Pimobendan improves right ventricular myocardial contraction and attenuates pulmonary arterial hypertension in rats with monocrotaline-induced pulmonary arterial hypertension

Yoshiyuki, Rieko; Nakata, Telma Mary; Fukayama, Toshiharu; Hamabe, Lina; Hsu, Huai-Che; Suzuki, Shuji; Motomura, Noboru; Fukushima, Ryuji; Tanaka, Ryou

doi:10.1007/s10396-013-0488-6

Cited by 5 publications

(3 citation statements)

References 30 publications

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“… 19 , 54 , 55 However, our previous study in rats with MCT-induced PAH (30 mg/kg of MCT subcutaneously) did not find differences between rats given 6 weeks of pimobendan at 1.25 mg per rat and those in the model group; these results may differ from those of the present results due to the different disease stage induced by the lower dose of MCT and higher dose of pimobendan administered. 56 Administration of PDE-3 inhibitors for prolonged periods is related to development of myocardial hypertrophy. 57 – 59 Although only a fixed dose was used in our investigation, a larger study is necessary to demonstrate the lowest effective dose, as has been suggested by successful individual treatments with single or combined administrations of pimobendan at lower than recommended doses.…”

Section: Discussionmentioning

confidence: 99%

Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

Nakata

Tanaka

Yoshiyuki

et al. 2015

Journal of Cardiovascular Pharmacology

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Abstract:This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

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Section: Discussionmentioning

confidence: 99%

Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

Nakata

Tanaka

Yoshiyuki

et al. 2015

Journal of Cardiovascular Pharmacology

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“…Several characteristics of maladaptive RV remodeling in the PAH model have been proposed, including RV dilation, reduced function, fibrosis, and capillary rarefication ( 29 , 150 ). However, as of the confounding effects of potentially altered pulmonary vascular resistance, hypoxia, molecular modulation (e.g., VEGF inhibition), or toxins on RV function, the MCT and SuHx models cannot be used to investigate isolated RV effects of potential therapies, and the PAB model is relevant in this regard ( 29 , 151 , 152 ).…”

Section: Surgical Modelsmentioning

confidence: 99%

A review on experimental surgical models and anesthetic protocols of heart failure in rats

et al. 2023

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Heart failure (HF) is a serious health and economic burden worldwide, and its prevalence is continuously increasing. Current medications effectively moderate the progression of symptoms, and there is a need for novel preventative and reparative treatments. The development of novel HF treatments requires the testing of potential therapeutic procedures in appropriate animal models of HF. During the past decades, murine models have been extensively used in fundamental and translational research studies to better understand the pathophysiological mechanisms of HF and develop more effective methods to prevent and control congestive HF. Proper surgical approaches and anesthetic protocols are the first steps in creating these models, and each successful approach requires a proper anesthetic protocol that maintains good recovery and high survival rates after surgery. However, each protocol may have shortcomings that limit the study's outcomes. In addition, the ethical regulations of animal welfare in certain countries prohibit the use of specific anesthetic agents, which are widely used to establish animal models. This review summarizes the most common and recent surgical models of HF and the anesthetic protocols used in rat models. We will highlight the surgical approach of each model, the use of anesthesia, and the limitations of the model in the study of the pathophysiology and therapeutic basis of common cardiovascular diseases.

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“…28 In rats with pulmonary arterial hypertension, pimobendan resulted in improved echocardiographic parameters of systolic function. 29 Healthy horses that received pimobendan IV had echocardiographic changes that indicated positive inotropic effects. 30 Empiric recommended dosing in rabbits is 0.1 to 0.3 mg/kg orally every 12 to 24 hours.…”

Section: Pharmacokinetics Of Pimobendan Following Oral Administration...mentioning

confidence: 99%

Pharmacokinetics of pimobendan following oral administration to New Zealand White rabbits (Oryctolagus cuniculus)

Ozawa

Guzmán

Hawkins

et al. 2022

ajvr

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OBJECTIVE To determine the pharmacokinetics and potential adverse effects of pimobendan after oral administration in New Zealand White rabbits (Ocytolagus cuniculi). ANIMALS 10 adult sexually intact (5 males and 5 females) rabbits. PROCEDURES 2 pilot studies were performed with a pimobendan suspension or oral tablets. Eight rabbits received 7.5 mg of pimobendan (mean 2.08 mg/kg) suspended in a critical care feeding formula. Plasma concentrations of pimobendan and O-demethylpimobendan (ODMP) were measured, and pharmacokinetic parameters were calculated for pimobendan by noncompartmental analysis. Body weight, food and water consumption, mentation, urine, and fecal output were monitored. RESULTS Mean ± SD maximum concentration following pimobendan administration was 15.7 ± 7.54 ng/mL and was detected at 2.79 ± 1.25 hours. The half-life was 3.54 ± 1.32 hours. Plasma concentrations of pimobendan were detectable for up to 24 hours. The active metabolite, ODMP, was detected in rabbits for 24 to 36 hours. An adverse event occurred following administration of pimobendan in tablet form in 1 pilot study, resulting in death secondary to aspiration. No other adverse events occurred. CLINICAL RELEVANCE Plasma concentrations of pimobendan were lower than previously reported for dogs and cats, despite administration of higher doses, and had longer time to maximum concentration and half-life. Based on this study, 2 mg/kg of pimobendan in a critical care feeding formulation should maintain above a target plasma concentration for 12 to 24 hours. However, further studies evaluating multiple-dose administration as well as pharmacodynamic studies and clinical trials in rabbits with congestive heart failure are needed to determine accurate dose and frequency recommendations.

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Pimobendan improves right ventricular myocardial contraction and attenuates pulmonary arterial hypertension in rats with monocrotaline-induced pulmonary arterial hypertension

Abstract: Both a reduction in RVSP and improvement in myocardial contraction were demonstrated with administration of pimobendan in rats with PH induced by MCT. Echocardiography evaluation of systolic function seems to be useful for monitoring excess administration of pimobendan.

Cited by 5 publications

References 30 publications

Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

A review on experimental surgical models and anesthetic protocols of heart failure in rats

Pharmacokinetics of pimobendan following oral administration to New Zealand White rabbits (Oryctolagus cuniculus)

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