Nebivolol Improves Diastolic Dysfunction and Myocardial Remodeling Through Reductions in Oxidative Stress in the Zucker Obese Rat

Zhou, Xinjie; Ma, Lixin; Habibi, Javad; Whaley‐Connell, Adam; Hayden, Melvin R.; Tilmon, Roger D.; Brown, Ashley N.; Kim, Jeong‐A; DeMarco, Vincent G.; Sowers, James R.

doi:10.1161/hypertensionaha.109.145136

Cited by 105 publications

(131 citation statements)

References 45 publications

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“…It could be possible to point out a relationship between increased cardiac oxidative stress by stimulation of NADPH oxidase activity (36,37) and enhanced CaMKII activity (22,31), both induced by chronic isoprenaline infusion. Although nebivolol-induced inhibition of NADPH oxidase activity is not shown in the present study, several groups observed the mentioned effect of nebivolol in different studies (12,25,30,35,39). The effects of nebivolol treatment seem not to be selective for a receptor subtype or mediator, because nebivolol restores both isoprenaline-and BRL37344-induced inotropic responses together with receptor-independent pathways of ␤-adrenoceptor signaling (forskolin).…”

Section: Discussioncontrasting

confidence: 49%

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β₁-adrenoceptor blockage

Özakça

Arioglu‐Inan

Esfahani

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Ozakca I, Arioglu-Inan E, Esfahani H, Altan VM, Balligand JL, Kayki-Mutlu G, Ozcelikay AT. Nebivolol prevents desensitization of ␤-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond ␤ 1-adrenoceptor blockage. Am J Physiol Heart Circ Physiol 304: H1267-H1276, 2013. First published March 1, 2013; doi:10.1152/ajpheart.00352.2012.-The importance of chronic stimulation of ␤-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of ␤-blockers in the treatment of heart failure. Nebivolol is a third-generation ␤-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or ␤3-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on ␤-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective ␤ 1-adrenoceptor blocker. Rats infused by isoprenaline (100 g·kg Ϫ1 ·day Ϫ1 , 14 days) were randomized into three groups according to the treatment with metoprolol (30 mg·kg Ϫ1 ·day Ϫ1 ), nebivolol (10 mg·kg Ϫ1 ·day Ϫ1 ), or placebo for 13 days starting on day 1 after implantation of minipump. Both metoprolol and nebivolol caused a similar reduction on heart rate. Nebivolol mediated a significant improvement on cardiac mass, coronary flow, mRNA expression levels of sarcoplasmic reticulum Ca 2ϩ ATPase (SERCA2a) and atrial natriuretic peptide and phospholamban (PLN)/ SERCA2a and phospho-PLN/PLN ratio compared with metoprolol and placebo. Nebivolol prevented the detrimental effects of isoprenaline infusion on isoprenaline (68% of control at 30 M), BRL37344 (63% of control at 0.1 M), and forskolin (64% of control at 1 M) responses compared with metoprolol (isoprenaline, 34% of control; BRL37344, no response; forskolin, 26% of control) and placebo (isoprenaline, 33% of control; BRL37344, 28% of control; forskolin, 12% of control). Both ␤-blockers improved the changes in mRNA expressions of ␤ 1-and ␤3-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of ␤-adrenoceptor signaling and the development of cardiac hypertrophy independent of its ␤1-adrenoceptor blocking effect. nebivolol; inotropy; adrenergic stimulation; ␤-adrenoceptors PLASMA CATECHOLAMINE LEVELS play a pivotal role in the shortand long-term regulation of cardiac function. In acute term, as seen in the fight-or-flight response, the activation of sympathetic drive induces positive effects on inotropy, chronotropy, and lusitropy, which are mediated especially by cardiac ␤ 1 -adrenoceptors. However, sustained activation of ␤-adrenoceptors by circulating catecholamines can cause detrimental effects on cardiac muscle. This phenomenon can be observed in the progress of the heart failure; in the early stages of the pathology, the increase of the plasma catecholamines compensates the dysfunction of the cardiac muscle, but in the long term the sympathetic overactivation contributes to dysfu...

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Section: Discussioncontrasting

confidence: 49%

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β₁-adrenoceptor blockage

Özakça

Arioglu‐Inan

Esfahani

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Noninvasive MRI scans were performed within 72 h of the end of the treatment period using a Varian 7-T horizontal-bore MRI (Varian, Palo Alto, CA) equipped with a 60-mm birdcage radiofrequency coil as previously described (36,44,47). Animals were weighed and anesthetized using 1.8 -2.7% isoflurane on a nose cone nonrebreathing system supplying continuous oxygen.…”

Section: In Vivo Cine Mrimentioning

confidence: 99%

“…ROS formation was evaluated in LV sections by chemiluminescense and further by immunostaining for 3-nitrotyrosine content, a marker of peroxynitrite formation, as previously described (36,43,44,47).…”

Section: Measurement Of Cardiac Tissue Oxidative Stressmentioning

confidence: 99%

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Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Habibi

