In this issue of the Journal, Khan et al1 study the third-generation beta-blocker, nebivolol, in a rat model of aldosterone/salt treatment–induced hypertensive heart disease and show that myocyte necrosis is incited by oxidative stress secondary to an increase in cytosolic free calcium and mitochondrial calcium overload—a process that overwhelms the endogenous zinc (Zn)-based antioxidants. Using the first-generation beta-blocker atenolol as a control, treatment with nebivolol induced activation of endothelial nitric oxide synthase, nitric oxide (NO) generation, and a marked increase in intracellular Zn. Conversely, there was a concomitant decrease in intracellular and subsarcolemmal mitochondrial calcium levels. Likewise, there was attenuation of mitochondrial hydrogen peroxide production and lipid peroxidation, inhibition of microscopic myocardial scarring, and a reduction in collagen volume fractions. They postulate an intriguing pathophysiologic phenomenon whereby nebivolol, acting as a β3 agonist, increases NO formation leading to a rise in cytosolic free Zn. This inhibits intracellular and mitochondrial calcium overload, which ameliorates many of the detrimental effects of reactive oxygen species (ROS), lipid peroxidation, and the eventual myocardial scarring.
Several important points can be gleaned from this study. First, this animal model of hypertensive cardiomyopathy serves as an effective model of sudden cardiac death as both myocardial fibrosis and adverse remodeling are key features of this disease process. This hypothesis, originally formulated by Weber and others, served as a fundamental basis for the RALES and EPHESUS trials. This concept was recently reviewed and confirmed by Esposito et al2 in a canine model of pacing-induced systolic heart failure, interstitial fibrosis, and myocardial electrical activation delays. They showed that mineralocorticoid receptor antagonism played a key role in preventing the activation of inflammatory pathways and in the development of ventricular arrhythmogenic foci. It is interesting to speculate that nebivolol may also induce similar cardioprotection.
Nebivolol is approved for the treatment of hypertension in the United States and is marketed as Bystolic. In Europe, it is approved for the treatment of both hypertension and left ventricular failure. At low doses, it is a selective β1-receptor blocker, and as the dose is up-titrated, it loses its selectivity. It is unique in that unlike carvedilol (Coreg), it has a NO potentiating ability, a property that Khan et al1 have effectively shown in their study.
Another plausible mechanism for the drug's efficacy is that it may act primarily within the mitochondria at the site of ROS production or as a ROS scavenger, inhibiting superoxide anion or hydrogen peroxide. Accordingly, the sequelae of pathology associated with excessive ROS production in hypertensive cardiomyopathy can effectively be targeted.
Nebivolol is not the first beta-blocker to demonstrate antioxidant properties. Carvedilol, the first of the third-generation beta-blockers, has been shown in a number of studies to be both an antioxidant and free radical scavenger.3 Its antioxidant property resides in its carbazole moiety, a property partly shared by nebivolol. The apparent underlying protective mechanism of carvedilol is through inhibition of lipid peroxidation primarily through free radical scavenging. Khan et al1 showed that nebivolol could similarly protect against lipid peroxidation. This unique property has not received a great deal of attention from our clinical colleagues, except in the burgeoning field of Cardio-Oncology. The chemotherapeutic anthracyclines are known to be one of the most effective anticancer treatments available but produce an excessive amount of free radicals within the myocardium, leading to cardiotoxicity and heart failure. It is of no surprise then that carvedilol is currently considered the “beta-blocker of choice” for patients suffering from anthracycline-induced heart failure. Perhaps, it is time when nebivolol was investigated for its antioxidant properties in oxidative pathological conditions also?
The use of the term “third-generation beta-blocker,” is a method we use to explain the hierarchy of beta-blockers in terms of development. Atenolol is a first-generation beta-blocker in terms of age, a drug known to have no antioxidant properties and a characteristic Khan et al1 use for control experiments. The second-generation beta-blockers include metoprolol, which although has cardioprotective effects, does not have any antioxidant effects. The current third-generation beta-blockers include carvedilol, a drug with antioxidant effects and free radical scavenging ability.4 Nebivolol can now be added to this list. It is rather interesting to recall that over the last several decades, both laboratory and clinical research with endogenous antioxidants such as superoxide dismutase, vitamin E, and catalase were all fraught with failure and frustration. Conceivably, the elusive and effective antioxidant has been right in front us for the past 20 years, and we were just a little slow in recognizing the potential expedient effects of these drugs.
1. Khan MU, Zhao W, Zhao T, et al.. Nebivolol, a multifaceted antioxidant and cardioprotectant in hypertensive heart disease. J Cardiovasc Pharmacol. 2013;62:445–451.
2. Esposito CK, Varahan S, Jeyaraj D, et al.. Spironolactone improves the arrhythmogenic substrate in heart failure by preventing ventricular activation delays associated with myocardial interstitial fibrosis and inflammation. J Cardiovasc Electrophysiol. 2013;24:806–812.
3. Yue TL, Cheng HY, Lysko PG, et al.. Carvedilol, a new vasodilator and beta-adrenoreceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther. 1992;263:92–98.
4. Arumananayagam M, Chan S, Tong S, et al.. Antioxidant properties of carvedilol and metoprolol in heart failure: a double-blind, randomized controlled trial. J Cardiovasc Pharmacol. 2001;37:48–54.