A short-time model to study relevant indices of cardiotoxicity of doxorubicin in the rat

Hole, Lisa Drange; Larsen, Terje H.; Fossan, Kjell Ove; Limé, Fredrik; Schjøtt, Jan

doi:10.3109/15376516.2013.773391

Cited by 12 publications

(7 citation statements)

References 19 publications

(11 reference statements)

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“…Pretreatment with diazoxide attenuated doxorubicin-induced cardiac dysfunction in the rat in the present study. Doxorubicin treatment produced a significant loss in left ventricular developed pressure (LVDP) (p < 0.05) both in volume- and pressure regulated perfusion similar to previous reports [ 15 , 16 ]. Diazoxide significantly attenuated this decrease in LVDP (p < 0.05) in both perfusion protocols.…”

Section: Discussionsupporting

confidence: 89%

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Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

Hole

Larsen

Fossan

et al. 2014

BMC Pharmacol Toxicol

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AimChemotherapy with doxorubicin is limited by cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. In this study we wanted to investigate if opening of mitochondrial KATP-channels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP-channel antagonist, abolished any protection by this intervention.MethodsWistar rats were divided into 7 groups (n = 6) and followed for 10 days with 5 intervention groups including the following treatments: (1) Diazoxide and doxorubicin, (2) diazoxide and 5-hydroxydecanoate (5-HD), (3) 5-HD and doxorubicin, (4) diazoxide and saline and (5) 5-HD and saline. On day 1, 3, 5 and 7 the animals received intraperitoneal (i.p.) injections with 10 mg/kg diazoxide and/or 40 mg/kg 5-HD, 30 minutes before i.p. injections with 3.0 mg/kg doxorubicin. One control group received only saline injections and the other control group received saline 30 minutes prior to 3.0 mg/kg doxorubicin. On day 10 the hearts were excised and Langendorff-perfused. Cardiac function was assessed by an intraventricular balloon and biochemical effects by release of hydrogen peroxide (H2O2) and troponin-T (TnT) in effluate from the isolated hearts, and by myocardial content of doxorubicin.ResultsDoxorubicin treatment produced a significant loss in left ventricular developed pressure (LVDP) (p < 0.05) and an increase in both H2O2 and TnT release in effluate (p < 0.05). Diazoxide significantly attenuated the decrease in LVDP (p < 0.05) and abolished the increased release of H2O2 and TnT (p < 0.05). 5-HD abolished the effects of pretreatment with diazoxide, and these effects were not associated with reduced myocardial accumulation of doxorubicin.ConclusionsPretreatment with diazoxide attenuates doxorubicin-induced cardiac dysfunction in the rat, measured by physiological indices and TnT and H2O2 in effluate from isolated hearts. The effect could be mediated by opening of mitochondrial KATP-channels, reduced doxorubicin-associated free radical generation and decreased cardiomyocyte damage. Diazoxide represents a promising protective intervention against doxorubicin-induced acute cardiotoxicity.

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Section: Discussionsupporting

confidence: 89%

“…Troponin-T is widely used as a specific marker to diagnose myocardial infarction. Doxorubicin is associated with increased TnT in serum and in heart effluate [ 15 , 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

Hole

Larsen

Fossan

et al. 2014

BMC Pharmacol Toxicol

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“…Acute toxicity was evaluated by comparing the body weights. The tissue concentrations (consisting of intracellular, extracellular, and microcirculatory levels) of doxorubicin and its active metabolite doxorubicinol were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) [16]. Histological images were used to evaluate the long-term cellular damage at the end of the study.…”

