The Cardiac β -Adrenoceptor-G-protein(s)-adenylyl Cyclase System in Monocrotaline-treated Rats

Seyfarth, Torsten; Gerbershagen, Hans-Peter; Giessler, C; Leineweber, Kirsten; Heinroth-Hoffmann, Ingrid; Pönicke, Klaus; Brodde, Otto‐Erich

doi:10.1006/jmcc.2000.1262

Cited by 50 publications

(62 citation statements)

References 36 publications

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“…Mortality due to right cardiac failure begins 3 to 4 weeks after the injection and the survival decreases to about 30% by 6 weeks after the injection. The actual cause of death by MCT is not completely understood, but the monocrotaline pyrrole obviously causes injury of the lung (31) and induces right ventricular (RV) failure confirmed by the presence of ascites, pericardial, or pleural effusions (32). The effect of sildenafil on PAH has previously been demonstrated in this model (33,34).…”

Section: Introductionmentioning

confidence: 79%

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Sawamura

Kato²,

Fujita³

et al. 2009

J Pharmacol Sci

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Abstract. The aim of this study was to assess the effect of tadalafil (0.5, 2.5, and 10 mg /kg per day) on the progression of pulmonary arterial hypertension (PAH) in early treatment and on the survival rate in late treatment on the monocrotaline (MCT)-induced PAH rat model. Tadalafil was administered once daily to rats for 3 weeks from the day of MCT-injection or 21 days after the injection. With early treatment, tadalafil at 10 mg/kg per day prevented the development of PAH by maintaining mean pulmonary artery pressure within the normal range and attenuated right ventricular hypertrophy. With late treatment, tadalafil tended to increase the partial pressure of oxygen in arterial blood and dose-dependently improved the survival rate by 55%, 60%, and 70% at 0.5, 2.5, and 10 mg /kg per day, respectively, versus 40% in the MCTcontrol group. Both early and late treatments with tadalafil were associated with elevated lung cyclic guanosine monophosphate (cGMP). These results suggest that tadalafil relaxes pulmonary arteries by elevating cGMP in lungs and extend survival time by improving pulmonary hemodynamics even when treatment occurs in the late phase of PAH. Thus, it is expected that tadalafil may be an effective, once-daily treatment option in humans with PAH.

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Section: Introductionmentioning

confidence: 79%

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Sawamura

Kato²,

Fujita³

et al. 2009

J Pharmacol Sci

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“…13,14 In patients with isolated RV failure because of primary PAH, Bristow et al found selective β1-receptor downregulation and decreased basal adenylyl cyclase activity. 15 Nervous stimulation of the ventricles and abnormalities of the adrenergic system are involved, because cardiac denervation prevents the progression of sympathetic abnormalities and cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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

