Beta-blockers: Historical Perspective and Mechanisms of Action

Beta-blockers are widely used molecules that are able to antagonize β-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon β-AR stimulation, numerous intracellular cascades are activated, ultimately leading to cardiac contraction or vascular dilation, depending on the relevant subtype and their location. Three subtypes have been described that are differentially expressed in the body (β₁-, β₂- and β₃-ARs), β₁ being the most abundant subtype in the heart. Since their discovery, β-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, β-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective β-blockers, cardioselective β-blockers (selective β₁-antagonists), and a third generation of these drugs able to block β₁ together with extra vasodilation activity (also called vasodilating β-blockers) either by blocking α₁- or by activating β₃-AR. More than 50 years after propranolol was introduced to the market due to its ability to reduce heart rate and consequently myocardial oxygen demand in the event of an angina attack, β-blockers are still widely used in clinics.