Section: Methodsmentioning

confidence: 99%

Ultrasound and Microbubbles Enhance Uptake of Doxorubicin in Murine Kidneys

et al. 2021

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The use of ultrasound and microbubble-enhanced drug delivery, commonly referred to as sonoporation, has reached numerous clinical trials and has shown favourable results. Nevertheless, the microbubbles and acoustic path also pass through healthy tissues. To date, the majority of studies have focused on the impact to diseased tissues and rarely evaluated the impact on healthy and collateral tissue. The aim of this study was to test the effect and feasibility of low-intensity sonoporation on healthy kidneys in a mouse model. In our work here, we used a clinical diagnostic ultrasound system (GE Vivid E9) with a C1-5 ultrasound transducer combined with a software modification for 20-µs-long pulses to induce the ultrasound-guided drug delivery of doxorubicin (DOX) in mice kidneys in combination with SonoVue® and Sonazoid™ microbubbles. The acoustic output settings were within the commonly used diagnostic ranges. Sonoporation with SonoVue® resulted in a significant decrease in weight vs. DOX alone (p = 0.0004) in the first nine days, whilst all other comparisons were not significant. Ultrasound alone resulted in a 381% increase in DOX uptake vs. DOX alone (p = 0.0004), whilst SonoVue® (p = 0.0001) and Sonazoid™ (p < 0.0001) further increased the uptake nine days after treatment (419% and 493%, respectively). No long-standing damage was observed in the kidneys via histology. In future sonoporation and drug uptake studies, we therefore suggest including an “ultrasound alone” group to verify the actual contribution of the individual components of the procedure on the drug uptake and to perform collateral damage studies to ensure there is no negative impact of low-intensity sonoporation on healthy tissues.

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“…Other short-term models use 2–3.4 mg/kg of DOX every other day, six times intraperitoneally (the total dose is 12–20 mg/kg) ( Zbinden et al, 1978 ; Lanza et al, 1989 ; Carvalho et al, 2010 ; Razmaraii et al, 2016 ; Cappetta et al, 2018 ; Aygun and Gul, 2019 ; Barış et al, 2019 ). Long-term rat models typically use 1–5 mg/kg every week for 2–12 weeks with a cumulative dose of 3–25 mg/kg ( Villani et al, 1991 ; Sacco et al, 2001 ; Sayed-Ahmed et al, 2001 ; Rahimi Balaei et al, 2010 ; Hydock et al, 2012 ; Hole et al, 2013 ; Toblli et al, 2014 ; Kang et al, 2017 ; Medeiros-Lima et al, 2019 ; Wang et al, 2019 ; Chakouri et al, 2020 ; Sharma et al, 2020 ). Thus, a short-term high-dose injection model would be suitable for assessing acute cardiotoxicity, while a long-term low-dose model would be suitable for assessing chronic cardiotoxicity.…”

Section: Anthracycline Cardiomyopathy Modelsmentioning

confidence: 99%

“…To date, acute cardiotoxicity has been distinguished, which developed at the time of chemotherapeutic treatment and manifested in the first year after completion of the anthracyclines administration. At the same time, chronic cardiotoxicity develops after the anticancer treatment ( Hole et al, 2013 ). Сhronic cardiovascular complications are of great importance in the prognosis of cancer patients as they can lead to a significant deterioration in the quality and expectancy of life of those who have been successfully treated for malignant neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician

et al. 2021

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Today the pharmacological possibilities of treating cancer are expanding and as a result, life expectancy is increasing against the background of chemotherapy and supportive treatment. In the conditions of successful antitumor treatment, complications associated with its toxic effect on healthy tissues and organs began to come to the fore. Anthracycline cardiomyopathy was the first serious cardiovascular complication to draw the attention of oncologists and cardiologists around the world. Anthracycline drugs such as doxorubicin, epirubicin, idarubicin are still widely used in oncological practice to treat a wide range of solid and hematological malignancies. Doxorubicin-induced cardiomyopathy is closely associated with an increase in oxidative stress, as evidenced by reactive oxygen species (ROS) nduced damage such as lipid peroxidation, and decreased levels of antioxidants. Myofibrillar destruction and dysregulation of intracellular calcium are also important mechanisms, usually associated with doxorubicin-induced cardiotoxicity. Despite the abundance of data on various mechanisms involved in the implementation of doxorubicin-induced cardiotoxicity, a final understanding of the mechanism of the development of doxorubicin cardiomyopathy has not yet been formed. It poses the most significant challenges to the development of new methods of prevention and treatment, as well as to the unambiguous choice of a specific treatment regimen using the existing pharmacological tools. In order to resolve these issues new models that could reflect the development of the chemotherapy drugs effects are needed. In this review we have summarized and analyzed information on the main existing models of doxorubicin cardiomyopathy using small laboratory animals. In addition, this paper discusses further areas of research devoted to the development and validation of new improved models of doxorubicin cardiomyopathy suitable both for studying the mechanisms of its implementation and for the preclinical drugs effectiveness assessment.

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A short-time model to study relevant indices of cardiotoxicity of doxorubicin in the rat

Cited by 12 publications

References 19 publications

Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat

Ultrasound and Microbubbles Enhance Uptake of Doxorubicin in Murine Kidneys

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician

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