Fifty Years of Beta-adrenergic Blockade: A Golden Era in Clinical Medicine and Molecular Pharmacology
Article Outline
The development and subsequent clinical application of various beta-adrenergic receptor blocking drugs during the past 50 years has represented one of the major advances in human pharmacotherapy. Beginning in 1958 with the introduction of dichloroisoproterenol, no other class of synthetic drugs has demonstrated such widespread clinical utility in the treatment of both cardiovascular and noncardiovascular diseases. In addition, these agents have served as molecular probes that contributed greatly to our understanding of both the structure and workings of the ubiquitous 7 transmembrane G protein-coupled receptors, which mediate the actions of many hormones, neurotransmitters, and drugs.
Beta-adrenergic blockers are competitive pharmacologic inhibitors of catecholamine actions that influence a wide number of physiologic and metabolic activities in human beings. It has been shown that the effects of catecholamines ultimately depend on their chemical interactions with specific adrenergic receptors, membrane-bound macromolecular glycoprotein structures located on cell membranes, conceptual entities that were not well defined until the 1980s. More than 100 years ago, early investigators conceived that catecholamines were binding selectively to receptor-like structures in mediating their pharmacologic actions. In 1948, Ahlquist conducted a series of classic pharmacologic studies and concluded from his findings that there were 2 distinct organ responses to catecholamine drugs that he called alpha- and beta-receptor mediated.1
In 1958, the compound dichloroisoproterenol, synthesized by Eli Lilly Laboratories, was found to inhibit the activities of epinephrine and was thus considered the first beta-adrenergic blocker.2 However, its potential clinical application was not initially appreciated. In the early 1960s, Black et al at Imperial Chemical Industries in Great Britain were working on a series of beta-adrenergic blocking compounds, pronethanol and propranolol, that they hypothesized would lower myocardial oxygen consumption by interfering with the effects of catecholamines, and, therefore, would be useful for the treatment of angina pectoris, hypertension, and arrhythmia.3 Although pronethanol was effective in patients with angina pectoris, it was propranolol that became the prototype beta-blocker with proven efficacy in both intravenous and oral forms for the treatment of cardiovascular disease. In 1964, propranolol became the first major advance in the treatment of angina pectoris since the introduction of nitroglycerin almost 100 years earlier. In addition, it quickly became an accepted treatment for arrhythmia, hypertension, and hypertrophic cardiomyopathy.
The potential adverse reactions related to the anti-catecholamine effects of propranolol on heart rate, myocardial contractility, and bronchial tone led to ongoing refinements in the pharmacologic structure of beta-blockers and subsequent advances in drug delivery.4 The evolution in drug development led to the introduction of drugs having relative selectivity for cardiac beta1-receptors (metoprolol, atenolol), partial adrenergic agonist activity (pindolol), concomitant alpha-adrenergic blocking activity (labetalol, carvedilol), and direct vasodilator activity (nebivolol). In addition, long-acting and ultra-short formulations of beta-blockers were developed.
Years after propranolol was introduced, studies showed the class of drugs also was useful for treating patients with mitral valve prolapse, pheochromocytoma (labetalol), the hereditary QT prolongation syndrome, hypertensive emergencies and urgencies (labetalol), and for the treatment and prevention of acute aortic dissection. Moreover, both intravenous and oral forms were able to reduce mortality in survivors of myocardial infarction, the first class of drugs shown to do so.5, 6
Remarkably, in the 1990s, some beta-blockers also were shown to reduce morbidity and mortality in symptomatic patients with congestive heart failure, a clinical diagnosis for which beta-blockers had been contraindicated previously.7 This revelation has led to a complete rethinking of the pathophysiology of heart failure, thought now to be aggravated by the adverse effects of increased neurohormonal stimulation of the heart.
Beta-blockers now have application that extends beyond cardiovascular use, to the prevention of migraine headache, the treatment of benign essential tremor, for patients with pheochromocytoma and thyrotoxicosis, and in topical ophthalmic formulations for reducing intraocular pressure in patients with open-angle glaucoma. The drugs also have been used to reduce portal hypertension in patients with liver cirrhosis and to aid in the management of delirium tremens and stage fright.
After decades of clinical use, the beta-blocking drugs have demonstrated a remarkable record of clinical safety in patients of all ages, and the ability to be combined successfully with other drug classes for the treatment of cardiovascular disease. Their continued use in patients undergoing cardiovascular and noncardiovascular surgery also has been shown to reduce both intra-operative and peri-operative mortality and morbidity.
