Adrenoceptors catecholamines

Catecholamines. The catecholamines, epinephrine (EPl adrenaline) (85), norepinephrine (NE noradrenaline) (86) (see Epinephrine and norepinephrine), and dopamine (DA) (2), are produced from tyrosine by the sequential formation of L-dopa, DA, NE, and finally EPl. EPl and NE produce their physiological effects via CC- and -adrenoceptors, a-Adrenoceptors can be further divided into CC - and a2-subtypes which in turn are divided... 

Catecholamine receptors are well estabUshed to be altered by a variety of homologous and heterologous influences (104). Thus, in hyperthyroidism, there is an increased level of sympathetic activity associated with increased expression of a- and P-adrenoceptors. 

The properties of -adrenoceptor blockers that contribute to antiarrhythmic effects are antagonism of neural/humoral P-adrenergic activity, and antagonism of catecholamine-mediated electrophysiological properties, ie, increase refractory period and decrease in the rate of diastoHc depolarization, ie, decrease automaticity and slow atrioventricular conduction (1,2). 

Propranolol. Propranolol hydrochloride, considered the prototype of the P-adrenoceptor blocking agents, has been in use since 1964. It is a nonselective, highly Hpid-soluble P-adrenoceptor blocker having no ISA. It is a mixture of (+) and (—) enantiomers, and the (—) enantiomer is the active moiety. The local anesthetic effects of propranolol are equipotent to those of Hdocaine [137-58-6] C 4H22N20, (see Anesthetics). Therapeutic effects include termination of catecholamine-induced arrhythmias, conversion of SA nodal tachycardias (including flutter and fibrillation) and AV nodal tachyarrhythmias to normal sinus rhythm, digitahs-induced arrhythmias, and ventricular arrhythmias (1,2). The dmg also has cardioprotective properties (37,39). 

Kessar, P. and Sa erson, E.D. (1980). Evidence that catecholamines stimulate renal gluconeogenesis through a-type of adrenoceptor. Biochem. J. 190, 119-123. 

Dichloro-isoprenaline was the first [3-adrenoceptor antagonist to he described (6). It was discovered in a search for specific (3-stimulants as bronchodilators. This compound is a partial agonist, i.e. it can antagonise the action of isoprenaline hut itself is a (3-stimulant. (The stimulant action of dichloro-isoprenaline is readily demonstrated in an animal depleted of natural catecholamines ( with say reserpine). In this type of preparation it will stimulate say heart rate to a maximum of 70% of that produced hy isoprenaline itself). 

The adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors, which are the targets of catecholamines. Adrenergic receptors specifically bind their endogenous ligands, the catecholamines, epinephrine, and norepinephrine (also called adrenaline and noradrenaline), and are activated by these. 

As mentioned above, the receptors which are sensitive to catecholamines are the so-called adrenoceptors. At least five major subtypes are present and of physiological relevance the a - (pharmacologically subdivided in a A, and ofio), 0(2- (pharmacologically subdivided in o 2A, oi2B and af2c) p2 and y03-adrenoceptor subtypes, which all belong to the G-protein coupled receptor superfamily. 

Noradrenaline and adrenaline increase blood pressure, although in various organs the perfusion can actually be reduced. Since adrenaline, in contrast to noradrenaline, stimulates a-and jSi-adrenoceptors and the jSi-subtype as well, its vascular effects are more complex than those of noradrenaline. In many vessel beds like the splanchnic area and the skin the O -adrenoceptor-mediated vasoconstriction is dominant. However, in others, like the active skeletal muscles, the jS2-adrenoceptor-mediated vasodilatation increases the blood flow. In the lower concentration range adrenaline induce an increase in blood pressure without elevated diastolic values. Catecholamines reduce the permeability of the vascular endothelium which might be of some importance for their antiallergic properties. 

The effect of catecholamines on the human uterus, which can be mediated by a- and /3-adrenoceptors, depends on its functional state. During pregnancy /32-adrenoceptor stimulation decrease the uteral tonus, an effect that can be used therapeutically. /32-Adrenoceptor agonists are in use as tocolytics. In the bladder base and the urethral sphincter a-adrenoceptors are present, mediating a contraction, whereas the /32-adrenoceptors of the bladder wall induce a relaxation of the particular smooth muscles present at these structures. Ejaculation is regulated by a-adrenoceptors. 

Catecholamines exert a pronounced effect on intermediary metabolism. An activation of /8-adrenoceptors leads to lipolysis and glycogenolysis resulting in increased plasma glucose and free fatty... 

