Pharmacological analysis of cx'il -adrenoceptors
Tt is weil established that noradrenaline, relcased in response to sympathetic stilTIulation, as weil as adrenaline, the honnone relcased from the adrenal medulla, interaet with spccific reccptors (adrenoceptors) that arc Iocated in the membrane ofthc vascular smooth muscle celis. Ahlquist [IJ proposed a division of adrenoceptors into a- and J3-adrcnoceptors, on the basis of different agonist potency orders in vascular smooth muscle preparations. The o:-adrcnoceptor rnediated vasoconstriction and the f3-adrenoceptor mcdiated vasodilation. This subdivisioll in a and n, was subsequently supported by the deveIopment of selectivc B- and a-adrenoceptor antagonists . During the 1970's it bccame clcarthat there were subtypes ofthe a-adrenoceptor. At first the a-adrenoceptors were subclassified on an anatomical basis into prejunctional a 2-adrenoceptors and postjunetional a,-adrcnoceptors . Bcrthelsen & Pettinger  noted that this anatomical c1assification was not completely satisfactory and sllggestcd to reclassify a-adrenoceptors on a fllnctional basis. According to this scheme aradrenoceptors mediated inhibitory responses (like inhibition ofthe release of neurotransmitter and renin etc.), whereas al-adrenoceptors mediate excitatory responses (Iike the vasoconstriction). However, shortly thereafter it becamc clear that in some vascular preparations not only a l- but also a1-adrenoccptors causcd vasoconstrietion [5-7]. Fram that time a classification scheme of a-adrenoccptors into al and a 2 evolved th at is neither anatomical nor fUllctional, but is based 011 the relative potency of selcetive agonists and antagonists . Examplcs of selectivc al-adrenoceptor agonists are phcnylephrine, methoxamine and cirazoline, while UK 14,304, BHT 920 and elonidine bch ave as scleetive a 2-adrenoceptor agonists. In the case of antagonists, prazosin is regarded as a l-sc1ective aud rauwolscine and yohimbine as a 2-sclective. Noradrenaline and phentolamille are examples of a relatively nonsclective a-adrenoceptor agonist aud antagonist, respectively. Because ofthe differenccs in the receptors it has been suggested that a classification of adrenoceptors into three graups: al' a 2 and t3 is more apprapriate that the historical division into two (a and B) classes . TIlC rationale behind this reasoning is threefold. First, differences in affinities of selectivc compounds for these three classes are large (3 to 4 orders of magnitude). Second, the amino acid scguences are more consistent with threc rather than two major types. Third, the tIuee classes couple to different secotld messenger systems. I3-Adrenoceptor subtypes, stimulatc adenylyl cyclase resulting in the generation of cAMP, a [-adrenoceptors arc believed to stimulate the phosphoinositide mctabolism and a 2-adrenoceptors inhibit adenylyl cyclase and deereasc eAMP levels .
|Publisher||Erasmus MC: University Medical Center Rotterdam|
|Promotor||Saxena, P.R. (Pramod Ranjan)|
|Sponsor||Dr Saai van Zwanen berg Foundation, Netherlands Heart Foundation|
Stam, W.B.. (2000, November 30). Pharmacological analysis of cx'il -adrenoceptors. Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/19708