HIGHLIGHTED MEETINGS ARTICLE Nebivolol: An Endothelium-Friendly Selective b 1 -Adrenoceptor Blocker Yuansheng Gao, PhD* and Paul M. Vanhoutte, MD, PhD† (See Editorial: Asian Society forVascular Biology by Paul M. Vanhoutte, J cardiovasc Pharmacol 2011;58:559.) Abstract: Nebivolol is a highly selective b 1 -adrenoceptor blocker, which also stimulates endothelial nitric oxide synthase and scavenges reactive oxygen species (ROS). These characteristics endow nebi- volol, compared with conventional b-blockers, with a favorable hemodynamic profile for the treatment of hypertension, chronic heart failure, and possibly other cardiovascular diseases. Nebivolol is a racemic mixture of d- and l-isomers. Its b 1 -antagonistic properties reside primarily with d-nebivolol although both isomers are capable of increasing the release of NO from the endothelium after binding to b 2 - or b 3 -adrenergic receptors. The latter action results in vaso- dilatation and reduced vascular resistance. Nebivolol also scavenges ROS in a receptor-independent manner by direct interaction with free radicals. By scavenging ROS nebivolol not only reduces oxidant stress but also augments NO bioavailability. The endothelial nitric oxide synthase –stimulating and ROS scavenging effects of nebivolol act synergistically to provide cardiovascular protection in addition to its b 1 -antagonistic action. Key Words: nitric oxide, b-blocker, reactive oxygen species, hypertension, chronic heart failure (J Cardiovasc Pharmacol TM 2012;59:16–21) INTRODUCTION Nebivolol is a highly selective and long-acting b 1 - adrenoceptor (AR) blocker synthesized by Janssen Pharma- ceutica in the 1980s. Soon after its discovery, nebivolol was found to exert favorable effects on peripheral vascular resistance (PVR) and cardiac function, in sharp contrast with conventional b-blockers. 1–3 Nebivolol is currently available for the treatment of hypertension and chronic heart failure (CHF) in several countries. This brief review will discuss the pharmacological properties of nebivolol, the mechanisms contributing to its favorable hemodynamic profile (in particular its vasodilator and antioxidant properties) and the therapeutic applicationds of this unique compound. PHARMACOLOGICAL CHARACTERISTICS b-AR blockers (b-blockers) have emerged in 3 genera- tions. The first and second generation b-blockers have no significant ancillary properties, with the former being non- selective and the latter selective for either b 1 or b 2 ARs. The third generation b-blockers may be selective or nonselective for b 1 or b 2 ARs but possess important ancillary properties. Among them, nebivolol is the most selective b 1 -blocker and the only b-blocker causing vasodilatation primarily by causing the release of endothelium-derived nitric oxide (EDNO). 4–6 Nebivolol is a racemic mixture of d- and l-enantiomers with the stereochemical designations of [SRRR]- and [RSSS]- nebivolol, respectively (Fig. 1). The b 1 -antagonistic properties of nebivolol reside almost entirely in d-nebivolol, whose affinity for the b 1 -ARs is about 175-fold greater than that of l-nebivolol. 2,7 Among the b-blockers used in clinical practice, nebivolol is the most b 1 -selective one. 6 Radioligand binding assays in myocardial membranes, studies with recombinant receptors, and functional assays reveal that d-nebivolol has a greater affinity for b 1 over b 2 -ARs. 8 For example, in crude membrane preparations of human nonfailing left ventricular myocardium, d-nebivolol has an affinity (measured as K i ) of 6.1 and 149.7 nM for b 1 - and b 2 -adrenoceptors, respectively [K i (b 2 )/K i (b 1 ) = 24.5]; by comparison, the affinities of l-nebivolol in the same preparations are 496.0 and 338.5 nM, respectively [K i (b 2 )/K i (b 1 ) = 0.68]. 7 The affinity of nebivolol for b 3 -ARs has not been well defined. Functional studies in human adipocytes show that the lipolysis caused by l- or racemic nebivolol is inhibited by SR59230A, a selective b 3 -AR antagonist. 9 b 3 -ARs may be involved in the release of nitric oxide (NO) and EDNO-dependent relaxations induced by racemic nebivolol or its d- and l-enantiomers. 10–13 Nebivolol is highly lipophilic with an octanol/water distribution coefficient of log P = 4.03 at pH 11.8 and 23°C. It is quickly absorbed after oral administration and undergoes extensive hepatic metabolism. Nebivolol is predominantly metabolized via direct glucuronidation of the parent drug and to a lesser extent via N-dealkylation and oxidation by cyto- chrome P450 2D6 (CYP2D6), a member of the cytochrome P450 mixed-function oxidase system. Most humans metab- olize CYP2D6 substrates extensively and are hence considered to be ‘‘extensive metabolizers.’’ However, due to genetic polymorphisms, in a minority of people, little functional CYP2D6 enzyme is present, and these ‘‘poor metabolizers’’ Received for publication October 19, 2010; accepted November 17, 2010. From the *Department of Physiology and Pathophysiology, Peking University, Health Science Center, Beijing, China; and †Department of Pharmacol- ogy, and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. Supported in part by the National Natural Science Foundation of China Grant No. 30770789 and 30870938 and by the Hong Kong Research Grant Council (University of Hong Kong-777507M). The authors report no conflicts of interest. Reprints: Yuansheng Gao, PhD, Department of Physiology and Pathophys- iology, Peking University Health Science Center, 38 Xue Yuan Road, Beijing 100191, China (e-Mail: ygao@bjmu.edu.cn). Copyright Ó 2012 by Lippincott Williams & Wilkins 16 | www.jcvp.org J Cardiovasc Pharmacol ä  Volume 59, Number 1, January 2012