(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Cardiomyopathies

Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, -29%; dp/dtmax, -45%; cardiac output, -68%; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor alpha and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiomyopathies; Doxorubicin; Drug Interactions; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoenzymes; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Oxidative Stress; Random Allocation; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Ventricular Function, Left

To investigate the effect of valsartan and fluvastatin on the expression of connective tissue growth factor in early diabetic cardiomyopathy.. Forty male SD rats were randomly divided into five groups: normal control group, diabetic model (DM) group, DM + valsartan group (30 mg x kg(-1) x d(-1)), DM + fluvastatin group (4 mg x kg(-1) x d(-1) ) and DM + valsartan + fluvastatin group (valsartan 30 mg x kg(-1) x d(-1) + fluvastatin 4 mg x kg(-1) x d(-1)). After 12 weeks, miniature cardiac catheter was inserted into the left ventricle to conduct hemodynamic examination. Then myocardial tissue was collected and collagen content was detected with Van-Gieson staining. The levels of connective tissue growth factor (CTGF) mRNA expression in myocardium were determined using RT-PCR and Western blot was used to detect the protein expression of transforming growth factor (TGF) beta, CTGF, collagen I and III.. By the end of the experiment, left ventricular diastolic function was significantly decreased in the DM group in comparison with the control group (P < 0.05). As compared with the normal control group, myocardial collagen content was significantly increased 1.1 fold (P < 0.05), and the heart weight/body weight ratio was increased 37% in the DM group, but it was significantly reduced in the valsartan group and the fluvastatin group in comparison with the DM group (both P < 0.05). The mRNA expression of CTGF was significantly higher in the DM group than in the control group, but it was significantly lower in the valsartan group and fluvastatin group than that in the DM group (both P < 0.05). The values of protein expression of CTGF, TGFbeta, collagen I and III were all significantly higher in the DM group than those in the control group (all P < 0.05). The protein expression of CTGF, TGFbeta, collagen I and III in the valsartan group and fluvastatin group was all significantly lower than that in the DM group (P < 0.05). It was shown that treatment with valsartan or fluvastatin was effective for myocardial fibrosis in diabetic SD rats and valsartan combined with fluvastatin would be still better.. Valsartan and fluvastatin can reduce myocardial fibrosis, resulting in prevention of left ventricular remodeling and improvement of cardiac function in an experimental model of diabetic cardiomyopathy. The process was related to the inhibition of the overexpression of CTGF and TGFbeta and reduction in cardiac extracellular matrix collagen content. It is also shown that a better result may be obtained with the coadministration of the two drugs than using one alone.

Topics: Animals; Cardiomyopathies; Connective Tissue; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Male; Rats; Rats, Sprague-Dawley; Tetrazoles; Valine; Valsartan

Mevalonic acid is a product of the enzyme HMG-CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of mevalonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG-CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis.

Topics: Analysis of Variance; Animals; Birth Weight; Cardiomyopathies; Cholesterol; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Female; Fertility; Fetal Death; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Litter Size; Mevalonic Acid; Obstetric Labor Complications; Pregnancy; Pregnancy Complications, Cardiovascular; Puerperal Disorders; Rats; Rats, Sprague-Dawley; Weight Loss