1. HORMONES OF THE ADRENAL MEDULA (A.M.)

2. Its considered to be part of the sympathetic nervous system where by the splanchic preganglionic nerve fibers terminate in the adrenal medulla where they innervate the chromaffin cells that produce the catecholamine hrs. Dopamine, Nor-epinephrine, and Epinephrine. The A.M is thus a specialized ganglion without axonal extensions, its chromaffin cells synthesize, store, and release products that act on distant sites, so that it also function as endocrine organ – so * the sympathoadrenal system consists of the: 1. Parasympathetic NS with cholinergic pre and postganglionic nerves. 2. The sympathetic NS with cholinergic pre – ganglionic and adrenergic post ganglionic nerves. 3. The A.M.

3. The hrs. of the sympathoadrenal system are required for adaptation to acute and chronic stress. Epinephrine, norepinephrine, and dopamine are the major elements in the response to sever stress. This response involves an acute integrated adjustment of many complex processes in the organs vital to the response ( brain, muscles, cardiopulmonary system, liver) at the expense of other organs that are less immediately involved (skin,GIT, lymphoid tissue ).

4. Biosynthesis of catecholamines These amines are synthesized in the chromaffin cells of the adrenal medulla, they are so named because they contain granules that develop a red – brown color when exposed to potassium dichromate stain. Collections of these cells are also found in (heart, liver, kidney, gonads, adrenergic neurons of the postganglionic sympatheticsystem, and central NS). Catecholamines are 3,4 dihydroxyderivatives of phenylethylamine. The major product of adrenal medulla is epinephrine-which is constitutes about 80% of the catecholamines in the medulla and its not made in the extra medullary tissue. While most of the nor-epinephrine present in organs innervated by sympathetic nerves is made insitu and most of the rest is made in other nerve endings and reaches the target tissue via the circulation.

5. In other ward in the extra-adrenal chromaffin cell catecholamine end by the formation of NEP, while cells of adrenal medulla can convert NEP to EP which is the major catecholamine product by the adrenal medulla. In addition the chromaffin cells of extraadrenal tissues have the property of the synthesis, storage and reup take of the discharged catecholamine, while the adrenal medulla cells can synthesized, store, and secrete but not uptake the discharge catecholamine.

6. Catecholamine usually derived from TYROSINE, the conversion of tyrosine to EPN. Requires 4- sequential steps : 1. Ring hydroxylation. 2. Decarboxylation. 3. Side-chain hydroxylation. 4.N- methylation.

8. 1- RING HYDROXYLATION Tyrosine is immediate precursor of catecholamine, and tyrosine hydroxylase is the rate-limiting enzyme in catecholamines biosynthesis. This enzyme is found in both soluble and particle- bound forms only in tissue synthesize CA. It functions as an oxidoreductase with tetrahydropteridine as a co-factor to convert L-tyrosine to L- dihydroxyphenyl alanine ( L-dopa). This step is regulated in variety ways the most important mechanism involves feed back inhibition by the catecholamine. Its also inhibited by a series of tyrosine derivatives including  methyltyrosine (this compound is occasionally used to treat catecholamine excess in pheochromocytoma). A third group inhibit this enzyme is  dipyridyl (by chelating iron and thus removing co factor.)

9. 2- DOPA Decarboxylation: This soluble enzyme present in all tissues of the body requires pyridoxal phosphate for conversion of L- dopa to 3,4 dihydroxyphenylethylamine (dopamine). Compounds that resemble L-dopa are competitive inhibitors of this reaction such as *  Methyldopa, *3- hydroxytyramine, * metaraminol, *  -methyl -tyrosine. These usually used in treatment of hypertension.

10. 3- SIDE CHAIN HYDROXYLATION : This step catalyzed by DBH (dopamine  - hydroxylase) and need ascorbate as an electron donor, copper at the active side and fumarate as modulator. This enzyme is in the particulate fraction of the medullary cells probably in the secretion granules, thus the conversion of dopamine to nor epinephrine occurs in this organelle.

11. 4- N- METHYLATION : It’s the addition of methyl group on nitrogen it catalyzed by (PNMT) phenyl ethanol amine N- methyl transferase and so convert NEP to EP (NEP EP),in the epinephrine forming cells of adrenal medulla since PNMT is soluble its assumed that the conversion occur in the cytoplasim.The synthesis of PNMT is induced by glucocorticoid hrs. That reach the medulla via the intra- adrenal portal system this system provides a 100 fold steroid concentration gradient over systemic arterial blood, and this high intra- adrenal concentration appears to be necessary for induction of PNMT. Following the formation of NE in the secretory granules these CA will leave the secretion granules to the cytoplasm where its conversion to E will take place, however the newly formed EP. And NE. Can be retaken by new population of secretion granules.

12. STORAGA AND SECRETION OF CA. The secretion chromaffin granules are capable of biosynthesis, uptake, storage and secretion of CA.these granules contain NO. of substances in addition to the CA. Including ATP,Mg +2,Ca +2,DBH,and the protein chromagranin A. Neural stimulation of the adrenal medulla results in the fusion of the membrane of the storage granules with the plasma membrane and this leads to the exocytosic release of NEP and EP. This process is calcium dependent and is stimulated by cholinergic and  -adrenergic agents. CA and ATP are released in proportion to their intra-granular ratio as the other contents including DBH, Ca +2, chromagranin A. (the ratio is 4\1),this mean the CA is 4 and the ATP is 1.

13. Storage granules

14. Neural reuptake of CA is an important mechanism for conserving these hrs.and for quickly terminating hormonal or neurotransmitter activity.The adrenal epinephrine goes to the liver and skeletal Ms. But then rapidly metabolized.( half life short 10-30 seconds.)

15. METABOLISM OF CATECHOLAMINES: Less than 5% of CA. Can be excreted unchanged in the urine,however 95% of CA. Usually undergo metabolized in to metabolites that excreted mainly as conjugated derivatives (with glucoronide or sulfate) that are excreted in urine.Two enzymes are involved in the metabolism of CA which are: 1.COMT (catechol O- methyl transferase) : Which is cytosolic enzyme found in many tissues it catalyzed the addition of a methylgroup usually at 3 position on the benzene ring the result of this reaction depending on the substrate is the production of (homovanillic acid, nor metanephrine,and metanephrine.)

17. 2.MAO (monoamine oxidase): is an oxidoreductase that deaminates mono- amines,its located in many tissues,but mainly in highest concentration in liver,stomach,kidney,and intestine, they are of two types : a-MAO-A is found in neural tissue and deaminates serotonin, epinephrine, and nor epinephrine. b-MAO-B is found in the extra-neural tissues and is most active against 2- phenylethylamine and benzylamine. Both forms metabolize dopamine and tyramine. VMA is the end product of NE. And EP. Metabolism and usually increase if there is tumor of the adrenal medulla. (pheochromocytoma.)

18. THANK YOU