β1-Adrenergic blockers exert antioxidant effects, reduce matrix metalloproteinase activity, and improve renovascular hypertension-induced cardiac hypertrophy

Abstract

Hypertension induces left-ventricular hypertrophy (LVH) by mechanisms involving oxidative stress and unbalanced cardiac matrix metalloproteinase (MMP) activity. We hypothesized that β1-adrenergic receptor blockers with antioxidant properties (nebivolol) could reverse hypertension-induced LVH more effectively than conventional β1-blockers (metoprolol) when used at doses that exert similar antihypertensive effects. Two-kidney one-clip (2K1C) hypertension was induced in male Wistar rats. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1)day(-1)) or metoprolol (20 mg kg(-1)day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly by tail-cuff plethysmography. LV structural changes and fibrosis were studied in hematoxylin/eosin- and picrosirius-stained sections, respectively. Cardiac MMP levels and activity were determined by in situ zymography, gel zymography, and immunofluorescence. Dihydroethidium and lucigenin-derived chemiluminescence assays were used to assess cardiac reactive oxygen species (ROS) production. Nitrotyrosine levels were determined in LV samples by immunohistochemistry and green fluorescence and were evaluated using the ImageJ software. Cardiac protein kinase B/Akt (AKT) phosphorylation state was assessed by Western blot. Both β-blockers exerted similar antihypertensive effects and attenuated hypertension-induced cardiac remodeling. Both drugs reduced myocyte hypertrophy and collagen deposition in 2K1C rats. These effects were associated with lower cardiac ROS and nitrotyrosine levels and attenuation of hypertension-induced increases in cardiac MMP-2 levels and in situ gelatinolytic activity after treatment with both β-blockers. Whereas hypertension increased AKT phosphorylation, no effects were found with β-blockers. In conclusion, we found evidence that two β1-blockers with different properties attenuate hypertension-induced LV hypertrophy and cardiac collagen deposition in association with significant cardiac antioxidant effects and MMP-2 downregulation, thus suggesting a critical role for β1-adrenergic receptors in mediating those effects. Nebivolol is not superior to metoprolol, at least with respect to their capacity to reverse hypertension-induced LVH.

Pretreatment with nebivolol attenuates level and expression of matrix metalloproteinases in a rat model of renal ischaemia–reperfusion injury

“…The effect of nebivolol on MMP‐2 and ‐9 levels in renal IRI model has not been reported so far. However, in an experimental two kidney one clamp (2K1C) renovascular hypertension model, nebivolol as a nitric oxide (NO) donator, was proven to reduce MMP‐2 activity induced by reactive oxygen species (ROS) . In support of this evidence, another anti‐oxidant drug, tempol, was shown to decrease both TGF‐β and MMP‐2 upregulation caused by oxidative stress in a 2K1C hypertensive rats and ameliorated cardiac hypertensive changes .…”

“…Inhibition of matrix metalloproteinases has been shown to reduce IRI in renal murine models . Treatment with β‐adrenergic blockers with anti‐oxidant properties attenuated hypertension‐induced increases in cardiac MMP‐2 levels, and inhibited MMP activity upregulation in two‐kidney one‐clamp induced hypertension in rats . Nebivolol, a third generation β 1 ‐adrenergic receptor blocker with the capability to release NO from endothelium, has been shown to attenuate detrimental effects of pro‐oxidant and inflammatory mechanisms involving tissue growth factor‐β (TGF‐β) and MMPs in renovascular hypertension …”

PEG-coated gold nanoparticles attenuate β-adrenergic receptor-mediated cardiac hypertrophy

“…The chronic cardiac hypertrophy model is used to simulate the chronic progression of heart remodeling in some chronic cardiovascular diseases such as hypertension. 18 The acute cardiac hypertrophy model reflects cardiac remodeling following acute cardiac injuries. 19 The safety of AuNPs in ISO-induced chronic cardiac hypertrophy model has been demonstrated in our previous study.…”

Metoprolol Inhibits Cardiac Apoptosis and Fibrosis in a Canine Model of Chronic Obstructive Sleep Apnea

“…Similarly, anti-fibrotic effect of metoprolol has been found in other studies. For example, metoprolol reduced myocyte hypertrophy and collagen deposition in a rat model of renovascular hypertension-induced cardiac hypertrophy [29]. Moreover, Serpi et al [30] suggested that metoprolol treatment attenuated adverse remodeling via decreased apoptosis and fibrosis in the peri-infarct region in a model of coronary ligation in rats.…”