A2 Adrenoceptor agonists

Rilmenidine. RiLmenidine is a central a2 adrenoceptor agonist and has been shown to be a potent centrally acting antihypertensive agent without the prominent side effect of sedation. 

The release of NO from the endothelium is induced by various chemical substances, including acetylcholine polypeptides such as substance P, bradykinin, and arginine vasopressin histamine ATP/ADP a2-adrenoceptor agonists thrombin and Ca2+ iono-phores. NO formed in response to mechanical stimuli like shear stress or transmural pressure plays an important role in maintaining basal blood flow. Endothelial NO causes vasodilatation, decreased... 

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... 

Alternative mechanisms are equally likely. One possibility arises from evidence that activation of a2-adrenoceptors reduces Ca + influx this will have obvious effects on impulse-evoked exocytosis. In fact, the inhibition of release effected by a2-adrenoceptor agonists can be overcome by raising external Ca + concentration. Finally, an increase in K+ conductance has also been implicated this would hyperpolarise the nerve terminals and render them less likely to release transmitter on the arrival of a nerve impulse. Any, or all, of these processes could contribute to the feedback inhibition of transmitter release. Similar processes could explain the effects of activation of other types of auto-or heteroceptors. 

Methyldopa is an false substrate for the dopamine-/ -hydroxylase resulting in a-methylnor-adrenaline. This metabolite is an a2-adrenoceptor agonist an induce, like clonidine, a centrally mediated reduction of sympathetic tonus. 

Sallinen, J., Link, R.E., Haapalinna, A., Viitamaa, T, Kulatunga, M., Sjoholm, B., MacDonald, E., Pelto-Huikko, M., Leino, T., Barsch, G.S., Kobilka, B.K., and Scheinin, M. (1997) Genetic alteration of a2c-adrenoceptor expression in mice influence on locomotor, hypothermic, and neurochemical effects of dexemedetomidine, a subtype-nonselective a2-adrenoceptor agonist. Mol Pharmacol 36 36 6. 

Another point is that talipexole and rauwolscine do not only decrease and increase, respectively, the effect of histamine but of course, in addition, decrease and increase NA release per se. One might argue that the alteration in the amount of NA release (rather than the activation or blockade of the a2-adrenoceptor) is the reason why the effect of histamine is decreased and increased, respectively. For clarification of this problem, experiments were done in which the current strength or the duration of the electrical pulses was changed in order to adjust the amount of NA release to the level obtained in brain slices not exposed to the a2-adrenoceptor agonist or antagonist. 

Figure 8. Original tracings showing the effects of (R)a-methylhistamine (MHA, pM), thioperamide (TH, pM), the selective a2 adrenoceptor agonist UK-14304 (UK, nM) and the a2-adrenoceptor antagonist idazoxan (ID, pM) on different in vitro assays from the guinea pig ileum A) Electrically-evoked longitudinal contractions of the whole ileum B) Peristaltic waves of the perfused ileum, C) Reflex-evoked circular muscle contractions Vertical calibrations represent (A and C) centimeters of isotonic contractions or (B) changes in perfusion pressure. Horizontal calibration is the chart speed, w = washing of the preparation...

Fluvoxamine 100 mg/day resulted in a large (about 30-fold) increase in plasma concentrations of tizanidine in 10 healthy volunteers (120). This interaction caused significant physiological consequences, including a substantial fall in systolic blood pressure, perhaps because tizanidine is an a2-adrenoceptor agonist. The authors suggested that the interaction was likely to be due to fluvoxamine -mediated inhibition of CYP3A4, which is involved in the metabolism of tizanidine. 

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... 

England G C, Clarke K W 1996 a2 adrenoceptor agonists in the horse a review. British Veterinary Journal 152 641-657... 

England G C, Clarke K W, Goossens L 1992 A comparison of the sedative effects of three a2-adrenoceptor agonists (romifidine, detomidine and xylazine) in the horse. Journal of Veterinary Pharmacology and Therapeutics 15 194-201... 

Sallinen J, Link RE, Haapalinna A, et al. Genetic alteration of a2C-adrenoceptor expression in mice influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective a2-adrenoceptor agonist. Mol Pharmacol 1997 51 36 16. 

At a dosage of 5 mg/kg (i.v.), tetrandrine was found to inhibit the pressor action of norepinephrine release induced by electrical stimulation of spinal cord Tn-L2. However, tetrandrine (5 mg/kg, i.a.) did not obviously attenuate the hypertensive responses to norepinephrine (0.51-16.91 pg/kg, i.v.), indicating that the alkaloid did not affect a1-adrenoceptor-mediated vasoconstriction. Tetrandrine (5 mg/kg, i.a.) was found to decrease the pressor responses to norepinephrine (0.05 and 0.17 pg/kg, i.v.) and markedly reduce the dose-dependent hypertensive responses to a selective a2-adrenoceptor agonist (B-HT920, i.v.), suggesting that the alkaloid reduced a2-adrenoceptor-mediated vasoconstriction [321]. 

Cascio MG, Gauson LA, Stevenson LA et al (2010) Evidence that the plant cannabinoid cannabigerol is a highly potent a2-adrenoceptor agonist and moderately potent 5HTiA receptor antagonist. Br J Pharmacol 159 129-141... 

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