Prevention of ventricular fibrillation requires central β-adrenoceptor blockade in rabbits

Åblad, Bengt; Bjurö, T; Björkman, Jan-Arne; Edström, Therese

doi:10.1080/14017430701383748

Cited by 15 publications

(12 citation statements)

References 25 publications

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“…Dogs treated with metoprolol showed an increase in LV EF and a reversal of LV global, structural and biochemical remodelling (Imai et al ., 2007). Ablad et al . (2007) found metoprolol reduced the inducibility of ventricular fibrillation.…”

Section: Discussionmentioning

confidence: 99%

“…Dogs treated with metoprolol showed an increase in LV EF and a reversal of LV global, structural and biochemical remodelling (Imai et al, 2007). Ablad et al (2007) found metoprolol reduced the inducibility of ventricular fibrillation. In addition, remodelling of noninfarcted myocardium is associated with myofilament function, which may contribute to depressed LV function (van der Velden et al, 2004).…”

Section: Figurementioning

confidence: 99%

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Ketamine‐induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol

Li¹,

Shi²,

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSE Growing evidence suggests that long‐term abuse of ketamine does harm the heart and increases the risk of sudden death. The present study was performed to explore the cardiotoxicity of ketamine and the protective effects of metoprolol. EXPERIMENTAL APPROACH Rats and rabbits were divided into control, ketamine, metoprolol alone and ketamine plus metoprolol groups. Ketamine (40 mg·kg−1·day−1, i.p.) and metoprolol (20 mg·kg−1·day−1, p.o.) were administered continuously for 12 weeks in rats and 8 weeks in rabbits. Cardiac function, electrophysiological disturbances, cardiac collagen, cardiomyocte apoptosis and the remodelling‐related proteins were evaluated. KEY RESULTS Rabbits treated with ketamine showed decreased left ventricular ejection fraction, slowed ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol prevented these pathophysiological alterations. In ketamine‐treated rats, cardiac collagen volume fraction and apoptotic cell number were higher than those of control animals; these effects were prevented by co‐administration of metoprolol. Consistently, the expressions of poly (ADP‐ribose) polymerases‐1, apoptosis‐inducing factor and NF‐κB‐light‐chain‐enhancer of activated B cells were all increased after ketamine treatment and sharply reduced after metoprolol administration. Moreover, ketamine enhanced sympathetic sprouting, manifested as increased growth‐associated protein 43 and tyrosine TH expression. These effects of ketamine were prevented by metoprolol. CONCLUSIONS AND IMPLICATIONS Chronic treatment with ketamine caused significant ventricular myocardial apoptosis, fibrosis and sympathetic sprouting, which altered the electrophysiological properties of the heart and increased its susceptibility to malignant arrhythmia that may lead to sudden cardiac death. Metoprolol prevented the cardiotoxicity of ketamine, indicating a promising new therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Ketamine‐induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol

Li¹,

Shi²,

et al. 2012

British J Pharmacology

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“…Previous studies also reported that metoprolol increased left ventricular ejection fraction (LVEF) and a reversal of left ventricular global, structural and biochemical remodeling in dogs [11]. Moreover, Ablad et al [12] found that metoprolol reduced the inducibility of ventricular fibrillation. Nevertheless, the potential role of metoprolol in chronic OSA-induced left ventricular structural remodeling remains unclear.…”

Section: Introductionmentioning

confidence: 90%

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

Yan

Zhao

et al. 2015

Cell Physiol Biochem

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Aims: Emerging evidence suggested that obstructive sleep apnea (OSA) was independently associated with the development of heart failure. In this study, we explored the influence of chronic OSA on left ventricular structural remodeling in canines, and the potential therapeutical role of metoprolol. Methods: Chronic OSA model was established by stopping the ventilator and closing the airway for 4 h/day apnea-ventilation cycles every other day for 12 weeks while metoprolol (5 mg· kg^-1· day^-1) were administered continuously. Norepinephrine concentration was measured by Enzyme Linked Immunosorbent Assay. Transmission electron microscopy, Hematoxylin and eosin, TUNEL and Masson trichrome staining were employed to detect the morphology, apoptosis and fibrosis of cardiomyocytes. Protein expression of apoptosis and fibrosis-related factors including apoptosis-inducing factor (AIF), caspase 3, Bcl-2, Bax, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and p38 mitogen-activated protein kinase (MAPK) were examined by Western blotting. Results: Norepinephrine concentration was markedly increased in chronic OSA dogs and reduced by metoprolol. Both the apoptotic ratio and collagen volume fraction were significantly increased in left ventricular myocytes of chronic OSA dogs, and was reversed by metoprolol. Moreover, chronic OSA-induced upregulation of AIF, cleaved caspase 3, Bax, α-SMA, and TGF-β1 as well as downregulation of Bcl-2 was markedly recovered by metoprolol, which was mediated by p38 MAPK. Conclusion: Metoprolol protects against chronic OSA-induced cardiac apoptosis and fibrosis in left ventricular myocytes of canines, which may provide new potential strategy for drug therapy of OSA.

