Postsynaptic a-adrenoceptor

P. Guicheney, P. Meyer (1979). Biochemical approach to pre- and postsynaptic a-adrenoceptors. Trends Pharmacol. Sci. 1 69-71. 

Postsynaptic a-adrenoceptors have been characterized in afferent and efferent arterioles isolated from rabbit renal cortex [263]. In both the afferent and efferent arteriole selective a 1-adrenoceptor agonists produced concentration-dependent vasoconstrictor responses with the maximum responses being equal to that of norepinephrine. Selective a 2-receptor agonists had less of an effect. The a 1-receptor antagonist, prazosin, produced a rightward shift in the concentration-response curve to norepinephrine, while the selective a 2-receptor antagonist, rauwolscine had no... 

Figure 9-10. Pre- and postsynaptic a adrenoceptors of noradrenergic synapses. (From Timmermen and Van Zwieten, 1972). NA = norepinephrine.

POSTSYNAPTIC a-ADRENOCEPTOR ANTAGONISTS [SEDA-31, 363 SEDA-32, 391 SEDA-33, 425]... 

The use of postsynaptic a-adrenoceptor antagonists in older patients with benign prostatic hyperplasia has been reviewed [102 ]. 

Methyldopa, through its metaboHte, CX-methyInorepinephrine formed in the brain, acts on the postsynaptic tt2-adrenoceptor in the central nervous system. It reduces the adrenergic outflow to the cardiovascular system, thereby decreasing arterial blood pressure. If the conversion of methyldopa to CX-methyl norepinephrine in the brain is prevented by a dopamine -hydroxylase inhibitor capable of penetrating into the brain, it loses its antihypertensive effects. 

Several findings support this model. For instance, an early report suggested that there is a positive correlation between the density of (postsynaptic) jS-adrenoceptors in rat cortex and behavioural resistance to a mild environmental stress (novelty and frustration) but a negative correlation between these parameters when the stress is intensified (Stanford and Salmon 1992). More recently, it has been proposed that the phasic response of neurons in the locus coeruleus (which governs attentiveness ) depends on their tonic activity (which determines arousal). Evidence suggests that the relationship between these two parameters is described by a bell-shaped curve and so an optimal phasic response is manifest only at intermediate levels of tonic activity (Rajkowski et al. 1998). 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

Phenoxybenzamine and phentolamine, in addition to blocking postsynaptic a-receptors, also block aj-receptors on nerves and therefore can enhance the release of norepinephrine. When norepinephrine exerts a postsynaptic action by means of -adrenoceptors (e.g., cardiac stimulation, renin release), blockade of presy-naptic a2-receptors by phenoxybenzamine and phentolamine may actually potentiate the responses. Prazosin blocks responses mediated by postsynaptic aj-receptors but has no effect on the presynaptic a2-receptors. Thus,... 

Trazodone (Apothecon) is also classified as an antidepressant agent. It is a selective serotonin reuptake inhibitor (SSRI), partial agonist at postsynaptic 5-HTia receptors, and exhibits a-adrenoceptor blocking actions. 

The postsynaptic S-adrenoceptors (jS-ARs) belong to the rhodopsin/ S2 adrenergic receptor-like receptors that belong to one of three major subfamilies of the GPCRs [83]. The S-AR family is subdivided into at least three discrete subtypes, the ySr, )S2-AR [84], and the atypical jSa-AR [85,86]. Additionally, a putative subtype has been identified in cardiac tissue, classified as the P4-AR [87], The P-]- and S2-AR are Gs-protein coupled, thereby elevating the intracellular level of cyclic adenosine monophosphate (cAMP) and causing positive inotropic and chronotropic effects [88]. The P2-AR can also couple to the Grprotein. 

Alpha-adrenoceptor antagonists inhibit the activation of a adrenoceptors by catecholamines. In the cardiovascular system these receptors are mainly located on the surface of smooth muscle cells in the walls of arteries and veins. On activation, they mediate an increase in intracellular free calcium, which induces smooth muscle contraction. Inhibition by an a antagonist causes arterial or venous vasodilatation. The postsynaptic effect is mainly mediated by ol adrenoceptors whereas o2 adrenoceptors are found on the presynaptic membranes of the sympathetic neurones. Activation of o2-adreno-ceptors results in auto-inhibition of catecholamine release. 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and a-methylnorepinephrine bind more tightly to a2 than to adrenoceptors. As noted in Chapter 6, a2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and -methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic a2 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects. 

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