Effects of a Pure .ALPHA./.BETA.-Adrenergic Receptor Blocker on Monocrotaline-Induced Pulmonary Arterial Hypertension With Right Ventricular Hypertrophy in Rats

Ishikawa, Masaya; Sato, Naoki; Asai, Kuniya; Takano, Teruo; Mizuno, Kyoichi

doi:10.1253/circj.cj-09-0213

Cited by 49 publications

(35 citation statements)

References 20 publications

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“…These data agree with the study of Koskenvuo et al (2010), in which pulmonary artery pressure was measured directly by using RV catheterization. In the present study, there was a slight increase in pulmonary pressure in female rats, while this parameter D r a f t was increased by about three times in male rats, as observed in previous reports (Ishikawa et al 2009, Koskenvuo et al 2010. Thus, this suggests that the animals in the present study, at this time point, are in a mild pulmonary hypertensive state.…”

Section: Discussionsupporting

confidence: 90%

Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

Siqueira

Colombo

Conzatti

et al. 2018

Can. J. Physiol. Pharmacol.

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The aim of this study was to evaluate the impact of ovariectomy on oxidative stress in the right ventricle (RV) of female rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Rats were divided into four groups (n=6/group):sham (S), sham + MCT (SM), ovariectomized (O), and ovariectomized + MCT (OM).MCT (60 mg/kg i.p) was injected 1 week after ovariectomy or sham surgery. Three weeks after,, echocardiographic analysis and RV catheterisation were performed. RV morphometric, biochemical, and protein expression analysis through western blotting were done. MCT promoted a slight increase in pulmonary artery pressure, without differences between the SM and OM groups, but did not induce RV hypertrophy. RV hydrogen peroxide increased in the MCT groups, but SOD, CAT, and GPx activities were also enhanced. Non-classical antioxidant defenses diminished in ovariectomized groups, probably due to a decrease in the nuclear factor Nrf2. Hemoxygenase-1 and thioredoxin-1 protein expression was increased in the OM group compared to SM, being accompanied by an elevation in the estrogen receptor β (ER-β). Hemoxygenase-1 and thioredoxin-1 may be involved in the modulation of oxidative stress in the OM group, and this could be responsible for attenuation of PAH and RV remodeling.

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Section: Discussionsupporting

confidence: 90%

Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

Siqueira

Colombo

Conzatti

et al. 2018

Can. J. Physiol. Pharmacol.

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“…Studies have demonstrated that sympathetic nerve activity is an important causal factor in PAH development. 15,16 In an animal model of PAH, sympathetic nervous system activity is markedly increased, and neurohumoral dysfunction contributes to the development of excessive muscularization and pulmonary artery fibrosis. 17 To the best of our knowledge, the relationship between the incidence of AF/AFL and the activity of the autonomic nerves in PAH has not been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Zhao¹,

Deng²,

Jiang³

et al. 2015

Hypertension

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S upraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL), are common in patients with pulmonary arterial hypertension (PAH) and are associated with poor outcomes.1,2 In 1 study, restoration and maintenance of sinus rhythm were invariably associated with clinical improvement and recovery. 3 However, it is difficult to treat AF/AFL in patients with PAH because existing antiarrhythmic agents have substantial side effects in patients with PAH.Previous studies have suggested that increased sympathetic nerve activation could contribute to disease severity in patients with PAH. 4,5 A recent study by Chen et al 6 demonstrated that pulmonary artery denervation decreased pulmonary arterial pressure and increased functional capacity. Our previous study showed that renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH.7 In a dog model with rapid atrial or ventricular pacing, a reduction in sympathetic tone or cardiac sympathetic denervation achieved by ablating extrinsic cardiac or renal sympathetic nerves was shown to be useful for controlling atrial arrhythmia. [8][9][10] However, to the best of our knowledge, the effect of sympathetic nerve activity on vulnerability to atrial arrhythmia in PAH has not been evaluated. The purpose of this study was to test the hypothesis that the activity of intrinsic and extrinsic cardiac nerves has an important role in vulnerability to atrial arrhythmia in a model of PAH. MethodsAdditional methodological details for each of the sections below are described in the online-only Data Supplement.Abstract-Atrial arrhythmia, which includes atrial fibrillation (AF) and atrial flutter (AFL), is common in patients with pulmonary arterial hypertension (PAH), who often have increased sympathetic nerve activity. Here, we tested the hypothesis that autonomic nerves play important roles in vulnerability to AF/AFL in PAH. The atrial effective refractory period and AF/AFL inducibility at baseline and after anterior right ganglionated plexi ablation were determined during left stellate ganglion stimulation or left renal sympathetic nerve stimulation in beagle dogs with or without PAH. Then, sympathetic nerve, β-adrenergic receptor densities and connexin 43 expression in atrial tissues were assessed. The sum of the window of vulnerability to AF/AFL was increased in the right atrium compared with the left atrium at baseline in the PAH dogs but not in the controls. The atrial effective refractory period dispersion was increased in the control dogs, but not in the PAH dogs, during left stellate ganglion stimulation. The voltage thresholds for inducing AF/AFL during anterior right ganglionated plexi stimulation were lower in the PAH dogs than in the controls. The AF/AFL inducibility was suppressed after ablation of the anterior right ganglionated plexi in the PAH dogs. The PAH dogs had higher sympathetic nerve and β1-adrenergic receptor densities, increased levels of nonphosphorylated connexin 43, and heterogeneo...

