P2-adrenoceptor

P-Adrenoceptors have been subdivided into P - and P2-adrenoceptors. A third subset called nontypical P-adrenoceptors or P -adrenoceptors have been described but are stiU the subject of debate. In terms of the interactions with various subsets of P-adrenoceptors, some antagonists are nonselective in that they antagonize the effects of activation of both P - and P2-adrenoceptors, whereas others are selective for either P - or P2-adrenoceptors. P - and P2-adrenoceptors coexist in almost all organs but generally, one type predominates. The focus herein is on the clinically relevant P -adrenoceptor-mediated effects on heart and on P2-adrenoceptor-mediated effects on smooth muscles of blood vessels and bronchioles, the insulin-secreting tissue of the pancreas, and skeletal muscle glycogenolysis for side effects profile (36). 

Adenosine A1 Adenosine A2a Adenosine A3 aja-adrenoceptor ocib-adrenoceptor a2a-adrenoceptor a2b-adrenoceptor a -adrenoceptor Pi-adrenoceptor P2-adrenoceptor Angiotensin AT] Bradykinin B] Bradykinin B2 CGRP... 

Muscarinic M2 plus Muscarinic M2 k-opioid plus p2-adrenoceptor... 

The answer is i. (Hardman, p 2312) Timolol is a p-adrenergic receptor antagonist that does not show selectivity for pi or p2 adrenoceptors ... 

So far three subtypes of ft receptors have been identified and cloned. They differ in their distribution, the Pi type being found in the heart, the P2 in lung, smooth muscle, skeletal muscle and liver, while the P type occurs in adipose tissue. There is evidence that P2 adrenoceptors occur on the lymphocyte membrane also but the precise function there is unknown. 

Fig. 2.13 Structures of salbutamol and salmeterol, rapid and slow offset p2-adrenoceptor agonists.

Catechol methyl transferases require the catechol function to be present to bind to the Mg ion. In the search for p2-adrenoceptor selectivity to produce potent bron-chodilators with low cardiovascular effects, changing the 3,4-hydroxy grouping of the catechol to 3,5- or 3-hydroxyl, 4-methyl-hydroxy, proved to be important (Figure 7.25). These compounds now have much improved bioavailability and pharmacokinetics due to their resistance to catechol methyl transferases. 

Tocolysis. The uterine relaxant effect of P2-adrenoceptor agonists, such as terbutaline or fenoterol, can be used to prevent premature labor. Vasodilation Ltillmann, Color Atlas of Pharmacology (... 

Isoproterenol, a synthetic sympathomimetic amine acting selectively at both Pi - and P2-adrenoceptors, is also able to induce panic attacks in a subset of patients suffering from panic disorder. There is, however, a discrepancy in the findings, and the rehability and mechanisms of isoproterenol-induced panic remain to be clarified. It should also be emphasized that isoproterenol is not able to cross the blood-brain barrier. 

Isoproterenol and epinephrine are potent P2-adrenoceptor agonists norepinephrine is a relatively weak P2-adrenoceptor agonist. Isoproterenol and epinephrine produce vasodilation in skeletal muscle, but norepinephrine does not rather it produces vasoconstriction through the aj-adrenoceptors. Isoproterenol,... 

The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenoceptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly a-adrenoceptors. The interaction of compounds with these adrenoceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for a-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains p2-adrenoceptors, the response in this tissue elicited by the action of p2-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for p2-adrenoceptors, cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for p2-adrenoceptors and has relatively weak bronchiolar relaxing properties. 

Bronchial smooth muscle is relaxed by epinephrine and isoproterenol through their interaction with P2-adrenoceptors. Epinephrine and isoproterenol are potent bronchodilators, while norepinephrine has a relatively weak action in this regard (see Chapter 39). 

D) Decreases peripheral resistance through P2-adrenoceptor stimulation predominantly in skeletal muscle vascular beds. 

Brodde O-E. Pi- and p2-adrenoceptors in the human heart Properties, function, and alterations in chronic heart failure. Pharmacol Rev... 

Selective p2-adrenoceptor agonists Albuterol Proventil Ventolin Oral... 

Ipratropium bromide (Atrovent) is a quaternary amine derivative that is used via inhalation in the treatment of chronic obstructive pulmonary disease and to a lesser extent, asthma. Ipratropium has a slower onset of action (1-2 hours for peak activity) than Pz-adrenoceptor agonists and thus may be more suitable for prophylactic use. Compared with p2-adrenoceptor agonists, ipratropium is generally at least as effective in chronic obstructive pulmonary disease but less effective in asthma. 

Terbutaline (Brethine, Bricanyl) is a relatively specific P2-adrenoceptor agonist (see Chapters 10 and 39). Terbutaline can prevent premature labor, especially in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate Pj-adrenoceptors. While it appears to be especially selective for P2-receptor activation, terbutaUne does have some Pi activity as well. 

In humans, blocking of p2-adrenoceptor-mediated cortical transmission suppress the numerical memory performance (Muller et al., 2005). On the other hand, there is an increase in cortical NE during the spatial memory performance. There is also evidence for a critical role of cortical a2-adrenoceptors in memory and cognition (Coull, 1994 Matthews et al., 2002). 

Brodde, O.E., Zerkowski, H.R., Doetsch, N., Motomura, S., Khamssi, M., and Michel, M.C. 1989. Myocardial P-adrenoceptor changes in heart failure concomitant reduction in fi1- and p2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J. Am. Coll. Cardiol. 14 323-331. 

Lemoine, H., Schonell, H., and Kaumann, A.J. 1988. Contribution of p3- and p2-adrenoceptors of human atrium and ventricle to the effects of noradrenaline and adrenaline as assessed with (-)-atenolol. Br. J. Pharmacol. 95 55-66. 

Liu, X., Callaerts-Vegh, Z., Evans, K.L., and Bond, R.A. 2002. Chronic infusion of p-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human P2-adrenoceptor. J. Cardiovasc. Pharmacol. 40 448 155. 

Steinfath, M., Danielsen, W., von der Leyen, H., Mende, U., Meyer, W., Neumann, J., Nose, M., Reich, T., Schmitz, W., Scholz, H., et al. 1992. Reduced Pj- and p2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure. Br. J. Pharmacol. 105 463-469. 

---