug is "Guanethidine", this inhibits the transport into vesicles and also blocks release of Noradrenaline so it acts like both "Reserpine and Bretylium".
Indirectly acting "Sympathomimetics" are capable of releasing stored Noradrenaline from nerve endings. They may displace free Noradrenaline in cytoplasmic pool which is in equilibrium with that in storage vesicles.
Binding by receptors:
Noradrenaline released from synaptic vesicles diffuses across synaptic space and binds either to:
Postsynaptic receptor on the effector organ or,
Presynaptic receptor on the nerve endings
resulting in formation of intracellular 2nd messenger.
Adrenergic receptors use both the cAMP 2nd messenger and phosphoionsitide cycle to transmit signals to effects.
Removal of Noradrenaline:
The termination of noradrenergic transmission results from several processes:
Reuptake into the nerve terminal (Reuptake 1) or into perisynaptic glia cells or smooth muscle cells (Reuptake 2).
The reuptake by neural membrane involves Na+ - K+ activated ATPase that can be inhibited by "tricylic antidepressants TCA" or "Cocaine".
Once adrenaline re-enters cytoplasm of the adrenergic neurons it may be taken into adrenergic vesicles by amine transporter system, or persist in a protected pool,
Alternatively, it can be oxidized by "Monoamine Oxidase MAO" present in neuronal mitochondria.
About 80% of released Noradrenaline is removed by reuptake.
Metabolism to O-methylated derivatives by postsynaptic cell membrane associated "Catechol O-Methyl Transferase COMT".in the synaptic space.
Diffusion out of synaptic space to enter the general circulation.
The metabolism of Catecholamines:
Norepinephrine Epinephrine
MAO MAO
COMT Dihydroxy Mandelic Acid COMT
Normetanephrine COMT Metanephrine
MAO MAO
3-Methoxy-4-Hydroxy Mandelic Acid
(Vanillyl Mandelic Acid VMA)
The inactive product of Noradrenaline metabolism are excreted in urine as VMA, metanephrine and normetanephrine are excreted in urine too.
Their concentration increase up to 95% in patients with Phenochromacytoma.
Sympathomimetics: are compounds that simulate or mimic the action of sympathetic nerves.
The Adrenoceptors (Adrenergic Receptors):
The term Adrenoceptors is widely used to describe receptors that respond to catecholamines.
Receptors were also named After nerves that usually innervate them,thus adrenergic receptors.
In 1948, Ahlquist proposed two different types of Adrenoceptors: α alpha and β Beta.
There are three steps to prove or discover a receptor:
Structure-Activity Analyses.
Careful comparison of potency with series of agonists and antagonists.
Molecular biology provides a new approach by making possible the discovery and expression of genes that code for related receptors.
So, by these means it was found that there are two types of adrenergic receptors: Alpha and Beta.
Alpha Adrenoceptors:
These are subdivided into:
Alpha 1 A, B, D and L
Alpha 2 A, B and C
Alpha 1 Adrenoceptors:
They're present on postsynaptic membrane of effecter organ.
Their function:
On Vessels: cause smooth muscle contraction so there will be Vasoconstriction of blood vessels found in skin, splanchnic vessels and skeletal muscles, this will cause pallor and increase peripheral vascular resistance.
On Eyes: contraction of radial muscles of the iris (papillary dilatory muscle) this will lead to dilation of the pupil Mydriasis.
Genitourinary Smooth muscles: contraction of sphincter of the bladder and contraction of prostate and prostatic capsule causing difficulty to urination.
Besides, contraction of smooth muscles of Vas Deferens and seminal vesicle ejaculation.
Pregnant uterus contraction affects blood flow to fetus low placental blood flow.
Skin: contraction of Pilo erector muscle goose flesh skin erection of hair.
Sweat glands: are of two types:
Apocrine gland involved in stress has alpha receptor so stimulation of this gland leads to increased secretion.
Acrine gland or thermoregulatory gland has muscarinic receptor even though they’re innervated by adrenergic nerves.
Metabolic functions: the effect on the liver is stimulation of lipolysis, Gluconeogenesis and Glycogenlysis and K+ release.
Heart: increase force of contraction ( not so important).
Mechanism of Activation of alpha 1 receptors:
Stimulation of alpha 1 receptor
Activation of a G-coupling protein
Activation of phospholipase C
It acts om phosphotidyl inositol biphosphate
The release of :
Diacylglycerol (DAG) b) Inositol triphosphate (IP3)
IP3 stimulates the release of sequestrate
Stores of Ca2+ leading to increased concentration of
Cytoplasmic calcium
DAG activates protein Kinase C
Ca2+ activates Ca2+ dependant protein kinase
Phosphorylates their substrate and the effect happens
Alpha 2 Adrenoceptors:
The location and actions are:
Location Function
1 Presynaptic receptor on adrenergic nerve terminal (auto receptor) They inhibit the release of noradreanline
2 Presynaptic receptor are present on cholinergic nerve terminal, they are called “Hetero receptors” The relaxation of GIT smooth muscles is probably due to Presynaptic inhibition of parasympathetic activity (because of the presence on alpha 2 receptors on cholinergic terminal on GIT)
3 Postsynaptic CNS adrenoceptors are present in the brain, e.g.: brain stem vasomotor center Decrease sympathetic stimulation.
Some drugs used as Antihypertensive act on these receptors for example “Clonidine”
4 On the beta cells of pancreas Alpha 2 receptors are inhibitory, they decrease the insulin release.
5 On platelets They produce aggregation
6 On vascular smooth muscles contraction
7 On fat cells Inhibition of lipolysis
Mechanism of Activation of alpha 2 receptors:
Alpha 2 receptors (with the help of inhibitory regulatory protein Gi) inhibit adenyl cyclase enzyme activity causing decrease in intracellular cAMP.
In addition there are other mechanisms include:
Activation of Potassium channels.
2)Closing of Calcium channel.
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