Prof.Dr.Arzu SEVEN Sympathoadrenal system Parasympathetic nervous system with cholinergic pre and postganglionic nerves Sympathetic nervous system with cholinergic preganglionic and adrenergic postganglionic nerves + adrenal medulla Adrenal medulla is actually an extension of the sympathetic nervous system where choromaffin cells produce catecholamine hormones: Dopamine Norepinephrine Epinephrine(80%) Adrenal medulla is a specialized ganglion without axonal extension Its chromaffin cells synthesize , store and release hormonesendocrine organ Catecholamines are major elements in response to severe stress Stress hormones: Catecholamines Glucocorticoids Growth hormone Vasopressin Angiotensin II Glucagon Conversion of tyrosine to epinephrine requires 4 sequential steps; 1. Ring hydroxylation 2. Decarboxylation 3. Side-chain hydroxylation 4. N_methylation Tyrosine hydroxylase is the rate limiting enzyme It functions as an oxidoreductase , with tetrahydropteridine as a cofactor Feedback inhibition by catecholamines Competitively inhibited by tyrosine derivatives α_methyltyrosine and by α,α,dipyridyl Catecholamines can’t cross the blood_brain barrier L_Dopa, the precursor of dopamine, readily crosses the blood brain barrier used in the treatment of Parkinson’s disease Dopa decarboxylase requires pyridoxal phosphate , competetively inhibited by α metil dopa Dopamine β hydroxylase (DBH) is a mixed function oxidase, uses ascorbate as an electron donor, copper at the active site and fumarate as modulator,conversion occurs in the secretion granule PNMT is induced by glucocorticoid hormones ,conversion occurs in the cytoplasm Catecolamines enter the granule via an ATP_dependent transport mechanism and binds this nucleotide in a 4:1 ratio(hormone:ATP) NE is stored in these granules, can be N_methylated Exocytotic release of NE and E are calcium dependent and are stimulated by cholinergic and β_adrenergic agents and inhibited by α_adrenergic agents The adrenal medulla, unlike the sympathetic nerves, does not have a mechanism for the reuptake and storage of discharged catecholamines The epinephrine discharged from the adrenal goes to the liver and skeletal muscle Very little adrenal NE reaches distal tissues Catecholamines circulate in plasma in a loose association with albumin They have an extremely short biological half life (10-30 sec.) Catecholamines are rapidly metabolized by catechol_O_methyl transferase(COMT) and monoamine oxidase (MAO) to form O_methylated and deaminated metabolites The concentration of metanephrines or VMA in urine is elevated in > 95% of patients with PHEOCHROMOCYTOMA Tumor of adrenal medulla NE causes hypertension by activating α_1_adrenoceptors on vascular smooth muscle, and epinephrine increases heart rate by activation β1_adrenoceptors Hypertension may be paroxysmal and severe, leading to stroke or heart failure Catecholamines can be classified by their mechanism at action. They act through 2 major classes of receptors ; α adrenergic β adrenergic α α1 α2 β1 Β β2 Epinephrine binds and activates both α and β receptors NE at physiologic concentrations primarily binds to α receptors The catecholamine receptors are members of the G protein-linked class of receptor Hormones that bind to β1, γ, β2 receptors activate adenylyl cyclase, whereas hormones that bind to α2 receptors inhibit the enzyme α1 receptors are coupled to processes that alter intracellular Ca+2 concentrations or modify phosphatidyl inositide met. (or both)