Focus on: Beta-blockers and Cardiovascular Disease (II) Beta-blockers: Historical Perspective and Mechanisms of Action Eduardo Oliver, a,b, * Federico Mayor Jr, b,c,d and Pilar D’Ocon e,f a Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain b Centro de Investigacio ´n Biome ´dica en Red en Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain c Departamento de Biologı´a Molecular and Centro de Biologı´a Molecular Severo Ochoa (UAM-CSIC), Universidad Auto ´noma de Madrid, Madrid, Spain d Instituto de Investigacio ´n Sanitaria La Princesa, Madrid, Spain e Departamento de Farmacologı´a, Universitat de Vale `ncia, Valencia, Spain f Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de Vale `ncia, Valencia, Spain INTRODUCTION From a classic pharmacological point of view, beta-blockers (or b-blockers) are antagonists of b-adrenergic receptors (ARs), which play an important role in the control of physiological processes such as blood pressure, heart rate and airway strength or reactivity, Rev Esp Cardiol. 2019;72(10):853–862 Article history: Available online 6 June 2019 Keywords: Beta-blockers Beta-adrenergic receptors Beta-adrenergic antagonists A B S T R A C T Beta-blockers are widely used molecules that are able to antagonize b-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon b-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 (b 1 -, b 2 - and b 3 -ARs), b 1 being the most abundant subtype in the heart. Since their discovery, b-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, b-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective b-blockers, cardioselective b-blockers (selective b 1 - antagonists), and a third generation of these drugs able to block b 1 together with extra vasodilation activity (also called vasodilating b-blockers) either by blocking a 1 - or by activating b 3 -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, b-blockers are still widely used in clinics.  C 2019 Sociedad Espan ˜ola de Cardiologı ´a. Published by Elsevier Espan ˜a, S.L.U. All rights reserved. Bloqueadores beta: perspectiva histo ´ rica y mecanismos de accio ´n Palabras clave: Bloqueadores beta Receptores adrene ´ rgicos beta Antagonistas adrene ´ rgicos beta R E S U M E N Los bloqueadores beta son mole ´ culas ampliamente utilizadas y capaces de antagonizar los receptores adrene ´ rgicos (RA) beta, pertenecen a la familia de receptores acoplados a proteı ´nas G y reciben el estı ´mulo de las catecolaminas endo ´ genas. Tras su estimulacio ´ n, se activan cascadas intracelulares que en u ´ ltima instancia originan la contraccio ´n cardiaca o la dilatacio ´n vascular, segu ´n el subtipo y su ubicacio ´ n. Se han descrito 3 subtipos, que se expresan de manera diferenciada en el organismo (RA-b 1 , b 2 y b 3 ), y el subtipo b 1 es el ma ´s abundante en el corazo ´ n. Desde su descubrimiento, los RA-b se han convertido en diana para combatir las enfermedades cardiovasculares. Desde su invencio ´n por James Black a finales de los an ˜os cincuenta, los bloqueadores beta han supuesto una revolucio ´n en la terapia cardiovascular. Hasta ahora se dispone de 3 generaciones: los bloqueadores beta no selectivos, los bloqueadores beta cardioselectivos (antagonista selectivo de b 1 ) y los bloqueadores beta vasodilatadores. Estos constituyen la tercera generacio ´n y son capaces de bloquear los b 1 adema ´s de tener actividad vasodilatadora, bien bloqueando los RA-a 1 o activando los RA-b 3 . Los bloqueadores beta todavı ´a se utilizan ampliamente en la clı ´nica tras ma ´s de 50 an ˜os desde la introduccio ´n del propranolol en el mercado por su capacidad para reducir la frecuencia cardiaca y, por lo tanto, la demanda mioca ´ rdica de oxı ´geno en el caso de una angina.  C 2019 Sociedad Espan ˜ola de Cardiologı ´a. Publicado por Elsevier Espan ˜a, S.L.U. Todos los derechos reservados. SEE RELATED CONTENT: https://doi.org/10.1016/j.rec.2019.04.014 * Corresponding author: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Ferna ´ ndez Almagro 3, 28029 Madrid, Spain. E-mail address: eoliver@cnic.es (E. Oliver). https://doi.org/10.1016/j.rec.2019.04.006 1885-5857/  C 2019 Sociedad Espan ˜ola de Cardiologı ´a. Published by Elsevier Espan ˜a, S.L.U. All rights reserved. Document downloaded from https://www.revespcardiol.org/?ref=1581959244, day 11/10/2022. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Document downloaded from https://www.revespcardiol.org/?ref=1581959244, day 11/10/2022. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.