Loss of Arterial and Renal Nitric Oxide Bioavailability in Hypertensive Rats With Diabetes: Effect of  -Blockers

Mason, R. Preston; Kubant, Ruslan; Jacob, Robert F.; Malinski, P. T.; Huang, Xiaoyan; Louka, Febee R.; Borowiec, Jan; Mizuno, Yoshiko; Maliński, Tadeusz

doi:10.1038/ajh.2009.163

Cited by 25 publications

(12 citation statements)

References 45 publications

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“…Our observation that nebivolol treatment improved insulin sensitivity in transgenic RAAS mediated insulin resistant rats complement prior observations in Ang II treated [23] and overweight rodents [20], as well as insulin resistant hypertensive persons [8,18,19,25,26]. Indeed, previous studies have demonstrated that nebivolol reduces oxidative stress and increases tissue bioavailable NO levels in cardiovascular and renal tissue [7,17,23,27]. Reduced tissue bioavailable NO levels appears to be an important factor involved in Ang II-mediated elevation of blood pressure and decreased delivery of insulin and uptake of glucose by the skeletal muscle, processes critical for skeletal muscle utilization of glucose [1,6,14,15,16,28].…”

Section: Discussionsupporting

confidence: 87%

“…On the other hand, classic beta adrenergic receptor blockers have been shown to aggravate insulin resistance in hypertensive individuals [4, 17]. In the context of treatment of hypertension in insulin resistant individuals, nebivolol a selective β 1 -adrenergic blocker with vasodilatory and anti-oxidant properties, has been shown to improve oxidant stress and systemic insulin sensitivity; likely through reductions in NADPH oxidase activity and enhancement of endothelial NO synthase activity [18,19,20].…”

Section: Introductionmentioning

confidence: 99%

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Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat

et al. 2011

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Objective Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β adrenergic receptor blockers in hypertension is limited due to potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β1adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling and glucose transport in the transgenic TG(mRen2)27rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance. Research design and methods Young (age 6-9 wks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/kg/day or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the Homeostasis Model Assessment (HOMA–IR). Additionally, insulin metabolic signaling, NADPH oxidase activity, reactive oxygen species (ROS), and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue. Results The Ren2 rat demonstrated systemic insulin resistance as examined by HOMA-IR, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels ROS in skeletal muscle tissue. Conclusions Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance, in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance and enhanced tissue RAS expression.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat

et al. 2011

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“…Further studies found that, compared with normotensive rats, spontaneously hypertensive rats had lower NO bioavailability despite increased levels of eNOS [23]. The effects were even more pronounced after induction of diabetes among the hypertensive animals [21•]. The results were consistent with studies in rats that developed hypertension after aortic banding [24].…”

Section: Endothelial Dysfunction and The Role Of Nosupporting

confidence: 65%

“…Furthermore, ONOO – molecules themselves are highly reactive and oxidize lipids, cause cellular injury, and enhanced arterial contraction (Fig. 1) [21•].…”

Section: Endothelial Dysfunction and The Role Of Nomentioning

confidence: 99%

Pleiotropic Effects of Calcium Channel Blockers

Mason

2012

Curr Hypertens Rep

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Clinical trials have reported reduced cardiovascular events with certain antihypertensive agents at a rate that could not be predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by pleiotropic effects of these agents and modulation of central blood pressures. This review focuses on the mechanisms by which calcium channel blockers exert pleiotropic effects, both alone and in combination with statins and inhibitors of the renin-angiotensin system. The essential role of nitric oxide (NO) in maintaining endothelial function and the relationship between NO and reactive oxygen species are discussed in the context of the etiology of hypertension. The importance of managing global cardiovascular risk is emphasized, as hypertension commonly clusters with dyslipidemia and loss of glucose control. From a mechanistic viewpoint, these risk factors contribute to endothelial dysfunction, oxidative stress, and inflammation in a synergistic fashion. A greater understanding of the mechanisms of actions of these cardiovascular agents may lead to more effective drug combinations, to the benefit of individual patients. Furthermore, by elucidating the biological mechanisms by which cardiovascular risk factors lead to vascular injury, we may highlight common pathways and identify novel therapeutic targets.

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“…In a number of independent studies, nebivolol-induced NO release has also been linked to β 3 -receptor interactions as well as ATP-dependent, P2Y-mediated eNOS activation [17-20]. Nebivolol has also been reported to reverse eNOS uncoupling and interfere with oxidative stress processes, by reducing NADPH oxidase activity or by directly scavenging oxygen-derived free radicals [13,20-23]. …”

Section: Introductionmentioning

confidence: 99%

The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells

Mason

Jacob²,

Corbalan

et al. 2013

BMC Pharmacol Toxicol

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BackgroundNebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood.MethodsUsing amperometric NO and peroxynitrite (ONOO-) nanosensors, β3-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO- stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO- were measured with nanosensors (diameter ~ 300 nm) placed 5 ± 2 μm from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO- were compared with those of ATP, 2-MeSATP, and L-755,507.ResultsNebivolol stimulates endothelial NO release through β3-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 ± 5 nM/s) as compared to the kinetics of ATP (194 ± 10 nM/s), L-755,507 (108 ± 6 nM/s), and 2-MeSATP (105 ± 5 nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO-] concentrations. This ratio for nebivolol was 1.80 ± 0.10 and significantly higher than that for ATP (0.80 ± 0.08), L-755,507 (1.08 ± 0.08), and 2-MeSATP (1.09 ± 0.09). Nebivolol induced ATP release in a concentration-dependent manner.ConclusionThe two major pathways (ATP efflux/P2Y receptors and β3 receptors) and several steps of nebivolol-induced NO and ONOO- stimulation are mainly responsible for the slow kinetics of NO release and low ONOO-. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO-] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis.

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Loss of Arterial and Renal Nitric Oxide Bioavailability in Hypertensive Rats With Diabetes: Effect of -Blockers

Abstract: Vascular and renal NO was significantly reduced in diabetic hypertensive rats and correlated with metabolic changes. Nebivolol reversed these effects in a manner consistent with enhanced endothelial function.

Cited by 25 publications

References 45 publications

Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat

Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat

Pleiotropic Effects of Calcium Channel Blockers

The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells

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