Ai-Adrenoceptors

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

Regulation of transmitter release does not rest solely on the frequency at which nerve impulses reach the terminals. Early experiments using stimulated sympathetic nerve/end-organ preparations in situ, or synaptosomes, indicated that release of [ HJnoradrenaline was attenuated by exposure to unlabelled, exogenous transmitter. This action was attributed to presynaptic adrenoceptors, designated a2-adrenoceptors, which were functionally distinct from either aj- or )S-adrenoceptors. Later experiments have confirmed that ai-adrenoceptors comprise a family of pharmacologically and structurally distinct adrenoceptor subtypes. 

Taking ai-adrenoceptors as an example, several possible mechanisms have been suggested (see Starke 1987). The first rests on evidence that these autoreceptors are coupled to a Gi (like) protein so that binding of an a2-adrenoceptor agonist to the receptor inhibits the activity of adenylyl cyclase. This leads to a fall in the synthesis of the second messenger, cAMP, which is known to be a vital factor in many processes involved in exocytosis. In this way, activation of presynaptic a2-adrenoceptors could well affect processes ranging from the docking of vesicles at the active zone to the actual release process itself... 

Tyramine is produced by decarboxylation of tyrosine and is present in the CNS in higher (threefold) concentrations than m-tyramine, the hydroxylated derivative of phenylethylamine. In the periphery / -tyramine is easily hydroxylated to octopamine, which has some direct effects on ai adrenoceptors, unlike tyramine which functions by releasing NA. When tested on central neurons tyramine always produces the same effects as NA but they are slower and less marked, implying an indirect action. By contrast octopamine often produces the opposite effect to NA and it is probable that octopamine may have a functional role in the invertebrate CNS where it is found in higher concentrations (5pg/g) than in the mammalian brain (0.5ng/g). Neither tyramine nor octopamine have distinct behavioural effects, unlike phenylethylamine,... 

Because the SSRIs are derived from different chemical groups, their receptor interactions vary from compound to compound but, apart from paroxetine, none of them shows any appreciable binding to muscarinic receptors, a prime objective of their development. However, compared with other SSRIs, fluoxetine binds with moderately high affinity to human 5-HT2A (.K) 280 nM) and 5-HT2C receptors (Aij 55 nM) sertraline is a relatively potent ligand for ai-adrenoceptors, 2-adrenoceptors and Dj receptors and citalopram shows appreciable binding to 5-HTia, oc]-adrenoceptors and Hi receptors (Table 20.6 Stanford 1996). The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. 

One of these compounds, venlafaxine (licensed in the UK in 1996), is regarded as an inhibitor of both 5-HT and noradrenaline reuptake but this is based on its actions in vitro. At low doses in vivo, it is a more potent inhibitor of 5-HT (Ki 39 nM) than noradrenaline reuptake (K 210 nM). Moreover, its active metabolite, O-demethylven-lafaxine, is a weaker inhibitor of NA reuptake, and has a longer half-life, than its parent compound. However, at high doses, venlafaxine inhibits reuptake of both these monoamines but has negligible activity at muscarinic, Hi-receptors or ai-adrenoceptors and... 

Sullivan AP, Dashwood MR, Dickenson AH (1987) ai adrenoceptor modulation of nociception in rat spinal cord location, effects and interaction with morphine. Eur J Pharmacol 138 169-177... 

Mydriasis is induced by ai-adrenoceptor-mediated contraction of the radial pupillary dilator muscle of the iris. Furthermore, activation of this receptor subtype induces an increased outflow of humor from the eye while /i-adrenoceptor stimulation mediate an enhanced humor production which contributes to an increased intraocular pressure. /3-Adrenoceptor antagonists (/3-blocker) can be used in the treatment of glaucoma. 

Urapidil is a selective ai-adrenoceptor antagonist with an additional central antihypertensive mechanism, mediated by the stimulation of serotonergic (5-HTia) receptors in the brain. It may be used in the treatment of essential, but also acute, peri-operative hypertension. The intravenous administration in the treatment of acute, peri-operative hypertension is not associated with a rise of intracranial pressure, in contrast to various other vasodilators. For this reason, urapidil may be used in neuro-surgical interventions. 

Dobutamine is the most frequently used drug of this category. It is considered to be a selective /3i-adrenoceptor stimulant, although it displays weak P2- and ai-adrenoceptor stimulation as well. It... 

Silodosin is an ai-adrenoceptor antagonist that is being marketed for the treatment of urinary disturbances associated with BPH (Figure 8.80). 

The nonselective (i-adrenergic blocking agent that is also a competitive antagonist at ai-adrenoceptors is... 

Ishikawa Y, Skowronski M T, Inoue N, Ishida H. 1999. ai-Adrenoceptor-induced trafficking of aquaporin-5 to the apical plasma membrane of rat parotid cells. Biochem Biophys Res Com 265 94-100. 

F., Barlocco, D., Dal Piaz, V., Leonardi, A., Poggesi, E., Fanelli, F., De Benedetti, P. G. Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their corresponding 4,5-disub-stituted-3-(2H)-pyridazinone analogues as new substrates for ai-adrenoceptor selective antagonists synthesis, modeling and binding studies. Bioorg. Med. Chem. 1998, 6, 925-935. 

Fig. 2 Presynaptic signaling mechanisms of ai adrenoceptor subtypes (Oia, 2B, Ofec)- Abbreviations W2abc> Pi23> adrenoceptor subtypes MAP, mitogen-activated protein kinase.

Antidepressant drugs can rarely cause priapism. The agent most often implicated has been trazodone, perhaps because of its ai-adrenoceptor antagonist properties. In general venlafaxine has an inhibitory effect on sexual function, but perhaps, like SSRIs, it can rarely cause priapism (23). 

It has been shown that excitatory ai-adrenoceptor is present on both On and Off cells, but the inhibitory a2-adrenoceptor is present only on the Off cells, and the activation of On cells can be involved in the increased pain sensitivity during opioid withdrawal (Bie et al., 2003). Thus, activation of a2-adrenoceptors in NRM may induce antinociceptive effects (Haws et al., 1990 Proudfit, 1988). The activation of LC neurons by a2-adrenoceptor agonists also produces antinociception, and a2-adrenoceptor activation might contribute to the antinociceptive effects of amygdala... 

Stone EA, Lin Y, Rosengarten H, Kramer HK, Quartermain D. Emerging evidence for a central epinephrine-innervated ai-adrenoceptor system that regulates behavioural activation and is impaired in depression. Neuropsychopharmacology 2003 28 1387-1399. 

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