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“…Also, no information was provided on possible side effects and tolerability. In addition, Ishikawa et al 31 reported beneficial effects of arotinolol (a nonspecific ␤-blocker) using the same PH rat model. However, the clinical implications of this study are limited; arotinolol was studied to prevent rather than to treat PH-associated RHF, and, unlike bisoprolol, arotinolol is not clinically used or Food and Drug Administration approved.…”

Section: Beneficial Effects Of Bisoprololmentioning

confidence: 95%

Bisoprolol Delays Progression Towards Right Heart Failure in Experimental Pulmonary Hypertension

Man

Handoko

Ballegoij

et al. 2012

Circ: Heart Failure

186

137

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Background-In pulmonary arterial hypertension (PH), sympathetic adrenergic activity is highly elevated. Sympathetic overactivity is a compensatory mechanism at first, but might be detrimental for cardiac function in the long run. We therefore investigated whether chronic low-dose treatment with bisoprolol (a cardioselective ␤-blocker) has beneficial effects on cardiac function in experimental PH. Methods and Results-PH was induced in rats by a single injection of monocrotaline (60 mg/kg). Pressure telemetry in PH rats revealed that 10 mg/kg bisoprolol was the lowest dose that blunted heart rate response during daily activity. Ten days after monocrotaline injection, echocardiography was performed and PH rats were randomized for bisoprolol treatment (oral gavage) or vehicle (nϭ7/group). At end of study (body mass loss Ͼ5%), echocardiography was repeated, with additional pressure-volume measurements and histomolecular analyses. Compared with control, right ventricular (RV) systolic pressure and arterial elastance (measure of vascular resistance) more than tripled in PH. Bisoprolol delayed time to right heart failure (PϽ0.05). RV afterload was unaffected, however, bisoprolol treatment increased RV contractility and filling (both PϽ0.01), and partially restored right ventriculo-arterial coupling and cardiac output (both PϽ0.05). Bisoprolol restored RV ␤-adrenergic receptor signaling. Histology revealed significantly less RV fibrosis and myocardial inflammation in bisoprolol treated PH rats. Conclusions-In experimental PH, treatment with bisoprolol delays progression toward right heart failure, and partially preserves RV systolic and diastolic function. These promising results suggest a therapeutic role for ␤-blockers in PH that warrants further clinical investigation. (Circ Heart Fail. 2012;5:97-105.)Key Words: pulmonary hypertension Ⅲ right ventricular dysfunction Ⅲ ␤-adrenergic receptor blocker Ⅲ pressure-volume relationship Ⅲ Wistar rats P ulmonary arterial hypertension (PH) is a fatal disease, characterized by progressive vascular remodeling and increased right ventricular (RV) afterload, which eventually leads to manifest right heart failure (RHF) and premature death. Current available medical treatments aim to reduce RV afterload, thereby secondarily improving RV function. 1 No treatment is currently available that improves RV function directly, partially because it was not considered a therapeutic target in PH. 2 Clinical Perspective on p 105Recently, several reports have shown that sympathetic activity is increased in patients with PH. [3][4][5][6][7] Similar to left heart failure (LHF), "ventricle-specific" down regulation of ␤ 1 -adrenergic receptors was observed in RV samples of PH patients. 8 In addition, we recently demonstrated that exercise training was detrimental in experimental and progressive PH. 9 The deleterious effects could be related to bouts of exercise-induced sympathetic stimulation.Although increased adrenergic activity is a compensatory mechanism to maintain cardiac function by increasi...

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Effects of a Pure .ALPHA./.BETA.-Adrenergic Receptor Blocker on Monocrotaline-Induced Pulmonary Arterial Hypertension With Right Ventricular Hypertrophy in Rats

Cited by 49 publications

References 20 publications

Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Bisoprolol Delays Progression Towards Right Heart Failure in Experimental Pulmonary Hypertension

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