Ishikawa

Sato

Asai

et al. 2009

Circ J

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ulmonary arterial hypertension (PAH) is a serious chronic disorder, similar to chronic kidney disease, which has varied causes and pathogenesis. PAH can potentially lead to right ventricular hypertrophy (RVH) and cardiovascular death related to RV failure. Among the types of PAH, idiopathic PAH has an especially poor prognosis and is difficult to manage clinically. Idiopathic PAH involves multiple factors, such as vasoconstriction, remodeling of the pulmonary vessels, and thrombosis, but it is unclear to what extent the sympathetic nervous activation plays a role in its development. Certainly, sympathetic nervous activity is reported to be increased in PAH; 1 however, it is unclear whether or not inhibition of sympathetic activity can prevent or reverse PAH. The benefits of inhibiting sympathetic nervous activation in PAH remain uncertain, although there have been several reports regarding the effects of α-and/or β-adrenergic receptor blockers, especially carvedilol, although it is not a pure α/ β-adrenergic receptor blocker. Arotinolol (Dainippon Sumitomo Pharma Co, Ltd, Osaka, Japan) is a nonselective α/ β-adrenergic receptor blocker lacking local anesthetic, membrane-stabilizing or intrinsic sympathomimetic properties, which means that arotinolol is a pure α/ β-adrenergic receptor blocker. 2,3 Editorial p 2212Therefore, we investigated whether or not arotinolol, which differs from carvedilol with regard to actions such as an antioxidant or calcium-channel blocking effect, 4,5 could prevent the development of PAH and/or RVH in a rat model of monocrotaline (MCT)-induced PAH. MethodsThe experimental procedures described in the present study were approved by the institutional Animal Care and Use Committee of Nippon Medical School. Six-week-old male Wistar rats (n=12) were used. MCT was dissolved in 1 N HCl, and the pH was adjusted to 7.4 with 1 N NaOH. Rats were injected subcutaneously with 2% MCT solution at a dose of 40 mg/kg. An intraperitoneal osmotic pump (Alzet Osmotic Pumps, Durect, Cupertino, CA, USA) containing either arotinolol (0.25 mg · kg -1 · day -1 , n=6) or 0.9% saline (n=6) was implanted randomly under anesthesia induced by intraperitoneal injection of sodium pentobarbital (30 mg/kg). A previous study showed intraperitoneal administration of arotinolol has almost the same effects as intravenous administration. 6 We did preliminary experiments to decide the dose of arotinolol required to reduce blood pressure (BP) Background: It is unclear how much the sympathetic nervous system is involved in the development of pulmonary arterial hypertension (PAH). The present study examined whether or not a pure α/ β-adrenergic receptor blocker (arotinolol) could prevent the development of PAH and right ventricular hypertrophy (RVH) in a rat model of monocrotaline (MCT)-induced PAH. Methods and Results:The heart rate, arterial blood pressure (BP), left ventricular pressure, pulmonary artery pressure (PAP), and right ventricular pressure (RVP) were measured after administration of arotinolol or saline for 2 week...

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“…In addition, changes in renal function were found in some groups and echocardiography revealed reduced LV dimension and substantially decreased RV EF. In comparison, studies using MCT treatment have only achieved RVSP values between 40 and 77 mmHg and a 100-200% increase in RV weight and most studies do not report formation of ascites or hydrothorax (Chen et al, 2001;Jones et al, 2004;Kogler et al, 2003;Leineweber et al, 2002;Miyauchi et al, 1993;Seyfarth et al, 2000). Previous studies have mainly used PTB for hypertrophy research.…”

Section: Present Findings Vs Previous Studiesmentioning

confidence: 99%

Characterization of a rat model of right-sided heart failure induced by pulmonary trunk banding

Schou

Peters

Kim

et al. 2007

Journal of Experimental Animal Science

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Animal models of disease are essential for cardiovascular research. However, animal models of right-sided heart failure are few and remain poorly characterized. The aim with this study was to establish a rat model of right-sided heart failure (HF) using pulmonary trunk banding (PTB) and subsequently to characterize the systemic and cardiac changes in this model, including protein expression of SERCA2 and a-sarcomeric actin. Rats underwent banding or sham operation. To evaluate the development of HF over time three groups were included in this study. They were killed 2-3, 5-7 or 16-17 weeks after operation, respectively. PTB rats showed marked hypertrophy of the right ventricle (RV). Catheterization of the RV showed a three-to four-fold increase in right ventricular systolic and diastolic pressures as well as increased dP/dT max and dP/dT min. Plasma analyses revealed increased liver enzymes in most PTB groups and post mortem examination revealed congestion of the liver as well as formation of ascites and hydrothorax in many PTB rats. Immunoblotting of the RV revealed no changes in SERCA2 or a-sarcomeric actin. In conclusion, PTB was an effective method to induce right-sided HF. The presence of HF was confirmed by severe signs of backward failure in conjunction with markedly elevated RV pressures and reduced RV ejection fraction (EF). r

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The Cardiac β -Adrenoceptor-G-protein(s)-adenylyl Cyclase System in Monocrotaline-treated Rats

Cited by 50 publications

References 36 publications

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

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

Characterization of a rat model of right-sided heart failure induced by pulmonary trunk banding

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