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“…Sanderson et al 19 demonstrated superior effects of metoprolol over hydrophilic vasodilating β-blocker celiprolol in restoring baroreflex gain and vagal tone in patients with chronic HF. Similarly, recent evidence by Ablad et al (2007) obtained in anaesthetized rabbits suggested that β-blockers are acting centrally to increase cardiac vagal tone. In contrast, there are data obtained in normal human subjects 20,21 and in post-MI patients 22,23 indicating that the effects of β-blockers on vagal tone are likely to be due to their peripheral actions.…”

Section: Heart Failure Autonomic Control Of the Heart And Metoprololmentioning

confidence: 99%

Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart

Gourine

Bondar

Spyer

et al. 2008

Circulation Research

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Heart failure patients are routinely given ␤-adrenoceptor antagonists (␤-blockers), although the mechanism(s) underlying their beneficial effects is not fully resolved. It is not entirely clear how long-term application of negative inotropic compounds improves cardiac performance, slows remodeling processes, and decreases mortality. All ␤-blockers, which produce a beneficial effect in heart failure, have in common a high degree of lipophilicity and, therefore, have the ability to cross the blood-brain barrier. Here, we show that blockade of ␤-adrenoceptors directly in the brain (chronic intracerebroventricular administration of metoprolol) attenuates the progression of left ventricular remodeling in a rat model of myocardial infarction-induced heart failure. These results provide the first direct evidence that the action of certain ␤-blockers in the brain could contribute to their beneficial effect on the failing heart. M ortality associated with heart failure (HF) still remains high, despite considerable achievements in medical therapy, device technology, and cardiac surgery. The use of ␤-adrenoceptor (␤-AR) antagonists (␤-blockers) pioneered in the 1970s for the treatment of arterial hypertension became one of the most important advances in HF therapy. 1,2 The efficacy of 3 ␤-blockers, bisoprolol, carvedilol, and metoprolol, in HF treatment have been demonstrated in large placebo-controlled clinical trials. [3][4][5] These studies have revealed a reduction in the number of deaths from worsening HF in patients treated with carvedilol and metoprolol resulting from an improvement in left ventricular (LV) function and a delayed progression of LV remodeling. 3,4 In contrast, bisoprolol decreased mortality mainly by preventing sudden cardiac death, 5 whereas several ␤-blockers (eg, bisindolol and others) have been found to be insufficiently effective to be used in HF therapy. 2 A number of mechanisms explaining variable effects of ␤-blockers in HF patients have been proposed (including polymorphism in the genes encoding ␤-ARs, modulation of systemic neurohormonal activity, antagonism of the toxic actions of norepinephrine on the myocardium, favorable effects on myocardial energetics, etc). 2,6,7 Interestingly, it appears that the ␤-blockers, which produce a beneficial effect in HF, all have in common a high degree of lipophilicity and, as a result, have the ability to cross the blood-brain barrier. 2,8 Beneficial actions of certain lipophilic ␤-blockers in preventing ventricular fibrillation have already been attributed to their possible action within the brain. 9 We, therefore, suggested that the favorable effects of ␤-blockers in HF may be attributable, at least in part, to their central nervous system (CNS) effects. To test this hypothesis, we infused metoprolol (a ␤ 1 -blocker widely used in HF therapy) directly into the brain and determined the effect of this treatment on the progression of LV remodeling after myocardial infarction (MI) in rats. Materials and MethodsMI in rats was induced using a permanen...

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Prevention of ventricular fibrillation requires central β-adrenoceptor blockade in rabbits

Abstract: Metoprolol reduced the incidence of VF by a better maintained discharge than atenolol in efferent cardiac vagal nerves, possibly due to inhibition of central nervous beta(1) adrenoceptors modulating vagal nervous outflow.

Cited by 15 publications

References 25 publications

Ketamine‐induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol

Ketamine‐induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol

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

Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart

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