P Adrenoceptors subtypes

Kaumann, A. J., and Marano, M. (1982). On equilibrium dissociation constants for complexes of drag receptor subtypes Selective and nonselective interactions of partial agonists with two P-adrenoceptor subtypes mediating positive chronotropic effects of (-) isoprenaline in kitten atria. Nannyn Schmiedebeberg s Arch. Pharmacol. 219 216—221. 

In addition to their peripheral functions, including presynaptic facilitation of noradrenaline release, p-adrenoceptors play a role in regulating numerous functions of the central nervous system, including sympathetic tone, learning and memory, mood, and food intake. Mice lacking dopamine p-hydroxylase or p-adrenoceptor subtypes were used to study the involvement in memory functions. Noradrenaline acting at p, -receptors was found to be essential for retrieval of contextual and spatial memory, but it was not necessary for retrieval of emotional memories (Murchison... 

Buxton, B.F., Jones, C.R., Molenaar, P., and Summers, R.J. 1987. Characterization and autoradiographic localization of P-adrenoceptor subtypes in human cardiac tissues. Br. J. Pharmacol. 92 299-310. 

Mak JCW, Nishikawa M, Haddad E-B, et al. Localisation and expression of P-adrenoceptor subtype mRNAs in human lung. Eur J Pharmacol 1996 302 215-221. 

Two different types of P-adrenoceptors have been characterized and categorized as P - and P2-subtypes. The P -receptors are associated primarily with the cardiac muscle, whereas the P2-subtype is located peripherally. Selective P -blockers include practolol (121) and (122), atenolol (123) and (124), and betaxolol (125) and (126). 

FIGURE 9.17 Venn diagram consisting of the various possible activities (agonism and antagonism) on two receptor subtypes (a- and P-adrenoceptors). Letters label the areas of intersection denoting joint activity. The table shows possible therapeutic application of such joint activity. 

De Benedetti, P.G., Heible, J.P. and Giardina, D. (1996) al-Adrenoceptors subtype- and organ-selectivity of different agents, in Perspectives in... 

De Benedetti, P.G., Fanelli, F., Menziani, M.C., Cocchi, M., Testa, R. and Leonardi, A. (1997) Alpha 1-adrenoceptor subtype selectivity molecular modelling and theoretical quantitative structure-affinity relationships. Bioorganic el Medicinal Chemistry, 5, 809-816. 

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. 

Epinephrine activates both a- and p-adrenoceptors, whereas isoproterenol is selective for p-adrenoceptors but does not discriminate between Pi- and Pz-adreno-ceptors. Much-improved selectivity is offered by agents such as albuterol, terbutaline, and salmeterol. These compounds have a higher affinity for Pj-adrenoceptors, the predominant subtype in the airway, than for Pi-adrenoceptors. Other P2-selective adrenomimetics used as bronchodilators are bitolterol (Tornalate) and pir-... 

Two main subtypes of P adrenoreceptors, P and P2, have been identified in the periphery and in the CNS (Minneman et ak, 1979 Palacios and Kuhar, 1980). Both are located at postsynaptic terminals and have been cloned. In the periphery, P receptors are located in myocardial tissue, and P2 receptors are located in pulmonary bronchi and bronchioli, as well as in some blood vessels. P Adrenoceptors are the major subtype throughout the brain, except for the cerebellum, where P2 receptors are predominant. Areas that contain high concentrations of P adrenoceptors include the superfi-... 

Marshall, I., Burt, R. P. and Chappie, C. R., 1999, Signal transduction pathways associated with alphal-adrenoceptor subtypes in cells and tissues including human prostate. Eur Urol 36 Suppl 1, 42—7 discussion 65. 

P-Adrenoceptors are best known for their role in the regulation of cardiovascular, airway, uterine, and peripheral metabolic functions. Mice lacking pj, p2 and p3 receptors have been generated (Chruscinski et al. 1999 Rohrer et al. 1996 Susulic et al. 1995), but only few studies have used these models to identify subtype-specific functions of P-adrenoceptors in neurons. 

Fig. 4 Presynaptic signaling mechanisms of /% adrenoceptors. Abbreviations (Xi/0, P, y, subunits of Gi/0 heterotrimeric GTP-binding proteins ociabd. ( 2abc. Pi23> adrenoceptor subtypes.

Frances, C., Nazeyrollas, P., Prevost, A., Moreau, F., Pisani, J., Davani, S., Kantelip, J.P., and Millart, H. 2003. Role of beta 1- and beta 2-adrenoceptor subtypes in preconditioning against myocardial dysfunction after ischemia and reperfusion. J. Cardiovasc. Pharmacol. 41 396 105. 

All adrenoceptors are members of the G-coupled family of receptor proteins i.e. the receptor is coupled to its effector protein through special transduction proteins called G-proteins (themselves a large protein family). The effector protein differs amongst adrenoceptor subtypes. In the case of p-adrenoceptors, the effector is adenylyl cyclase and hence cyclic AMP is the second messenger molecule. For a-adrenoceptors, phospholipase C is the commonest effector protein and the second messenger here is IP3. It is the cascade of events initiated by the second messenger molecules that produces the variety of tissue effects as shown in Table 22.1 It should be clear that specificity is provided by the receptor subtype, not the messengers. 

Some p-adrenoceptor blockers have higher affinity for cardiac pj-receptors than for cardiac and peripheral p -receptors (see Table 23.1). The ratio of the amount of drug required to block the two receptor subtypes is a measure of the selectivity of the drug. (See the note to Table 22.1, p. 449, regarding use of the terms selective and cardioselective.) The question is whether the differences between selechve and nonselective P-blockers constitute clinical advantages. In theory pj-blockers are less likely to cause bronchoconstriction, but in practice few available... 

The p adrenoceptor antagonists (beta blockers) are class II antiarrhythmic agents. They prolong phase 4 of the cardiac action potential (pacemaker potential), slowing the heart rate. There are three subtypes of P adrenoceptors Pi, P2 and P3. Stimulation of Pi adrenoceptors in the heart increases the force and rate of cardiac contraction, as well as increasing automaticity of the pacemaker sites and conduction through the AV node. The P2... 

Jarajapu YPR, Coats P, McGrath JC, Hillier C, MacDonald A. Functional characterization of aj-adrenoceptor subtypes in human skeletal muscle resistance arteries. BrJ Pharmacol 2001 133 679-686. 

Intropin ) is a catecholamine that occurs in the mammalian CNS, in several higher plants and alga. It is a major central neurotransmitter, a dopamine receptor agonist and a SYMPATHOMIMETIC, with predominantly (Pi-subtype) p-ADRENOCEPTOR AGONIST actions. It Can be used as a cardiac STIMULANT and ANTIHYPOTENSIVE in cardiogenic hypotension. Its precursor amino acid, levodopa, is used as an ANTIPARKINSONIAN AGENT. 

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