dinoprost and Diabetic-Cardiomyopathies

Cardioprotective actions of ischemic postconditioning (IPostC) against ischemia/reperfusion (I/R) injury are abolished in diabetic hearts. This study has investigated the combined effects of IPostC and vildagliptin (Vilda) on myocardial function and infarct size (IS) against I/R injury in diabetic myocardium.. Diabetes was induced by a high-fat diet/low dose of streptozotocin (35 mg/kg; intraperitoneally) in Wistar rats (200-250 g) and lasted for 12 weeks. Vilda (6 mg/kg/d) was orally administered for 5 weeks in diabetic groups after seventh week of diabetes. At the end of the 12-week period, the hearts of rats were removed and subjected to 35-minute regional ischemia (through left anterior descending ligation) followed by 60-minute reperfusion, on Langendorff apparatus. Ischemic postconditioning was induced by 6 repetitive cycles of 10-second ischemia and 10-second reperfusion, immediately at the onset of the reperfusion. Myocardial hemodynamic was measured throughout the experiment. The IS was assessed by triphenyltetrazolium chloride staining method. The myocardial contents of troponin-I (cTnI), interleukin-6 (IL-6), and 8-isoprostane were measured in the homogenate from ischemic zone of left ventricles by enzyme-linked immunosorbent assay kit.. Pretreatment of the diabetic rats with Vilda significantly recovered the diabetes-induced reduction in left ventricular developed pressures and contractility at the baseline ( P < .05 to P < .01). After I/R injury, IPostC could not significantly improve the myocardial function, cTnI content, and IS of the diabetic hearts. However, in Vilda-treated hearts, concomitant application of IPostC significantly recovered the heart functions, returned cTnI content as well as myocardial IL-6 and 8-isoprostane levels back to the control values ( P < .01 to P < .001), and reduced IS more effectively (by 45%) in comparison to the diabetic group ( P < .001).. Besides its glycemic and lipid profile controlling effects, Vilda has a protective effect on heart function and tends to restore cardioprotective effects of IPostC on diabetic hearts.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dinoprost; Dipeptidyl-Peptidase IV Inhibitors; Insulin; Interleukin-6; Ischemic Postconditioning; Isolated Heart Preparation; Lipids; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Rats, Wistar; Troponin I; Ventricular Function, Left; Ventricular Pressure; Vildagliptin

Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O2- (superoxide anion) and 15-F2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCβ2 activation and prevention of NADPH oxidase subunit p67phox membrane translocation and p22phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications.

Topics: Acetylcysteine; Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dinoprost; Drug Evaluation, Preclinical; Enzyme Activation; Free Radical Scavengers; Hypertrophy, Left Ventricular; Indoles; Isoprostanes; Male; Maleimides; Myocytes, Cardiac; NADPH Oxidases; Oxidative Stress; Protein Kinase C; Protein Kinase C beta; Rats; Rats, Sprague-Dawley; Superoxides; Ultrasonography

Xanthine oxidase-derived superoxide production and oxidative stress contribute to the development of diabetic complications including diabetic cardiomyopathy. We hypothesized that xanthine oxidase-inhibitor allopurinol (ALP) may decrease hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis, and attenuate the development of left ventricle (LV) diastolic dysfunction in rats with streptozotocin (STZ)-induced diabetes.. Control Sprague Dawley (C) or streptozotocin-induced diabetic (D) rats were either untreated or treated with allopurinol (100 mg/kg/day) for 4 weeks starting at 1 week after streptozotocin injection. Free 15-F2t-isoprostane, a specific indicator of oxidative stress was measured by enzymatic immunoassay. The cardiomyocyte cross-sectional area was assessed by hematoxylin and eosin-stained paraffin-embedded sections of LVs. Myocardial collagens I and III were assessed by immunol histochemistry and Western blotting. Echocardiography was performed to characterize cardiac structure and function.. In diabetic rats, both plasma and cardiac tissue levels of free 15-F2t-isoprostane were increased (p < 0.05 vs. control), accompanied with significant increase (p < 0.05 vs. control) in cross-section area and myocardial collagen deposition of LV cardiomyocyte. Echocardiography in diabetic rats showed that LV weight/body weight ratio was significantly higher than in control rats, whereas the levels of LV end-diastolic volume and stroke volume were decreased (all p < 0.05 diabetic vs. control). All these changes were either attenuated or prevented by allopurinol. In addition, LV ejection fraction in diabetic rats treated with allopurinol was higher than that in untreated diabetic rats (p < 0.05).. Allopurinol can attenuate hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis and subsequently prevent left ventricular dysfunction in early diabetes.

Topics: Allopurinol; Animals; Antimetabolites; Blotting, Western; Collagen Type I; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dinoprost; Echocardiography; Immunoenzyme Techniques; Isoprostanes; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left