exclusively on the meta-OH group of the catechol, regardless of whether the catechol is NE, E, or one of the metabolic products. For example, the action of COMT on NE and E gives normetanephrine and metanephrine, respectively. A converging pattern of the metabolism of NE and E in which 3'-methoxy-4'-hydroxymandelic acid (VMA) and 3'-methoxy-4'-hydroxyphenylethylene glycol are common end products thus occurs, regardless of whether the first metabolic step is oxidation by MAO or o-methylation by COMT. In patients with tumors of chromaffin tissue that secrete these amines (a rare cause of high blood pressure), the urinary excretion of VMA is markedly increased and is used as a diagnostic test for this condition.
Under normal circumstances, VMA is the principal urinary metabolite of NE, although substantial amounts of 3'-methoxy-4'-hydroxyphenylethylene glycol are excreted along with varying quantities of other metabolites, both in the free form and as sulfate or glucuronide conjugates (not shown in the schemes). Endogenous E is excreted primarily as metanephrine and VMA. These pathways of metabolism are also important to drugs that are structural analogs of NE. Tolcapone (Tasmar) and entacapone (Comtan) are COMT inhibitors presently available.
CAs released from either noradrenergic nerve terminals or the adrenal medulla are recognized by and bind to specific receptor molecules on the plasma membrane of the neuroeffector cells. These receptor ligand interactions produce a physiological response. Many cells possess these receptors, and the binding of an agonist will generally cause the organism to respond in a fight-or-flight manner. For instance, the heart rate will increase and the pupils will dilate, energy will be mobilized, and blood flow will be diverted from other organs to skeletal muscle.
o ADRENERGIC RECEPTORS Adrenergic Receptor Subtypes
Membrane receptors transfer information from the environment to the cell's interior. A few nonpolar signal molecules such as estrogens and other steroid hormones are able to diffuse through the cell membranes and, hence, enter the cell. However, most signaling molecules such as CAs are too polar to pass through the membrane, and no appropriate transport systems are available. Thus, the information that they present must be transmitted across the cell membrane without the molecules themselves entering the cell. A membrane-associated receptor protein such as adrenergic receptors often performs the function of information transfer across the membrane.
In 1948, Ahlquist9 proposed and designated a- and [-adrenoceptors based on their apparent drug sensitivity. The diverse physiological responses of CAs are mediated via a1-, a2-, and [-adrenoceptors, which are further divided into aiA, aiB, aiD, a2A, a2B, a2C, [1, [2, and [3. They all belong
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