Cardiac adrenoceptors: Physiological and pathophysiological relevance

At present, nine adrenoceptor (AR) subtypes have been identified: a(1A)-, a(1B)-, a(1D)-, a(2A)-, a(2B)-, a(2C)-, beta(1)-, beta(2)-, and beta(3)AR. In the human heart, beta(1)- and beta(2)AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in beta AR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, beta AR are chronically (over)stimulated, and that results in beta 1AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of beta(2)AR in CHF? What is the role of increases in cardiac Gi-protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does beta AR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of beta(1)- and beta(2)AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, PAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and/or might influence progression of disease. Furthermore, beta AR polymorphisms might influence drug responses. Thus, evidence has accumulated that a beta(1)AR polymorphism (the Arg389GIy beta(1)AR) may affect the response to,beta 1AR-blocker treatment.