Effect of the Angiotensin-converting Enzyme Inhibitor Alacepril on Ventricular Function and Beta-Adrenoceptor Number in Rabbits with Aortic Regurgitation.

Yoshikawa, Tsutomu; Handa, Shunnosuke; Nagami, Keiichi; Suzuki, Masahiro; Wainai, Yumiko; Minami, Takeo; Suzuki, Kazutoshi; Kitazawa, Shigeru

doi:10.1536/ihj.36.91

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…The role of ␤-blockade in the management of AR has been explored by other investigators in animal models (1,19,21,(23)(24)(25)(26)(27) (Table 4). These studies have suggested that adrenergic blockade may be beneficial in animal models of acute AR, although none of them evaluated the long-term effects in a chronic AR model.…”

Section: Discussionmentioning

confidence: 99%

“…␤-Blockers may have acted in the same way in our animals with severe chronic AR but preserved LV ejection fraction. Indeed, we observed that Met improved the ratio of gene expression of the ␤ 1 -and ␤ 2 -adrenergic receptors, which (19) Rat AR (chronic) Met (25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 6 mo Improvement of LVEF, decrease in LVH, increase in ␤1-AR expression Suzuki et al (21) Rabbit AR (acute) Intravenous propranolol for 7 days Prevention of ␤-AR downregulation Wright et al (23) Rabbit AR (8 wk) Bradycardial pacing Improvement of myocardial capillary density and cardiac work per minute in AR Xiong et al (24) Rabbit AR (acute, 14 days) Propranolol Improvement of fractional shortening; no effect on ␤-AR; possible protection against toxic effects of catecholamines Yamazaki et al (25) Rat AR (8 wk) No treatment Increase in synthesis of ␤-AR from week 1 to week 4 and return to baseline by week 8 Yoshikawa et al (26) Rabbit AR (acute, 7 days) Alacepril (ACEI) for 7 days Prevention of acute decrease in myocardial ␤-AR density and NE content LVEF, LV ejection fraction; LVH, LV hypertrophy; ACEI, angiotensin-converting enzyme inhibitor; ␤-AR, ␤-adrenergic receptor; NE, norepinephrine. …”

Section: Discussionmentioning

confidence: 99%

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Benefits of long-term β-blockade in experimental chronic aortic regurgitation

Plante¹,

Lachance²,

Champetier³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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The objective of this study was to assess the long-term effects of beta-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a beta-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg.kg(-1).day(-1)) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). beta-Adrenergic receptor ratio (beta(1)/beta(2)) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the beta-adrenergic receptor ratio.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Benefits of long-term β-blockade in experimental chronic aortic regurgitation

Plante¹,

Lachance²,

Champetier³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…20 Significant abnormalities of the adrenergic system have also been identified in humans and animals submitted to chronic volume overload. [2][3][4][5][6][7][8][9][10][11][12]21,22 Others have reported significant decreases in ␤-adrenoreceptor density in the LV of patients with chronic volume overload compared with pressure-overload and normal controls. 23 In subjects with clinical heart failure from severe AR, intense adrenergic activity is present, as in other causes of heart failure.…”

Section: Discussionmentioning

confidence: 99%

“…In rabbits with severe AR, significant changes in catecholamine levels were reported. [3][4][5][6] ␤ARs are also significantly affected, as well as the activity of adenylate cyclase. It has been shown in a similar model that sympathectomy can protect against volume overload, thereby suggesting an important role of the sympathetic system in this hemodynamic state.…”

Section: Discussionmentioning

confidence: 99%

“…1 Significant alterations of the adrenergic system and adrenergic receptors have been reported in animal models of chronic volume overload. [3][4][5][6][7][8][9][10][11][12] Despite these interesting findings, the hypothesis that ␤-adrenergic blocking agents might be effective to protect the volume-overloaded LV has not been adequately tested. A few studies have suggested that a short-term treatment with ␤-blockers might be beneficial in volume overload.…”

mentioning

confidence: 99%

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Effectiveness of β-Blockade in Experimental Chronic Aortic Regurgitation

et al. 2004

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Background-Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. Methods and Results-Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, ␤-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of ␤ 1 -adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented. Conclusions-In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.

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Effects of methylprednisolone on hemodynamics and β-adrenergic receptor signaling in rabbits with acute left ventricular failure

et al. 1997

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Studies suggest that corticosteroids may restore the responsiveness to catecholamines in hypotensive patients. Since the significance of this promising intervention in congestive heart failure remains to be explored, we determined the effects of methylprednisolone, a potent activator of beta-adrenergic receptor signaling, on hemodynamics and beta-adrenergic receptor regulation in an animal model of heart failure. Acute left ventricular overloading was produced by aortic regurgitation (AR) in 22 Japanese white rabbits. Eleven animals received an intravenous administration of methylprednisolone (AR + PSL), while 11 received saline (AR + C) for 1 week. A sham operation was performed on 10 other rabbits (S). There was no difference between the AR + C and AR + PSL groups in the decrease in aortic diastolic pressure immediately after the production of AR. The aortic diastolic pressure and regurgitant fractions were also similar in the two groups. The left ventricular end-diastolic and end-systolic dimensions were both larger, and the left ventricular end-diastolic pressure was higher in AR + C or AR + PSL than in S rabbits. Between the AR + C and AR + PSL, there were no differences in any of these variables. Cardiac output was lower in AR + C, but not in AR + PSL, than in S. Cardiac output in AR + PSL was significantly higher than in AR + C. The myocardial concentration of norepinephrine and the number of beta-adrenergic receptors were both lower in the AR + C and AR + PSL than in the S groups. The number of receptors in AR + PSL was higher than in AR + C. Maximal isoproterenol-stimulated adenylyl cyclase activity was similar in the AR + C and AR + PSL groups. Results suggest methylprednisolone yielded some benefits, including an increase in cardiac output and in total beta-adrenergic receptor number, in this animal model of heart failure.

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Effect of the Angiotensin-converting Enzyme Inhibitor Alacepril on Ventricular Function and Beta-Adrenoceptor Number in Rabbits with Aortic Regurgitation.

Cited by 9 publications

References 25 publications

Benefits of long-term β-blockade in experimental chronic aortic regurgitation

Benefits of long-term β-blockade in experimental chronic aortic regurgitation

Effectiveness of β-Blockade in Experimental Chronic Aortic Regurgitation

Effects of methylprednisolone on hemodynamics and β-adrenergic receptor signaling in rabbits with acute left ventricular failure

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