Fig. 5. Influence of substituents at the catecholamine molecule the hydroxyl-groups at the phenyl-ring are mendantory for any affinity to all adrenoceptor subtypes. The substituent at the nitrogen in the side chain determines the degree of affinity...

O -Adrenoceptor antagonists (o -blockers) are competitive inhibitors at the level of Q -adrenoceptors. These receptors are found in many organs and tissues, but their predominant functional importance is to mediate the vasoconstrictor effects of endogenous catecholamines (noradrenaline, adrenaline) released from the sympathetic nerve endings. Conversely, Q -adrenoceptor antagonism by means of an a-blocker will inhibit this constrictor activity and hence cause vasodilatation. This vasodilator effect occurs in both resistance vessels (arterioles) and capacitance vessels (veins), since a-adrenoceptors are present in both types of vascular structures. Accordingly, both cardiac afterload and preload will be lowered, in particular when elevated. 

Adrenoceptors of the /3-subtype are important mediators of the sympathetic activation of the heart, kidney, and bronchi. /3-Adrenoceptors are also found in other organs and tissues such as blood vessels and the central nervous system. Accordingly, /3-adrenoceptor antagonists or jS-blockers inhibit the stimulating influence of the endogenous catecholamines (noradrenaline, adrenaline) on the various organs and tissues which are subject to sympathetic innervation. In cardiovascular medicine the /3-blockers are used in particular to blunt the sympathetic activation of the heart and kidneys. These effects are mediated by the /3i-subtype of the /3-adrenoceptors. The currently used /3-blockers are all competitive antagonists of the /3i-adrenoceptor, which is the basis of their therapeutic application. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

The adrenomimetic drugs, including the naturally occurring catecholamines, initiate their responses by combining with a-, P-, or dopamine adrenoceptors. This interaction triggers a series of biochemical events starting within the effector cell membrane that eventually culminates in the production of a physiological response. 

In general, the responses to administered catecholamines are similar to those seen after sympathetic nerve stimulation and depend on the type of adrenoceptor in the muscle. 

Uterine muscle contains both a- and (3-adrenoceptors, which mediate contraction and relaxation, respectively. The response of the human uterus to catecholamines is variable and depends on the endocrine balance of the individual at the time of amine administration (see Chapter 62). During the last stage of pregnancy and during parturition, epinephrine inhibits the uterine muscle, as does isoproterenol norepinephrine contracts the uterus. 

The catecholamines can play an important role in the short-term regulation of plasma potassium levels. Stimulation of hepatic a-adrenoceptors will result in the release of potassium from the liver. In contrast, stimulation of (32-adrenoceptors, particularly in skeletal muscle, will lead to the uptake of potassium into this tissue. The (32-adrenoceptors are linked to the enzyme Na"", K+ adenosine triphosphatase (ATPase). Excessive stimulation of these (32-adrenoceptors may produce hypokalemia, which in turn can be a cause of cardiac arrhythmias. 

Molecular genetic techniques have confirmed the existence of multiple subtypes of p-adrenoceptors. Pi-Receptors and Pj-receptors have been cloned, and recent molecular biological evidence indicates the existence of at least one additional p-receptor sub-type, called the p3-receptor. It is suggested that the P3-receptor may mediate some of the metabolic effects of catecholamines, although no available p-blocker has been shown to rely on Pa-receptor antagonism for its therapeutic effectiveness. 

The rate of pacemaker discharge within these specialized myocytes is influenced by the activity of both divisions of the autonomic nervous system. Increased sympathetic nerve activity to the heart, the release of catecholamines from the adrenal medulla, or the exogenous administration of adrenomimetic amines will cause an increase in the rate of pacemaker activity through stimulation of -adrenoceptors on the pacemaker cells (Figure 16.3). 

Class II antiarrhythmic drugs competitively inhibit /3-adrenoceptors and inhibit catecholamine-induced stimulation of cardiac 15-receptors. In addition, some members of the group (e.g., propranolol and acebutolol) cause electrophysiological alterations in Purkinje fibers that resemble those produced by class I antiarrhythmic drugs. The latter actions have been called membrane-stabilizing effects. 

The myocardial response to exercise includes an increase in heart rate and myocardial contractility. These effects are mediated in part by the sympathetic nervous system. Propranolol and other p-adrenoceptor blockers antagonize the actions of catecholamines on the heart... 

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. 

D) Antagonism of CNS adrenoceptors to reduce inhibition produced by catecholamines... 

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