b-ADRENOCEPTORS FUNCTION IN THE CARDIOVASCULAR SYSTEM

Abstract

b

-adrenoceptors (b-AR) are classified as classic b-AR (b1, b2) and atypical b-AR (b3,b4). b-AR are coupled to G protein and enzymes such as adenylyl-cyclase and protein kinase-A(PKA) that is activated by 3´-5´adenosine-monophosphate (cAMP). This b-AR-enzymes complex can directly bind to ionic channels in the membrane, but the main mechanism of action induced by cAMP is the phosphorylation of several proteins via the action of PKA. The activation of b-AR in the endothelial cells increases the Ca+2 cytosolic levels that facilitate Ca+2 binding to calmodulin activating endothelial nitric oxide synthase and the production of nitric oxide. The main mechanism of cAMP in inducing vascular smooth muscle relaxation is due to the phosphorylation via PKA that decreases the cytosolic Ca+2 concentration by several mechanisms that lowers its affinity for calmodulin. Major b-AR agonists are classified as nonselective b-AR (isoprenaline), selective b1-AR (xamoterol) and b2-AR (terbutaline, salbutamol). Several b-AR agonists have been used in clinical situations but they play their main role in the treatment of the patients with asthma or as cardiac stimulant. The development of novel compounds b3-AR agonists as BRL-37344, CGP-12177 and CL-316243 open new pespectives for the treatment of hypertension. Considerable interest has focused on the development of b-AR antagonists due to their efficacy on the treatment of hypertension, cardiac arrhytmias and angina. Efforts for more selective b-AR antagonists have resulted in the synthesis of several compounds as atenolol, bisoprolol, betaxolol, practolol and CFP20712A (b1-AR), ICI 118551 (b2-AR), SR59230A (b3-AR), bupranolol and CGP20712A (b4-AR).