1. Dr Asma Jabeen Assistant professor, Physiology Transmission in ANS(Catecholamines)

2. At the end of this session, the student should be able to: List the sites of release of norepinephrine as a chemical transmitter. Diagram the steps of catecholamines synthesis. Describe the actions of norepinephrine and classify the adrenergic receptors according to these actions. Describe the removal of norepinephrine. Learning Objectives

3. Transmitters of ANS  Acetylcholine -- para -sympathetic transmitter.  Nor epinephrine – sympathetic transmitter.

4. Adrenergic fibers: Most of the postganglionic sympathetic neurons are adrenergic.

5. Function of Adrenal medulla: 80% Epinephrine 20% Norepinephrine  Effects of circulating epinephrine and Norepinephrine last 5 to 10 times longer than direct sympathetic stimulation.(2 to 4 min, after stimulation is over.  Both the hormones are removed from blood slowly

6.  The dual mechanism of sympathetic stimulation,direct and indirect, provides a safety factor, one mechanism substituting for the other if it is missing.  Epinephrine and norepinephrine can stimulate structures that are not directly innervated by sympathetic fibers. e.g. metabolic rate of every cell is increased. Importance of adrenal medulla as a part of Sympathetic NS

7. Difference in action of Epinephrine and Norepinephrine  Epinephrine has greater effect on cardiac stimulation (ß-receptors)  Norepinephrine causes stronger constriction of muscle blood vessels. Thus it greatly increases TPR and elevates arterial pressure.  Epinephrine has 5 to 10 times greater metabolic effect.

8. Synthesis and removal of Nor epinephrine Synthesis begins in axoplasm,completed in secretary vesicle. hydroxylation 1. Tyrosine Dopa 2. Dopa decarboxylation Dopamine 3. Transport into vesicle Hydroxylation 4. Dopamine Norepinephrine

10. In adrenal medulla, methylation 5. Nor epinephrine Epinephrine Removal: 1. Reuptake 2. Diffusion 3. Destruction

11. Sites of Synthesis Epinephrine- Produced exclusively in adrenal medulla with a small amount in the brain. Essentially all the circulating epinephrine is derived from adrenal medulla. Norepinephrine- It is widely distributed in neural tissues including the adrenal medulla, sympathetic post-ganglionic fibers and the central nervous system. In brain its concentration is highest in the hypothalamus Epinephrine- Produced exclusively in adrenal medulla with a small amount in the brain. Essentially all the circulating epinephrine is derived from adrenal medulla. Norepinephrine- It is widely distributed in neural tissues including the adrenal medulla, sympathetic post-ganglionic fibers and the central nervous system. In brain its concentration is highest in the hypothalamus

12. Metabolism: Removal and Inactivation The plasma half life of catecholamine is 1-3 minutes. The biological effects of catecholamine is terminated rapidly by following two processes 1.Neuronal uptake (non enzymatic inactivation) This is presynaptic reuptake accounts for inactivation of about 85% of released NE. It is less pecific for Ep than for NE 2. Extraneuronal uptake (enzymatic inactivation) It is mediated by postsynaptic cells and is followed by intracellular metabolic inactivation. The enzymes involved are mono amine oxidase (MAO) and catechol-o-methyl transferase (COMT) The plasma half life of catecholamine is 1-3 minutes. The biological effects of catecholamine is terminated rapidly by following two processes 1.Neuronal uptake (non enzymatic inactivation) This is presynaptic reuptake accounts for inactivation of about 85% of released NE. It is less pecific for Ep than for NE 2. Extraneuronal uptake (enzymatic inactivation) It is mediated by postsynaptic cells and is followed by intracellular metabolic inactivation. The enzymes involved are mono amine oxidase (MAO) and catechol-o-methyl transferase (COMT)

13. Mechanism of action:  The transmitter binds with specific receptor on the effector cells  Receptor is on outside of a protein molecule that penetrates the membrane.  This causes a conformational change in protein molecule

14.  Altered protein molecule excite or inhibit the cell by:  Change of cell membrane permeability  Activating or inactivating an enzyme e.g. Adenyle cyclase → CAMP

15. Adrenergic Receptors: 1. Alpha receptors (Alpha 1 and Alpha 2) 2. Beta receptors (Beta 1 and Beta 2)

16. α-Adrenergic Receptors α-Adrenergic Receptors are sensitive to both Ep and NE These receptors are again of two types i.α-1 receptors-located on post synaptic membranes and are mainly excitatory, e.g. in blood vessels and non pregnant uterus ii.α-2 receptors- located on presynaptic nerve terminals of cholinergic and adrenergic nerves. Activation of neuronal α-2 receptors is inhibitory α-Adrenergic Receptors are sensitive to both Ep and NE These receptors are again of two types i.α-1 receptors-located on post synaptic membranes and are mainly excitatory, e.g. in blood vessels and non pregnant uterus ii.α-2 receptors- located on presynaptic nerve terminals of cholinergic and adrenergic nerves. Activation of neuronal α-2 receptors is inhibitory

17. β-adrenergic receptors These receptors respond to Ep and in general are relatively insensitive to NE. These are associated with most of the inhibitory function of the body with one most important function i.e. excitation of myocardium. There are following three types of β adrenergic receptors i.β-1: cardiac muscle ii.β-2:skeletal muscle blood vessel, GIT and bronchioles iii.β-3:adipose tissue These receptors respond to Ep and in general are relatively insensitive to NE. These are associated with most of the inhibitory function of the body with one most important function i.e. excitation of myocardium. There are following three types of β adrenergic receptors i.β-1: cardiac muscle ii.β-2:skeletal muscle blood vessel, GIT and bronchioles iii.β-3:adipose tissue

18. Neuroscience, Sinauer Asssoc., Inc Adrenergic receptors in the sympathetic system Norepinephrine  11 22

19. Functions of Alpha Receptors: Vasoconstriction Iris dilation Intestinal relaxation Intestinal sphincter contraction Pilomotor contraction Bladder sphincter contraction

20. Functions of Beta Receptors: Vasodilation ß2 Cardioacceleration ß1 Increased myocardial strength ß1 Intestinal relaxation ß2 Uterus relaxation ß2 Bronchodilation ß2 Calorigenesis ß2 Glycogenolysis ß2 Lipolysis ß2 Bladder wall relaxation ß2

21. α1 receptors vascular smooth muscle, on GI and bladder sphincters, and radial muscle of the eye causes excitation (contraction) α2 receptors presynaptic nerve terminals, platelets, fat cells, walls of GI tract causes inhibition (relaxation, dilation) Location of specific adrenergic receptors

22. β1 receptors SA node, AV node, ventricular muscle of heart Produces excitation, increases heart rate, contractility, and conduction velocity β2 receptors Vascular smooth muscle of skeletal muscle, bronchioles, walls of GI tract and bladder Produces relaxation: dilation of vascular smooth muscle and relaxation of bladder, bronchioles

23. Sympathetic Action and Receptors at Target Organs Receptors at Target Organs Organ ActionReceptor Heart heart rate  1 contactility AV node conduction Vascular smooth differential effects! Muscle constrict blood vessels  1 (dilates blood vessel  2 in skeletal muscles) Gastrointestinal motility  2,  2 Tract constricts sphincters Bronchioles dilates bronchiolar  2 smooth muscle Males sex organs ejaculation  Bladder relaxes bladder wall  2 constricts sphincter 

24. organ actionreceptor sweat glands sweating muscarinic goose bumps contracts  skin blood flow kidney renin secretion  1 fat cells lipolysis  1 pupil dilation  1 salivary glands secretion  Sympathetic Action Cont…d

27. Thank you