Bradykinin receptor participates in doxorubicin-induced cardiotoxicity by modulating iNOS signal pathway.

Doxorubicin (DOX), an effective and broad-spectrum anthracycline antibiotic, is widely used in the treatment of numerous malignancies. However, dose-dependent cardiotoxicity limits the clinical application of DOX, and the molecular mechanisms are still unknown. In this study, we used the BK receptor B1/B2 double-knockout (B1B2 -/- ) mice to observe the role of BK receptor in cardiotoxicity induced by DOX and the underlying mechanisms. DOX induced myocardial injury with increased serum levels of AST, CK, and LDH, upregulated tissue expression of bradykinin B1/B2 receptor, FABP4 and iNOS, and downregulated expression of eNOS. However, these altered releases of myocardial enzyme and the expression level of iNOS were significantly prevented in the B1B2-/- mice. We concluded that the activation of both B1 and B2 receptors of BK were involved in the DOX-induced acute myocardial injury, possibly mediated through iNOS signaling pathways.

Protective effect of berberine on aconite­induced myocardial injury and the associated mechanisms.

Aconitum plants, which have analgesic, diuretic and anti­inflammatory effects, have been widely used to treat various types of disease. However, the apparent toxicity of Aconitum­derived agents, particularly in the cardiovascular system, has largely limited their clinical use. Thus, the present study investigated whether berberine (Ber), an isoquinoline alkaloid, may reduce myocardial injury induced by aconitine (AC) in rats and the underlying mechanisms. Rats (n=40) were randomly divided into four groups: Control, Chuan­wu and Chuan­wu + Ber (8 and 16 mg/kg doses). Electrocardiograms (ECG) of the rats were recorded and serum biomarkers of cardiac function [lactate dehydrogenase (LDH), creatine kinase (CK) and CK­MB] were assayed. Histopathological changes were assessed using myocardial tissue sectioning and hematoxylin and eosin staining. Additionally, the effects of Ber on AC­induced arrhythmias in rats were observed. The changes in ECG following AC perfusion were observed, and the types and onset time of arrhythmias were analyzed. Furthermore, the effects of Ber and AC on papillary muscle action potentials were observed. The results suggested that Ber ameliorated myocardial injury induced by Chuan­wu, which was indicated by reduced arrhythmias and decreased LDH, CK and CK­MB levels in serum. Furthermore, histological damage, including dilation of small veins and congestion, was also markedly attenuated by Ber. In addition, the occurrence of arrhythmias was significantly delayed, and the dosage of AC required to induce arrhythmias was also increased by Ber pretreatment. Additionally, AC­induced changes in action potential amplitude, duration of 30% repolarization and duration of 90% repolarization in the papillary muscle were attenuated by Ber. All of these results indicate that Ber had a preventive effect on acute myocardial injury induced by Chuan­wu and arrhythmias caused by AC, which may be associated with the inhibition of delayed depolarization and triggered activity caused by AC. Thus, combination treatment of Ber with Aconitum plants may be a novel strategy to prevent AC­induced myocardial injury in clinical practice.

Protective effect of berberine on acute cardiomyopathy associated with doxorubicin treatment.

Doxorubicin (DOX) is a potent and broad-spectrum anthracycline chemotherapeutic agent, but dose-dependent cardiotoxic side effects limit its clinical application. This toxicity is closely associated with the generation of reactive oxygen species (ROS) radical during DOX metabolism. The present study investigated the effects of Berberine (Ber) on DOX-induced acute cardiac injury in a rat model and analysed its mechanism in cardiomyocytes in vitro. Serum creatine kinase (CK), creatine kinase isoenzyme (CK-MB) and malondialdehyde (MDA) levels were significantly increased in the DOX group compared with the control group. This increase was accompanied by cardiac histopathological injury and a decrease in cardiomyocyte superoxide dismutase (SOD) and catalase (CAT). CK, CK-MB and MDA levels decreased and SOD and CAT levels increased in the Ber-treated group compared to the DOX group. Ber ameliorated the DOX-induced increase in cytosolic calcium concentration ([Ca2+]i), attenuated mitochondrial Ca2+ overload and restored the DOX-induced loss of mitochondrial membrane potential in vitro. These results demonstrated that Ber exhibited protective effects against DOX-induced heart tissue free radical injury, potentially via the inhibition of intracellular Ca2+ elevation and attenuation of mitochondrial dysfunction.

Protective effect of berberine on doxorubicin­induced acute hepatorenal toxicity in rats.

Doxorubicin (DOX), a potent broad­spectrum chemotherapeutic agent used for the treatment of several types of cancer, is largely limited due to its serious side effects on non­target organs. Thus, the present study aimed to investigate whether berberine (Ber), an isoquinoline alkaloid, could reduce DOX­induced acute hepatorenal toxicity in rats. Fifty rats were randomly divided into five groups: i) Control group, ii) DOX group, iii) DOX+Ber (5 mg kg) group; iv) DOX+Ber (10 mg kg), and v) DOX+Ber (20 mg kg) group. In the tests, body weight, organ index, general condition and mortality were observed. In addition, the serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total cholesterol (TCHO) and blood urea nitrogen (BUN) were determined to evaluate hepatorenal function. Hepatorenal toxicity was further assessed using hematoxylin and eosin stained sections. Furthermore, the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and malondialdehyde (MDA) in rat serum or tissue homogenate were also assessed to determine the mechanisms of action. Results suggested that pretreatment with Ber ameliorated the DOX­induced liver and kidney injury by lowering the serum ALT, AST, TCHO and BUN levels, and the damage observed histologically, such as hemorrhage and focal necrosis of liver and kidney tissues induced by DOX were also attenuated by Ber. Furthermore, Ber also exerted certain antioxidative properties through reversing the changes in the levels of MDA, SOD, GSH and MDA induced by DOX. These findings indicate that Ber has protective effects against DOX­induced acute hepatorenal toxicity in rats. Combination of Ber with DOX is a novel strategy that has the potential for protecting against DOX­induced hepatorenal toxicity in clinical practice.