Function of the Adrenal Medulla

The adrenal medulla synthesizes and secretes norepinephrine and epinephrine directly into the bloodstream. Typically, the secretion from the adrenal medulla contains about 20 percent norepinephrine and 80 percent epinephrine.7 These two hormones are 

Consequently, the adrenal medulla serves to augment the sympathetic division of the ANS. In situations where a sudden increase in sympathetic function is required (i.e., the fight-or-flight scenario), the adrenal medulla works with the sympathetics to produce a more extensive and lasting response. 

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Cl. Cannon, W. B The emergency function of the adrenal medulla in pain and the major emotions. 

Proteoglycans are also found in intracellular locations such as the nucleus their function in this organelle has not been elucidated. They are present in some storage or secretory granules, such as the chromaffin granules of the adrenal medulla. It has been posm-lated that they play a role in release of the contents of such granules. The various functions of GAGs are summarized in Table 48-8. 

Finally, the preganglionic neuron may travel to the adrenal medulla and synapse directly with this glandular tissue. The cells of the adrenal medulla have the same embryonic origin as neural tissue and, in fact, function as modified postganglionic neurons. Instead of the release of neurotransmitter directly at the synapse with an effector tissue, the secretory products of the adrenal medulla are picked up by the blood and travel throughout the body to all of the effector tissues of the sympathetic system. 

Noradrenaline is not only present in the sympathetic nerve endings but in the glandular cells of the adrenal medulla as well. The contents of noradrenaline in the medulla is dependent on the functional state of the gland and the species. Noradrenaline is always the precursor of adrenaline. In the central nervous system there are regions with a high noradrenaline content the hypothalamus and vegetative centers. 

Norepinephrine modulates many behavioral, cognitive, and physiological functions [72, 73], The catecholamine neurotransmitters dopamine and norepinephrine are stored in synaptic vesicles prior to release from the cell. It is within these vesicles that DpH is localized. Although most of the DpH is bound to the membrane of the vesicles, some DpH is free and is co-released with the catecholamines during synaptic transmission from neurons and into the blood from neurosecretory cells of the adrenal medulla [74], The levels found in serum are highly correlated between sibs, but varies between unrelated subjects [75], This variation has been found to be heritable in family and twin studies in both serum and CSF [76]. 

Adrenaline is the major component of the hormonal secretion of the adrenal medulla and in the adrenal gland noradrenaline can be regarded simply as a precursor of the active substance. In sympathetic nerves, however, catecholamine synthesis proceeds no further than noradrenaline, which exists there as a transmitter substance in its own right, with properties different from those of adrenaline. Noradrenaline and small amounts of adrenaline are present in the brain also, but in addition, certain areas of the brain contain amounts of dopamine quite out of prop>ortion to their noradrenaline content and there is suggestive evidence that dopamine has an independent neurohumoral function. The unique situation thus arises that one, or probably two of the precursors of adrenaline have specialized functions of their own. 

Pituitary Adenylyl Cyclase-activating Polypeptide (PACAP) is a 38-amino acid peptide (PACAP-38), which is widely expressed in the central nervous system. PACAP is most abundant in the hypothalamus. It is also found in the gastrointestinal tract, the adrenal gland and in testis. Its central nervous system functions are ill-defined. In the periphery, PACAP has been shown to stimulate catecholamine secretion from the adrenal medulla and to regulate secretion from the pancreas. Three G-protein coupled receptors have been shown to respond to PACAP, PAQ (PACAP type I) specifically binds PACAP, VPACi and VPAC2 also bind vasoactive intestinal peptide (VDP). Activation of PACAP receptors results in a Gs-mediated activation of adenylyl cyclase. 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

Vertebrates also show expression of AADC in both neural and non-neural tissues. AADC has been purified from kidney (Christenson et al., 1972), liver (Ando-Yamamoto et al., 1987), adrenal medulla (Albert et al., 1987), and pheochromocytoma (Coge et al., 1989 Ichinose et al., 1989). In the adrenal medulla dopamine is further processed into epinephrine and norepinephrine, which are released from the chromaffin cells during stress to increase heart rate and blood pressure. There are no detectable monoamines in the liver and kidney, and the function of AADC in these tissues is unknown. AADC activity has also been... 

Cuanethidine possesses high affinity for the axolemmal and vesicular amine transporters, it is stored instead of NE, but is unable to mimic the functions of the latter, in addition, it stabilizes the axonal membrane, thereby impeding the propagation of impulses into the sympathetic nerve terminals. Storage and release of epinephrine from the adrenal medulla are not affected, owing to the absence of a re-uptake process. The drug does not cross the blood-brain barrier. 

Adrenaline is the main hormone released from the adrenal medulla. The glandular cells in this structure correspond to the second, postganglionic neuron of the sympathetic nervous system. Furthermore, adrenaline can be found in chromaffin cells in various tissues. For the better understanding of the function of noradrenaline it is important to realize that this substance, as a neuronal transmitter, affects only the innervated target structure, that is it acts mainly locally. Among these effects are the activation of the musculus dilatator to widen the pupillae in response to a reduced light intensity, an increase in heart rate as a response to a blood pressure drop due to a reduction of the peripheral resistance or constriction... 

Table 9-4). Activation of 32 receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, epinephrine functions largely as a hormone after release from the adrenal medulla into the blood, it acts on distant cells. Norepinephrine (levarterenol, noradrenaline) is an agonist at both 0 and tx2 receptors. Norepinephrine also activates receptors with similar potency as epinephrine, but has relatively little effect on 32 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine however, the positive inotropic effects on the heart are maintained (Table 9-4). 

AT2 receptors are present at high density in all tissues during fetal development, but they are much less abundant in the adult where they are expressed at high concentration only in the adrenal medulla, reproductive tissues, vascular endothelium, and parts of the brain. AT2 receptors are up-regulated in pathologic conditions including heart failure and myocardial infarction. The functions of the AT2 receptor appear to include fetal tissue development, inhibition of growth and proliferation, cell differentiation, apoptosis, and vasodilation. 

The general scheme of the biosynthesis of catecholamines was first postulated in 1939 (29) and finally confirmed in 1964 (Fig. 2) (30). Although not shown in Figure 2, in some cases the amino acid phenylalanine [63-91-2] can serve as a precursor it is converted in the liver to (-)-tyrosine [60-18-4] by the enzyme phenylalanine hydroxylase. Four enzymes are involved in E formation in the adrenal medulla and certain neurons in the brain tyrosine hydroxylase, dopa decarboxylase (also referred to as L-aromatic amino acid decarboxylase), dopamine-P-hydroxylase, and phenylethanolamine iV-methyltransferase. Neurons that form DA as their transmitter lack the last two of these enzymes, and sympathetic neurons and other neurons in the central nervous system that form NE as a transmitter do not contain phenylethanolamine N-methyl-transferase. The component enzymes and their properties involved in the formation of catecholamines have been purified to homogeneity and their properties examined. The human genes for tyrosine hydroxylase, dopamine- 3-oxidase and dopa decarboxylase, have been cloned (31,32). It is anticipated that further studies on the molecular structure and expression of these enzymes should yield interesting information about their regulation and function. 

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