Continuing evolution of the role of β-blockers in the treatment of hypertension

The classifi cation of αand β-adrenoceptors by Ahlquist and colleagues in 1948 provided the foundation for the development of drugs that could modulate the sympathetic nervous system (SNS) [1]. The fi rst β-blocker, pronethalol, developed by Sir James Black, was limited clinically due to safety concerns. However, the subsequent development of its successor, propranolol, earned Black the Nobel Prize for Medicine in 1988, and revolutionized the process of the laboratory development of cardiovascular drugs [2]. The development of the β-blocking class of drugs provided clinicians with new tools to treat many cardiovascular disorders that now include: hypertension, heart failure, angina pectoris, certain arrhythmias, post-myocardial infarction ventricular dysfunction and high-risk patients, including those with diabetes mellitus [3–5]. The fi rst widely used β-blocker, propranolol, had equal blocking properties at both the β1 and β2 adrenoceptor subtypes. Since blocking β2 receptors produced unwanted side effects (e.g., vasoconstriction and bronchoconstriction), new (second-generation) drugs were developed that were more selective for the β1 receptor, for example, metoprolol and atenolol. These drugs were called cardioselective. However, at higher doses, blockade occurred at both receptors [6]. The traditional β-blocking drugs are associated with many side effects, including fatigue, sexual dysfunction (erectile dysfunction), cold hands and weight gain [7], and have limited effi cacy in obese patients [8]. Moreover, these traditional β-blockers have a propensity to increase insulin resistance and hasten the appearance of hyperglycemia (diabetes mellitus). Additionally, the use of β-blockers in African–American hypertensive patients may be limited owing to the fact that traditional β-blockers are less effective in lowering blood pressure (BP) in hypertensive African–American patients compared with hypertensive Caucasian patients [9,10]. The newer (‘third-generation’) β-blocking drugs are characterized by the ability to produce vasodilation, and include carvedilol, labetalol and nebivolol. Carvedilol and labetalol achieve vasodilation by interfering with the α1 adrenoceptor, whereas nebivolol utilizes a mechanism that is endothelial dependent and results in increased bioavailability of nitric oxide (NO) (vide infra).