DeMarco²,

Ma³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Habibi J, DeMarco VG, Ma L, Pulakat L, Rainey WE, WhaleyConnell AT, Sowers JR. Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression. Am J Physiol Heart Circ Physiol 300: H1484 -H1491, 2011. First published January 14, 2011; doi:10.1152/ajpheart.01000.2010.-There is emerging evidence that aldosterone can promote diastolic dysfunction and cardiac fibrosis independent of blood pressure effects, perhaps through increased oxidative stress and inflammation. Accordingly, this investigation was designed to ascertain if mineralocorticoid receptor blockade improves diastolic dysfunction independently of changes in blood pressure through actions on myocardial oxidative stress and fibrosis. We used young transgenic (mRen2)27 [TG(mRen2)27] rats with increases in both tissue ANG II and circulating aldosterone, which manifests age-related increases in hypertension and cardiac dysfunction. Male TG(mRen2)27 and age-matched Sprague-Dawley rats were treated with either a low dose (ϳ1 mg·kg Ϫ1 · day Ϫ1 ) or a vasodilatory, conventional dose (ϳ30 mg · kg Ϫ1 · day Ϫ1 ) of spironolactone or placebo for 3 wk. TG(mRen2)27 rats displayed increases in systolic blood pressure and plasma aldosterone levels as well as impairments in left ventricular diastolic relaxation without changes in systolic function on cine MRI. TG(mRen2)27 hearts also displayed hypertrophy (left ventricular weight, cardiomyoctye hypertrophy, and septal wall thickness) as well as fibrosis (interstitial and perivascular). There were increases in oxidative stress in TG(mRen2)27 hearts, as evidenced by increases in NADPH oxidase activity and subunits as well as ROS formation. Low-dose spironolactone had no effect on systolic blood pressure but improved diastolic dysfunction comparable to a conventional dose. Both doses of spironolactone caused comparable reductions in ROS/3-nitrotryosine immunostaining and perivascular and interstitial fibrosis. These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure.aldosterone; fibrosis; renin-angiotensin-aldosterone system REMODELING OF CARDIAC TISSUE in hypertension is characterized by myocyte hypertrophy and interstitial fibrosis, which facilitate the development of left ventricular (LV) diastolic dysfunction (27,41). In this context, increases in aldosterone levels are associated with increased heart failure mortality (9, 22), and blockade of mineralcorticoid receptors (MRs) improves morbidity and mortality (22,25,26), including those with preserved ejection fraction (EF), e.g., diastolic dysfunction (15, 18). Both cardiac myocytes and fibroblasts express MRs with a high affinity for aldosterone (17,32,38). However, the development of interstitial fibrosis and diastolic dysfunction by aldosterone actions on the MR occur when the renin-angiotensin-aldosterone system (RAAS) is inappropriately acti...

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“…However, many of the obesity studies have been conducted in genetic animal models, 11,12 which may not reflect most of human obesity causes. Thus, in the present study, we tested whether 10 weeks of exercise training and/or caloric restriction would improve cardiac function in obese rats fed with a high-fat and sucrose diet that mimics food habits of humans living in Western countries.…”

mentioning

confidence: 99%

Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca ²⁺ -Handling Protein Profile in Obese Rats

et al. 2010

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Abstract-Previous studies show that exercise training and caloric restriction improve cardiac function in obesity.However, the molecular mechanisms underlying this effect on cardiac function remain unknown. Thus, we studied the effect of exercise training and/or caloric restriction on cardiac function and Ca 2ϩ handling protein expression in obese rats. To accomplish this goal, male rats fed with a high-fat and sucrose diet for 25 weeks were randomly assigned into 4 groups: high-fat and sucrose diet, high-fat and sucrose diet and exercise training, caloric restriction, and exercise training and caloric restriction. An additional lean group was studied. The study was conducted for 10 weeks. Cardiac function was evaluated by echocardiography and Ca 2ϩ handling protein expression by Western blotting. Our results showed that visceral fat mass, circulating leptin, epinephrine, and norepinephrine levels were higher in rats on the high-fat and sucrose diet compared with the lean rats. Cardiac nitrate levels, reduced/oxidized glutathione, left ventricular fractional shortening, and protein expression of phosphorylated Ser 2808 -ryanodine receptor and Thr 17 -phospholamban were lower in rats on the high-fat and sucrose diet compared with lean rats. Exercise training and/or caloric restriction prevented increases in visceral fat mass, circulating leptin, epinephrine, and norepinephrine levels and prevented reduction in cardiac nitrate levels and reduced:oxidized glutathione ratio. Exercise training and/or caloric restriction prevented reduction in left ventricular fractional shortening and in phosphorylation of the Ser 2808 -ryanodine receptor and Thr 17 -phospholamban. These findings show that exercise training and/or caloric restriction prevent cardiac dysfunction in high-fat and sucrose diet rats, which seems to be attributed to decreased circulating neurohormone levels. In addition, this nonpharmacological paradigm prevents a reduction in the Ser 2808 -ryanodine receptor and Thr 17 -phospholamban phosphorylation and redox status. (Hypertension. 2010;56:629-635.)

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Nebivolol Improves Diastolic Dysfunction and Myocardial Remodeling Through Reductions in Oxidative Stress in the Zucker Obese Rat

Cited by 105 publications

References 45 publications

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β₁-adrenoceptor blockage

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β₁-adrenoceptor blockage

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca ²⁺ -Handling Protein Profile in Obese Rats

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Nebivolol Improves Diastolic Dysfunction and Myocardial Remodeling Through Reductions in Oxidative Stress in the Zucker Obese Rat

Cited by 105 publications

References 45 publications

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β1-adrenoceptor blockage

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β1-adrenoceptor blockage

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca 2+ -Handling Protein Profile in Obese Rats

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Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β₁-adrenoceptor blockage

Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β₁-adrenoceptor blockage

Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca ²⁺ -Handling Protein Profile in Obese Rats