Protective effects of carvedilol against doxorubicin-induced cardiomyopathy in rats

doi:10.1016/S0024-3205(99)00362-8

Life Sciences

Volume 65, Issue 12, 13 August 1999, Pages 1265-1274

https://doi.org/10.1016/S0024-3205(99)00362-8 Get rights and content

Abstract

Carvedilol (CAR) is a vasodilating β-blocker which also has antioxidant properties. CAR produces dose-related reduction in mortality in patients with congestive heart failure. In the present study, we tested the hypothesis that CAR protects against doxorubicin (DOX)-induced cardiomyopathy in rats. Sprague-Dawley rats were treated with DOX, CAR, CAR+DOX, or atenolol (ATN)+DOX. DOX (cumulative dose, 15 $mg kg$ ) was administered intraperitoneally, and CAR (30 $mg kg$ daily) or ATN (150 $mg kg$ daily) was administered orally. Three weeks after the completion of these treatments, cardiac performance and myocardial lipid peroxidation were assessed. Mortality was observed in the DOX (25%) and ATN+DOX (12.5%) groups. Compared with control rats, DOX significantly decreased systolic blood pressure (104 ± 4 vs. 120 ± 4 mmHg, P < 0.05) and left ventricular fractional shortening (38.8 ± 3.1 vs. 55.4 ± 1.3%, P < 0.01), and resulted in a significant accumulation of ascites (14.4 ± 4.9 vs. 0 ml, P < 0.01). CAR significantly prevented the cardiomyopathic changes caused by DOX, while ATN did not. The myocardial thiobarbituric acid reactive substances (TBARS) content was significantly higher in DOX-treated rats than in control rats (80.4 ± 7.1 vs. 51.5 ± 1.2 $nmol g$ heart, p < 0.01). CAR prevented the increase in TBARS content (48.8 ± 3.0 $nmol g$ heart, P < 0.01 vs. DOX group), whereas ATN had no significant effect (74.3 ± 5.2 $nmnol g$ heart). CAR also significantly prevented the increase in both myocardial and plasma cholesterol concentrations caused by DOX. These data indicate that CAR protects against DOX-induced cardiomyopathy and that this effect may be attributed to the antioxidant and lipid-lowering properties of CAR, not to its β-blocking property.

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There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both.
CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.
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Cardiotoxicity is one of the most detrimental effects of cancer treatment. It causes substantial morbidity and mortality. Most cancer treatments adversely affect the cardiovascular system, leading to heart failure with ventricular systolic dysfunction. There are several other toxic effects, including hypertension, thromboembolism, pericardial disease, arrhythmia, and myocardial ischemia. Cancer therapy-induced cardiomyopathy was predominantly associated with higher doses of anthracyclines, which result in permanent cellular damage. Several drugs that are commonly used for cardioprotection may even increase the risk of cancer. Since G-protein-coupled receptors (GPCRs) are target of 40% of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, and cannabidiol. Further studies are needed to examine these GPCRs as a potential target for the treatment of heart failure induced by anticancer drugs.
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Evaluation of cardioprotective effects of carvedilol in dogs receiving doxorubicin chemotherapy: A prospective, randomized, double-blind, placebo controlled pilot study
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Citation Excerpt :
In breeds at high-risk for developing dilated cardiomyopathy the incidence is 15.4% and in low-risk breeds the incidence is 3.0% (Hallman et al., 2019). A number of studies have shown the cardioprotective effects of carvedilol in doxorubicin treatments and some have shown that carvedilol prevents structural and functional damage such as apoptosis and mitochondrial dysfunction, and consequently reduces left ventricular systolic and diastolic dysfunction in vitro (Park and Steinberg, 2018; Spallarossa et al., 2004), in vitro and mice (Zhang et al., 2019), rats (Matsui et al., 1999; Oliveira et al., 2004; Santos et al., 2002) and in human patients (Abuosa et al., 2018; Avila et al., 2018; El-Shitany et al., 2012; Kalay et al., 2006). Meta-analysis of randomized controlled trials in human cancer patients reported that prophylactic administration of carvedilol may reduce early left ventricular dysfunction, improve diastolic function and decrease troponin I levels (Kheiri et al., 2018; Zhan et al., 2019).
The aim of this pilot study was to evaluate the cardioprotective effects of carvedilol in dogs receiving doxorubicin chemotherapy and provide suggestions to future studies based on results and limitations of our study. Thirteen dogs were randomized into two experimental groups: 6 dogs in carvedilol group and 7 dogs in placebo group. In carvedilol group, 0.39 mg/kg ± 0.04 twice-daily oral carvedilol was started on the day of the first doxorubicin treatment and continued throughout the chemotherapy protocol until the final cardiological evaluation. Cardiological evaluations were performed before the first doxorubicin administration and then 10 to 15 days after each subsequent dose. Troponin I and oxidative stress tests were performed with serum collected from dogs at the initial and final cardiological evaluation. Carvedilol produced some echocardiographic and electrocardiographic changes (reduced E velocity and E/IVRT ratio, as well reduced heart rate and increased PR and QT interval) due to its beta-block effect. In placebo group Doppler study showed a significant increase in mitral flow deceleration time (EDT), as well increased amplitude of the S wave in the right, and R wave in the left, precordial chest leads. There were significant difference in the EDT, E/IVRT and A' velocity, as well heart rate, PR interval and R wave in V4/CV6LU precordial chest lead between groups. In conclusion, some indexes of diastolic function and in precordial chest leads were less affected by doxorubicin in carvedilol than in control group. This suggests that carvedilol may have a beneficial effect in canine cancer patients receiving doxorubicin.
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Doxorubicin (DOX) is widely used as a broad-spectrum anti-tumor anthracycline to treat various cancers. The serious adverse effects of DOX on cardiotoxicity limit its clinical application. There are several different mechanisms involved in DOX-induced cardiotoxicity. Oxidative stress (OS) is caused by an imbalance between reactive oxygen species (ROS) and endogenous antioxidants in response to injury, which can lead to myocardial toxicity. The aim of this review was to investigate the mechanisms underlying the effects of oxidative stress injury on myocardial toxicity, from three different aspects: the increase in downstream oxidative stress products, the reduction in upstream antioxidative stress products, and subcellular organelles. Finally, there are some anti-oxidative drugs that show efficacy in limiting DOX-induced cardiotoxicity. It is necessary to fully understand the toxicity of DOX to the myocardium and achieve symptomatic treatment.
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Protective effects of carvedilol against doxorubicin-induced cardiomyopathy in rats

Abstract

J Mol Cell Cardiol

J Biol Chem

Biochem Pharmac

J Mol Cell Cardiol

Meth Enzymol

Biochem Med

Life Sci

Biochim Biophys Acta

Life Sci

J Mol Cell Cardiol

Hum Pathol

J Am Coll Cardiol

J Am Coll Cardiol

Drugs Today

J Hypertens

N Engl J Med

Circulation