According to updated guidelines on the management of hypertension , the major drug classes recommended for its treatment [renin–angiotensin–aldosterone system inhibitors, beta-blockers, calcium-channel blockers (CCBs), and diuretics] are similarly effective in reducing major cardiovascular events and mortality, provided that blood pressure (BP) control is achieved. Nevertheless, some differences in their ability to prevent specific outcomes have emerged, together with compelling or possible contraindications and preferential use in specific conditions for each drug class [1,2]. In this scenario, beta-blockers have been shown to be particularly useful for the treatment of hypertension in patients with symptomatic angina, postmyocardial infarction (MI) with left ventricular (LV) dysfunction, heart failure with reduced ejection fraction, arrhythmias in particular when heart rate (HR) control is required, and in hypertensive pregnant women or in women of child-bearing potential with high BP . In parallel, beta-blockers have been associated with a less favorable metabolic profile, with reduced ability in preventing or regressing cardiovascular damage, including LV hypertrophy, carotid intima–media thickness, aortic stiffness, and small artery remodeling , and with consistently limited efficacy in the prevention of stroke, possibly due to their lower ability to reduce central BP and BP variability (BPV).
In this issue of Journal of Hypertension, Del Mauro et al. compare the effects on hemodynamic parameters and on hypertension-mediated organ damage of the so-called third-generation beta-blockers carvedilol and nebivolol with those of amlodipine and of a ‘second-generation’ beta-blocker, atenolol, in spontaneously hypertensive rats (SHR) . As widely known, in fact, beta-blockers are not a homogeneous class, and different selectivity at the receptor level combined with additional vasodilating properties characterize molecules such as carvedilol, nebivolol, labetalol, compared with other nonselective (propranolol, sotalol) or beta1-selective (atenolol, bisoprolol, metoprolol) ones (Table 1). The study by Del Mauro et al. shows better hemodynamic properties for vasodilating beta-blockers compared with atenolol, as highlighted by a greater attenuation of central BP and short-term BPV. This effect was similar to what observed for amlodipine, which has an established efficacy on BPV modulation. In addition, chronic treatment with carvedilol, nebivolol, or amlodipine compared with treatment with atenolol was more effective in the prevention of organ damage, expressed in terms of cardiac hypertrophy, cardiac and aortic collagen deposit, and local expression of fibrotic and inflammatory biomarkers.
The more favorable properties of these ‘third-generation’ beta-blockers compared with atenolol in reducing central BP are not novel. A retrospective study on hypertensive patients aged 35–65 years on chronic therapy with either angiotensin receptor blockers (ARBs), carvedilol/nebivolol, or atenolol showed that, for similar brachial BP and aortic stiffness, treatment with vasodilating beta-blockers was associated with lower central SBP than treatment with atenolol . The more favorable central hemodynamic effects observed for carvedilol and nebivolol were similar to those of ARBs. Similarly, a study on sinoaortic-denervated rats treated with either carvedilol/nebivolol, atenolol, and verapamil, showed that the ‘third-generation’ beta-blockers induced a greater reduction in short-term BPV compared with atenolol, which was similar to that induced by the CCB, supporting the added benefit of these drugs to cardiovascular protection besides their effect on BP lowering .
The CENTRAL study, a prospective, open-label, randomized small controlled trial compared the effects of atenolol (n = 19) and carvedilol (n = 22) on brachial and central hemodynamic parameters in patients with uncomplicated essential hypertension . After 4 weeks of treatment, central and brachial SBP and DBP were reduced by both drugs to a similar extent, but carvedilol resulted in more favorable pulse pressure (PP) amplification and augmentation index (P = 0.02) by increasing arterial compliance and reducing the magnitude of wave reflection, respectively.
Nebivolol and atenolol have also been compared in another small, double-blind, randomized, cross-over study in 16 naïve individuals with isolated systolic hypertension . Brachial BP and arterial stiffness were significantly reduced after both drugs, but nebivolol reduced aortic PP more than atenolol (50 ± 2 versus 54 ± 2 mmHg; P = 0.02), potentially due to a mixed beta-blocker/nitro-vasodilator effect of the former, translating in less bradycardia and less increase in augmentation index than treatment with the latter. Endothelial function is, in fact, improved after nebivolol, an effect suggested to be due to greater nitric oxide bioavailability following the reduction of its oxidative inactivation and the stimulation of constitutive nitric oxide-synthase .
Nebivolol has also been compared with metoprolol in a randomized, double-blind study on 80 hypertensive patients . In this study, both drugs significantly reduced HR, brachial BP, and mean arterial pressure to a similar extent, but only nebivolol determined a significant reduction in central SBP and DBP, central PP, and LV wall thickness. Reduction in the latter, in particular, was found to be significantly correlated with changes in central SBP (P = 0.001) and in central PP (P = 0.01).
