Catecholamines released by the orthosympathetic system play a major role in the short- and long-term regulation of cardiovascular function. Beta1- and beta2-adrenoreceptors (ARs) have classically been considered as mediating most of their effects on cardiac contraction. After their initial cloning and pharmacologic characterization in the late 1980s, beta3-ARs have been mostly thought of as receptors mediating metabolic effects (e.g., lipolysis) in adipocytes. However, definitive evidence for their expression and functional coupling in cardiovascular tissues (including in humans) has recently initiated a re-examination of their implication in the pathophysiology of cardiovascular diseases. Distinctive pharmacodynamic properties of beta3-AR, e.g., their upregulation in disease and resistance to desensitization, suggest that they may be attractive targets for therapeutic intervention. They may substitute efficient vasodilating pathways when beta1/2-ARs are inoperative. In the heart, their contractile effects, which are functionally antipathetic to those of beta1/2-AR, may protect the myocardium against adverse effects of excessive catecholamine stimulation and perhaps mediate additional ancillary effects on key aspects of electrophysiology or remodeling. Longitudinal studies in animals and patients with different stages of heart failure are now needed to identify the optimal therapeutic scheme using specific combinations of agonists or antagonists at all three beta-ARs.
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