Nebivolol: impact on cardiac and endothelial function and clinical utility

Abstract

Endothelial dysfunction is a systemic pathological state of the endothelium characterized by a reduction in the bioavailability of vasodilators, essentially nitric oxide, leading to impaired endothelium-dependent vasodilation, as well as disarrangement in vascular wall metabolism and function. One of the key factors in endothelial dysfunction is overproduction of reactive oxygen species which participate in the development of hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, ischemia-reperfusion injury, and stroke. Because impaired endothelial activity is believed to have a major causal role in the pathophysiology of vascular disease, hypertension, and heart failure, therapeutic agents which modify this condition are of clinical interest. Nebivolol is a third-generation β-blocker with high selectivity for β1-adrenergic receptors and causes vasodilation by interaction with the endothelial L-arginine/ nitric oxide pathway. This dual mechanism of action underscores several hemodynamic qualities of nebivolol, which include reductions in heart rate and blood pressure and improvements in systolic and diastolic function. Although nebivolol reduces blood pressure to a degree similar to that of conventional β-blockers and other types of antihypertensive drugs, it may have advantages in populations with difficult-to-treat hypertension, such as patients with heart failure along with other comorbidities, like diabetes and obesity, and elderly patients in whom nitric oxide-mediated endothelial dysfunction may be more pronounced. Furthermore, recent data indicate that nebivolol appears to be a cost-effective treatment for elderly patients with heart failure compared with standard care. Thus, nebivolol is an effective and well tolerated agent with benefits above those of traditional β-blockers due to its influence on nitric oxide release, which give it singular hemodynamic effects, cardioprotective activity, and a good tolerability profile. This paper reviews the pharmacology structure and properties of nebivolol, focusing on endothelial dysfunction, clinical utility, comparative efficacy, side effects, and quality of life in general with respect to the other antihypertensive agents.

Keywords: beta-blockers; cardiovascular protection; endothelial function; nebivolol; nitric oxide; oxidative stress.

Figure 1

Synthesis of nitric oxide by endothelial cells. Nitric oxide is produced by the action of endothelial nitric oxide synthase on L-arginine. Several cofactors, including tetrahydrobiopterin (BH₄) and nicotinamide adenine dinucleotide phosphate, are required to generate this reaction. Endothelial nitric oxide synthase is activated as a consequence of the dislodgement of the inhibitor caveolin from calmodulin in response to vasodilator agonists or shear stress. Nitric oxide diffuses to vascular smooth muscle and produces relaxation through activation of guanylate cyclase, thus augmenting intracellular cyclic guanosine monophosphate. Abbreviations: eNOS, endothelial nitric oxide synthase; NO, nitric oxide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; CaM, calmodulin; GTP, guanosine 5′-triphosphate; GC, guanylate cyclase; cGMP, cyclic guanosine monophosphate.

Figure 2

Effect of acute and chronic β-adrenergic activation on endothelial nitric oxide synthase activity, expression, and uncoupling. (A) In normal conditions, basal endothelial nitric oxide synthase activity oxidizes L-arginine, generating L-citrulline and nitric oxide at physiological rates which contributes to maintenance of vascular tone in healthy vessels. (B) Acute β-adrenergic activation caused by β-adrenoceptor agonists stimulates endothelial nitric oxide synthase activity and could increase release of endothelial nitric oxide. (C) Permanently high catecholamine levels could lead to overactivation of β-adrenoceptors, increasing activity and protein expression of endothelial nitric oxide synthase. Nevertheless, this condition may lead to uncoupling of endothelial nitric oxide synthase, which produces superoxide anions and peroxynitrite (reactive oxygen species). Abbreviations: eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.

Figure 3

Chemical structure of the two isomers of nebivolol as a hydrochloride salt. Nebivolol has four asymmetric centers; the d-isomer refers to (S,R,R,R)-nebivolol and the l-isomer to (R,S,S,S)-nebivolol. The enantiomers have unequal potency with regard to β-receptor blocking activity and nitric oxide-mediated vasodilation. Abbreviation: MW, molecular weight.

Figure 4

Mechanisms of action of nebivolol in the cardiovascular system. Antagonism of cardiac β₁-adrenergic receptors by nebivolol maintains or improves left ventricular function in healthy subjects and in patients with hypertension by decreasing heart rate, increasing cardiac output, and stroke volume. In addition, nebivolol protects health by reducing oxidative stress and increasing nitric oxide bioavailability through nonreceptor dependent scavenging of O₂ ⁻ and β₃-adrenergic receptor-dependent inhibition of NADPH oxidase and endothelial nitric oxide synthase uncoupling. In the vasculature, nebivolol acts through β₃-adrenergic receptors to augment nitric oxide bioavailability and exerts a direct scavenging effect, leading to vasodilation and an improvement of endothelial function. Notes: stimulation, inhibition. Abbreviations: NADPH, reduced nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.