Long-term treatment with nebivolol attenuates renal damage in Zucker diabetic fatty rats

Toblli, Jorge Eduardo; Cao, Gabriel; Giani, Jorge F.; Muñoz, Marina Cecilia; Angerosa, Margarita; Dominici, Fernando Pablo

doi:10.1097/hjh.0b013e328349064c

Cited by 25 publications

(26 citation statements)

References 54 publications

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“…The ability of nebivolol to increase renal reduced glutathione and to decrease renal malondialdehyde levels is consistent with the finding of Toblli et al . who reported that nebivolol increased the renal level of the antioxidant reduced glutathione and normalized renal malondialdehyde level in Zucker diabetic fatty rats. Recently, Akgullu et al .…”

Section: Discussionmentioning

confidence: 96%

Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Morsy

Heeba

2016

Basic Clin Pharma Tox

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Treatment with cisplatin is associated with dose-limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a b 1 -adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor-alpha, caspase-3, angiotensin II and endothelin-1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre-treatment with N x -nitro-L-arginine methyl ester, the non-specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin-induced nephrotoxicity that is most likely through its antioxidant, anti-inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin-1 levels.

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Section: Discussionmentioning

confidence: 96%

Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Morsy

Heeba

2016

Basic Clin Pharma Tox

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“…Experimental data in animals with metabolic syndrome indicate that nebivolol has an actual protective role, not only in cardiovascular structures but also in renal tissue, in comparison with atenolol 58,63,80. Evaluation of immunoexpression of plasminogen activator inhibitor-1 and cell adhesion molecules, such as VCAM-1 and PECAM-1, in the vascular wall of diabetic rats which received nebivolol for 6 months showed favorable modification of these prothrombotic and vascular inflammatory markers when compared with atenolol 63.…”

Section: Comparative Impact On Cardiovascular Riskmentioning

confidence: 99%

Nebivolol: impact on cardiac and endothelial function and clinical utility

Toblli

DiGennaro²,

Giani³

et al. 2012

VHRM

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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.

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“…Previous studies in humans and experimental animals have demonstrated an antioxidant effect of Nebivolol (Ignarro, 2004; Mollnau et al, 2003; Oelze et al, 2006; Whaley Connell et al, 2009, Varagic et al, 2010; Toblli et al, 2011; Moningka et al, 2012); therefore, we also examined the effect of Nebivolol on measures of systemic and renal oxidative stress and renal cortex antioxidant enzyme abundance. The 5/6 A/I model was associated with an increase in nitrotyrosine immunoreactivity and a decrease in mnSOD abundance in the renal cortex vs. control.…”

Section: Discussionmentioning

confidence: 99%

“…Nebivolol exerts short (4 weeks) and long (6 months) term renal protection in the 5/6 nephrectomy (Nx) model (Gschwend et al, 2009; Pires et al, 2007), the transgenic Ren 2 rat (Whaley-Connell et al, 2009; Hayden et al, 2010), high-salt fed spontaneously hypertensive rats (Varagic et al, 2010), and the zucker obese rat (Habibi et al, 2011; Toblli et al, 2011). In addition, we recently reported that nebivolol is protective against hypertension and CKD during chronic NOS inhibition with L-NAME, (Moningka et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Nebivolol does not protect against 5/6 ablation/infarction induced chronic kidney disease in rats — Comparison with angiotensin II receptor blockade

et al. 2012

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Aims Nitric oxide (NO) deficiency contributes to chronic kidney disease progression. Nebivolol, a beta adrenergic receptor antagonist, may enhance endogenous NO. Here, we investigated whether nebivolol attenuates hypertension and renal injury after 5/6 ablation/ infarction (A/I). Efficacy was compared to the AT1 receptor antagonist olmesartan. Main Methods Kidney disease and hypertension were induced by right kidney ablation and ~2/3 infarction of the left kidney. Rats were treated orally with vehicle (Placebo), nebivolol (5 mg/kg b.i.d.), or olmesartan (2.5 mg/kg/day) for 6 weeks after A/I. Key Findings With placebo, glomerular sclerosis and tubulointersititial fibrosis developed with increased blood pressure and proteinuria, and a fall in NOx excretion. Olmesartan prevented these changes, but Nebivolol had no effect on these measures but lowered heart rate. Neither treatment reduced systemic oxidative stress (urinary hydrogen peroxide and TBARS). Compared to controls, renal cortex abundance of nNOSα decreased and nNOSβ increased in rats after 5/6 A/I, with no changes in eNOS. Neither treatment restored nNOSα; however, both reduced nNOSβ. Activity of DDAH was decreased by 5/6 A/I but restored by both treatments despite no increase in DDAH protein abundance. Kidney cortex abundance of manganese SOD fell after 5/6 A/I and was restored by treatment with olmesartan but not nebivolol. Extracellular and copper/zinc SOD abundances were not changed. Significance In conclusion, nebivolol showed no benefit after 6 weeks in rapidly progressing, ANG II-dependent 5/6 A/I model of chronic kidney disease. This contrasts to the protection seen with 6 months nebivolol in the slowly progressing 5/6 ablation model.

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Long-term treatment with nebivolol attenuates renal damage in Zucker diabetic fatty rats

Abstract: Our current finding underscores the importance of this therapy in hypertensive states concomitant with altered lipid and glucose metabolism.

Cited by 25 publications

References 54 publications

Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Nebivolol: impact on cardiac and endothelial function and clinical utility

Nebivolol does not protect against 5/6 ablation/infarction induced chronic kidney disease in rats — Comparison with angiotensin II receptor blockade

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