The positive effect of nebivolol on short-term BPV has also been reported in patients with intradialytic hypertension, where short-term BPV was reduced after nebivolol, but not after irbesartan treatment . A possible explanation of these findings is that nebivolol, but not irbesartan, was able to reduce the sympathetic overdrive that might affect BPV in intradialytic hypertensive patients . Nebivolol was also shown to exert significant renal vasodilating effects, increasing both renal plasma flow and glomerular filtration rate, with greater urinary excretion of fluid and solutes, through the 5-hydroxytryptamine1A receptor/nitric oxide pathways [12,13]. Increased nitric oxide formation following treatment with nebivolol was also shown to increase cytosolic free zinc at the myocardiocytes level, with inhibition of intracellular and mitochondrial calcium overload and consequent protection against the effects of reactive oxygen species and lipid peroxidation involved in hypertensive heart disease [14,15].
The same authors have also recently compared the effects of chronic treatment with carvedilol or amlodipine on BP, BPV and target organ damage in N-nitro-l-arginine methyl ester hypertensive rats . Their findings indicated that carvedilol was comparable with amlodipine in reducing SBP and mean arterial pressure, attenuating BPV, and protecting against target organ damage and tissue fibrosis and inflammation, expressed in terms of collagen deposition, metalloproteinases activity, and expression of proinflammatory cytokines . Further evidence from animal studies indicated that chronic administration of carvedilol restored the variance of BPV altered by MI in rats .
The results of the study by Del Mauro et al., besides the confirmatory nature of the reported findings on the occurrence of more favorable hemodynamic changes following treatment with nebivolol or carvedilol than with the nonvasodilating beta-blocker atenolol in SHR rats, add to the available literature regarding the protective cardiovascular effects of vasodilating beta-blockers in uncomplicated hypertension, by exploring possible mechanisms involved in the BPV attenuation induced by these drugs. These effects appear to be similar to those induced by amlodipine, a first line antihypertensive drug shown to have a buffering effect on BPV. Moreover, chronic treatment with carvedilol or nebivolol was more effective than treatment with atenolol in the prevention of cardiac and aortic damage, with effects again similar to those observed with CCBs . These findings therefore suggest that some of the adverse hemodynamic changes associated with nonvasodilating beta-blockers in hypertensive patients might not apply to vasodilating beta-adrenergic blocking agents.
These animal data cannot be directly translated to humans, but should stimulate the organization of longitudinal clinical trials to explore whether these vasodilating beta-blockers could be reconsidered as first-line antihypertensive agents.
Conflicts of interest
There are no conflicts of interest.
1. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens
2. Del Pinto R, Ferri C. Hypertension management at older age: an update. High Blood Press Cardiovasc Prev
3. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens
4. Del Mauro JS, Prince PD, Allo MA, Santander Plantamura Y, Moretto’n MA, Gonza’lez GE, et al. Effects of third-generation β-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats. J Hypertens
5. Polónia J, Barbosa L, Silva JA, Bertoquini S. Different patterns of peripheral versus central blood pressure in hypertensive patients treated with β-blockers either with or without vasodilator properties or with angiotensin receptor blockers. Blood Press Monit
6. Bertera FM, Del Mauro JS, Lovera V, Chiappetta D, Polizio AH, Taira CA, et al. Acute effects of third generation β-blockers on short-term and beat-to-beat blood pressure variability in sinoaortic-denervated rats. Hypertens Res
7. Shah NK, Smith SM, Nichols WW, Lo MC, Ashfaq U, Satish P, et al. Carvedilol reduces aortic wave reflection and improves left ventricular/vascular coupling: a comparison with atenolol (CENTRAL Study). J Clin Hypertens
8. Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens
9. Agabiti-Rosei E, Porteri E, Rizzoni D. Arterial stiffness, hypertension, and rational use of nebivolol. Vasc Health Risk Manag
10. Kampus P, Serg M, Kals J, Zagura M, Muda P, Karu K, et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension
11. Loutradis C, Bikos A, Raptis V, Afkou Z, Tzanis G, Pyrgidis N, et al. Nebivolol reduces short-term blood pressure variability more potently than irbesartan in patients with intradialytic hypertension. Hypertens Res
12. Kakoki M, Hirata Y, Hayakawa H, Nishimatsu H, Suzuki Y, Nagata D, et al. Effects of vasodilatory beta-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney. Hypertension
13. Greven J, Gabriëls G. Effect of nebivolol, a novel beta 1-selective adrenoceptor antagonist with vasodilating properties, on kidney function. Arzneimittelforschung
14. Khan MU, Zhao W, Zhao T, Al Darazi F, Ahokas RA, Sun Y, et al. Nebivolol: a multifaceted antioxidant and cardioprotectant in hypertensive heart disease. J Cardiovasc Pharmacol
15. Del Pinto R, Ferri C. Inflammation-accelerated senescence and the cardiovascular system: mechanisms and perspectives. Int J Mol Sci
16. Del Mauro JS, Prince PD, Donato M, Fernandez Machulsky N, Morettón MA, González GE, et al. Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability. J Am Soc Hypertens
17. Dantas EM, Pimentel EB, Andreão RV, Cichoni BS, Gonçalves CP, Zaniqueli DDA, et al. Carvedilol recovers normal blood pressure variability in rats with myocardial infarction. Auton Neurosci