Almost in parallel with the clinical introduction of beta-adrenergic blockers came an explosion of research studies that contributed to the scientific understanding of receptor structure, function, and regulation on the molecular level. Beta-adrenergic receptor agonists and blockers have served as the biologic probes to help answer fundamental molecular pharmacology questions.
The concept of adrenergic receptor stimulation for mediating catecholamine actions had been recognized throughout the 20th century, and during the past 35 years, scientists began to study the molecular steps that lay between the putative receptors and agonists and the response elements within the cell.8 It was found that adrenergic receptors, when stimulated, can trigger the production of second messengers (eg, adenyl cyclase) via an interaction with the coupling proteins attached to the beta receptor. The beta- and alpha-receptors are part of a major class of G protein-coupled receptors or 7 transmembrane receptors—the most important targets of clinically used drugs—that also zero in on serotonin receptors, histamine receptors, and angiotensin-II receptors.8
Using radioligand labeling techniques and purification methods, Lefkowitz and his colleagues8 helped to identify the structures of the adrenergic receptors as membrane-bound polypeptide chains with a molecular weight of about 67,000 Da. The beta-receptors consist of 7 transmembrane alpha-helices of 20-28 amino acids joined by alternating extracellular and cytoplasmic loops.8 Lefkowitz was successful in reconstituting the beta-receptors and demonstrated that the receptors could convey catecholamine responsiveness when transplanted to previously unresponsive organic systems.8 Subsequently, the receptor genes and cDNAs for beta-receptors were cloned in 1986, and the 3-dimensional crystalline structure of the beta2 receptor was recently described in 2007.
A major contribution to our understanding of beta-receptor functioning came with the fundamental description of receptor desensitization.8 In contrast to the older concepts of adrenergic receptors as static entities on cell membranes that simply serve to initiate a chain of events, newer concepts suggest that adrenergic receptors are subject to a wide variety of controlling influences, resulting in the dynamic regulation of receptor sites and their sensitivity to catecholamine agonists. Changes in tissue concentration or sensitivity of receptors are important in drug activity and in the pathophysiology of disease. This desensitization phenomenon has been shown to be caused not by a change in receptor function or degradation, but rather by catecholamine-induced changes in the conformation of the receptor sites, which renders them ineffective. Rapid desensitization of beta receptors was proved to be mediated by agonist stimulation of beta-adrenergic receptor kinases (βARK) or GRK2, which phosphorylate receptors and decrease the coupling of G proteins to adenyl cyclase.8
However, it also was found that phosphorylation of the receptor itself was not sufficient to fully desensitize receptor function. A second reaction must occur that involves an arresting protein known as beta-arrestin.8 Through this desensitization process, internalization of receptors on the cell membrane also occurs. In contrast to adrenergic agonists, beta-adrenergic blocking drugs by themselves do not induce desensitization or changes in the conformation of receptors. They also can block the ability of catecholamines to desensitize receptors. More work is being carried out with beta-arrestin agonists to form “super” beta-blockers that can turn off G protein-mediated signaling of the beta receptor but still maintain the benefits of continued beta-arrestin-mediated signaling on cell survival systems.8
Based on the concept of a functional adrenergic receptor that mediated the effects of catecholamines, the introduction of the first beta-blocker caused a revolution in human pharmacotherapy that has impacted favorably on the health of millions of patients with a wide variety of cardiovascular and noncardiovascular diseases. Their introduction further opened the door to fundamental discoveries of basic receptor structure and function, which have influenced the development of other drug classes for other medical conditions. In addition, the 50 years of beta-blocker experience, with the ability to modulate successfully excessive catecholamine activity, has reaffirmed the early observations and descriptions of the “ancients” who believed that imbalances in naturally occurring humors could cause disease, while the reestablishment of humoral balance would contribute to health. Indeed, how golden is the legacy the beta-blockers have given us.
References
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- . beta-Adrenergic blockade in survivors of acute myocardial infarction. N Engl J Med. 1984;310:830–837
- . Alpha and beta-adrenergic blocking drugs. In: Frishman WH, Sonnenblick EH, Sica DA editor. Cardiovascular Pharmacotherapeutics. 2nd edn.. New York: McGraw-Hill; 2003;p. 67–97
- . Carvedilol. N Engl J Med. 1998;339:1759–1765
- . Seven transmembrane receptors: something old, something new. Acta Physiol. 2007;190:9–19
PII: S0002-9343(08)00675-X
doi:10.1016/j.amjmed.2008.06.025
© 2008 Elsevier Inc. All rights reserved.
