Catecholamines actions

There is good evidence that the facilitation of peripheral sympathetic nervous system transmission prcxluced by the amphetamines also occurs in the CNS.The possibihty that amphetamines act indirectly (i.e., by releasing monoamines) at monoaminergic synapses in the brain and spinal cord seems likely. However, amphetamine has effects beyond displacement of catecholamines these include inhibition of neuronal amine uptake, direct stimulation of dopamine and serotonin receptors, antagonism of catecholamine action at certain subtypes of adrenoceptors, and inhibition of monoamine oxidase. Interestingly, none of these actions explains the therapeutic benefit of the amphetamines in hyperkinetic children. 

Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38). The 13 antagonists are beneficial in this condition. The effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one 13 antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism) it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure. 

Melchiorre, C., Belleau, B., 1981. Recent developments in structure-activity relationships among inhibitors of the adrenergic a-receptor. In Kunos, G. (Ed.), Adrenoceptors and Catecholamine Action, Part A. Wiley, New York, pp. 131-179. 

Although much detail at the molecular level is still not fully known, it is clear that the majority of effects seen as a result of catecholamine actions at (3-adrenoceptors are mediated via adenyl cyclase activation and the resultant increase of c-AMP within cells. Thus the excitatory cardiac effects or increased inotropic response are the result of ( stimulation. (32 stimulation leads to inhibitory effects on smooth muscles. 

Comment - Earlier research interest has shifted from anticholinergic to catecholamine actions. Is the formation of 6-hydroxydopamine, which causes adrenergic nerve terminal destruction, the ca ise of the biochemical lesion of Parkinson s disease If true, new possibilities for cure or prevention through influencing the cause could emerge from the intensive catecholamine research effort. 

Ephedrine, which is not a catecholamine, has weak oral activity as a bronchodilator and although it has some direct action at adrenergic receptors, its predominant mode of action is by displacing norepinephrine from storage vesicules. 2"Agonists which are in use or are under investigation are the result of quests for improved selectivity, retention of potency, oral activity, and longer duration of action. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Besides behavior and blood pressure, catecholamine neurons also have important roles in other brain functions. Regulation of neuroendocrine function is a well-known action of catecholamines for example, DA agonists reduce semm prolactin concentration, especially in conditions of hypersecretion. Ingestive behavior can be modulated by brain catecholamines, and some appetite-suppressing dmgs are beheved to act via catecholaminergic influences. Catecholamines also participate in regulation of body temperature. 

Catecholamines are also intimately involved in cardiac function, with 3-sympathetic agonists having a generally stimulant action on the heart. Some effort has thus been devoted to the synthesis of agents that would act selectively on the heart. (Very roughly speaking, 3 -adrenergic... 

Adrenaline (epinephrine) is a catecholamine, which is released as a neurotransmitter from neurons in the central nervous system and as a hormone from chromaffin cells of the adrenal gland. Adrenaline is required for increased metabolic and cardiovascular demand during stress. Its cellular actions are mediated via plasma membrane bound G-protein-coupled receptors. 

A cell generates late afterdepolarizations (typically induced by catecholamines or digitalis) following a complete repolarization that may elicit an action potential. 

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

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