All sympathetically innervated tissue Adrenal medulla Liver
Stomach Pancreas DA ~ Epi >> NE Liver
Chromaffin cells Capillary endothelial cells Syncytiotrophoblast
Parietal and endothelial cells Pancreatic duct
Intestine Epithelial cells
Kidney (not human) Distal tubule
Liver Brain Heart
Blood vessels Kidney
Medullary proximal and distal tubules Glial cells of DArich regions, some nonadrenergic neurons
Hepatocytes Glial cells, others Myocytes Endothelial cells Cortex, proximal and distal tubules Syncytiotrophoblast (basal membrane) Photoreceptors, ganglion amacrine cells
Desipramine, cocaine, nisoxetine
Isocyanines, corticosterone, O-methyl-isoproterenol
ABBREVIATIONS: NET, norepinephrine transporter, originally known as uptake 1; DAT, dopamine transporter; ENT (OCT3), extraneuronal transporter, originally known as uptake 2; OCT1, OCT2, organic cation transporters; Epi, epinephrine; NE, norepinephrine; DA, dopamine.
neurotransmitter release. Numerous heteroreceptors on sympathetic nerve varicosities also inhibit the release of sympathetic neurotransmitters; these include: M2 and M4 muscarinic, 5-HT, PGE2, histamine, enkephalin, and DA receptors. Enhancement of sympathetic neurotransmitter release can be produced by activation of b2 adrenergic receptors, angiotensin II receptors, and nACh receptors. All these receptors are targets for agonists and antagonists.
TERMINATION OF THE ACTIONS OF CATECHOLAMINES The actions of NE and Epi are terminated by (1) reuptake into nerve terminals by NET; (2) dilution by diffusion out of the junctional cleft and uptake at end organs and extraneuronal sites by ENT, OCT1, and OCT2. Subsequent to uptake, the catecholamines are subject to metabolic transformation by MAO and catechol-O-methyltransferase (COMT). In addition, catecholamines are metabolized by sulfotransferases (see Chapter 3). Termination of action by a powerful degradative enzymatic pathway, such as that provided by AChE in cholinergic transmission, is absent from the adrenergic system. Inhibitors of neuronal reuptake of catecholamines (e.g., cocaine, imipramine) potentiate the effects of the neurotransmitter, whereas inhibitors of MAO and COMT have relatively little effect, demonstrating the predominant role of uptake in termination of effect. However, MAO metabolizes transmitter that is released within the nerve terminal cytosol. COMT, particularly in the liver, plays a major role in the metabolism of endogenous circulating and administered catecholamines.
Both MAO and COMT are distributed widely throughout the body, including the brain; the highest concentrations of each are in the liver and the kidney. However, little or no COMT is found in sympathetic neurons. In the brain, there is also no significant COMT in presynaptic terminals, but it is found in some postsynaptic neurons and glial cells. In the kidney, COMT is localized in proximal tubular epithelial cells, where DA is synthesized, and is thought to exert local diuretic and natriuretic effects. The physiological substrates for COMT include L-dopa, all three endogenous catecholamines (DA, NE, and Epi), their hydroxylated metabolites, catecholestrogens, ascorbate, and dihydroxyindolic intermediates of melanin. MAO and COMT are differentially localized: MAO associated chiefly with the outer surface of mitochondria, COMT largely cytosolic. These factors help to determine the primary metabolic pathways followed by catecholamines in various circumstances and to explain effects of certain drugs. Two different isozymes of MAO (MAO-A and MAO-B) are found in widely varying proportions in different cells in the CNS and in peripheral tissues. In the periphery, MAO-A is located in the syncytiotrophoblast layer of term placenta and liver, whereas MAO-B is located in platelets, lymphocytes, and liver. In the brain, MAO-A is located in all regions containing catecholamines, with the highest abundance in the locus ceruleus. MAO-B, on the other hand, is found primarily in regions that are known to synthesize and store serotonin. MAO-B is most prominent in the nucleus raphe dorsalis but also in the posterior hypothalamus and in glial cells in regions known to contain nerve terminals. MAO-B is also present in osteocytes around blood vessels.
Selective inhibitors of these two isozymes are available (see Chapter 17). Irreversible antagonists of MAO (e.g., phenelzine, tranylcypromine, and isocarboxazid) enhance the bioavailability of tyramine contained in many foods by inhibiting MAO-A; tyramine-induced NE release from sympathetic neurons may lead to markedly increased blood pressure (hypertensive crisis); selective MAO-B inhibitors (e.g., selegiline) or reversible MAO-A—selective inhibitors (e.g., moclobe-mide) are less likely to cause this potential interaction. MAO inhibitors are useful in the treatment of Parkinson's disease and mental depression (see Chapters 17and 20).
Most of the Epi and NE that enters the circulation—from the adrenal medulla, sympathetic discharge or exogenous administration—is methylated by COMT to metanephrine or normetanephrine, respectively (Figure 6-6). NE that is released intraneuronally by drugs such as reserpine is deaminated initially by MAO and the aldehyde is reduced by aldehyde reductase or oxidized by aldehyde dehydrogenase. 3-Methoxy-4-hydroxymandelic acid [generally but incorrectly called vanillylmandelic acid (VMA)] is the major metabolite of catecholamines excreted in the urine. The corresponding product of the metabolic degradation of DA, which contains no hydroxyl group in the side chain, is homovanillic acid (HVA). Other metabolic reactions are described in Figure 6-6. Measurement of the concentrations of catecholamines and their metabolites in blood and urine is useful in the diagnosis of pheochromocytoma, a catecholamine-secreting tumor of the adrenal medulla/chromaffin tissue.
Inhibitors of MAO (e.g., pargyline and nialamide) can cause an increase in the concentration of NE, DA, and 5-HTin the brain and other tissues accompanied by a variety of pharmacological effects. No striking pharmacological action in the periphery can be attributed to the inhibition of COMT. However, the COMT inhibitors entacapone and tocapone are efficacious in the therapy of Parkinson's disease (see Chapter 20).
CLASSIFICATION OF ADRENERGIC RECEPTORS Understanding the diverse effects of the catecholamines and sympathomimetic agents requires understanding the properties of the different types of adrenergic receptors and their distribution on various tissues and organs (Tables 6-1, 6-5, 6-6, 6-7, and 10-6).
MOLECULAR BASIS OF ADRENERGIC RECEPTOR FUNCTION Adrenergic receptors are divided into two main classes, a and and thence into subclasses. All of the adrenergic receptors are GPCRs that link to heterotrimeric G proteins, each receptor showing a preference for a particular class of G proteins, that is, a1 to Gq, a2 to Gi, and all b to Gs (Table 6-6). The responses that follow activation of adrenergic receptors result from G protein-mediated effects on the generation of second messengers and on the activity of ion channels.
Was this article helpful?