Heart Function In Diabetic Rats Research Articles

Modulation of hydrogen sulfide synthesis improves heart function and endothelium-dependent vasorelaxation in diabetes.

Diabetes dramatically increases the risk of cardiovascular complications. The endothelial dysfunction and diastolic heart dysfunction are associated with a decreasing level of hydrogen sulfide (H2S) and inhibition of the activity of endothelial nitric oxide synthase (NOS) in diabetes. The aim of this study is to investigate the effect of modulation of H2S synthesis on heart functions and vasorelaxation in diabetes. The dl-propargylglycine and l-cysteine were administered intraperitoneally. H2S content in the heart tissue, markers of oxidative stress, inducible NOS and constitutive NOS (cNOS) activities, endothelium-dependent vasorelaxation of the aortic rings, and heart function were studied. We demonstrate that our combination increased H2S synthesis 13 times and cNOS activity 5 times in the heart tissue of diabetic rats. Increasing NO and H2S production caused improvement and restoration of endothelium-dependent relaxation of aorta, effective arterial elastance, and diastolic heart function in diabetic rats. The endothelium-dependent relaxation increased 2.4 times; effective arterial elastance decreased by 47%. The end-diastolic myocardial stiffness decreased 2.2 times. Thus, modulation of H2S synthesis leads to increased cNOS activity by up to 5 times in the cardiovascular system. Increasing NO and H2S production restored endothelium-dependent relaxation of aorta and improved heart function in diabetes.

Attenuation of Myocardial ischemia reperfusion injury by Geniposide preconditioning in diabetic rats

Studies have shown that the NRF-2 /HO-1 pathway participates in myocardial ischemic reperfusion injury (MI/R) and that Geniposide (GEN) could protect the myocardial against MI/R. This study aims to examine the protective effects of GEN on MI/R in diabetic rats and further explore the possible mechanism of action. During MI/R in rats, NRF-2 /HO-1signals changed significantly including NRF-2 and HO-1up-regulation, resulting in heart dysfuction, histological damage and increasing oxidative stress and cell apoptosis. Treatment with GEN can significantly improve the general condition and heart function in diabetic rats with decreasing the expression of cTnI, CK-MB, blood glucose, MDA, ROS, cell apoptosis and pathological damage in MI/R. In addition, GEN precondition can also significantly increase the weight of rats and the activity of SOD, CAT and GPx with up-regulating the expression of NRF-2 and HO-1 in MI/R. This study implied that Geniposide has a protective effect on myocardial ischemia reperfusion injury in diabetic rats, and its mechanism is associated with activating NRF2/HO-1 signaling pathway to suppress oxidative stress.

Effect of exenatide on the cardiac expression of adiponectin receptor 1 and NADPH oxidase subunits and heart function in streptozotocin-induced diabetic rats

BackgroundThis study investigated the effect of exenatide on the cardiac expression of adiponectin receptor 1 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and heart function in streptozotocin-induced diabetic rats.MethodsMale Sprague–Dawley rats were randomly divided into four groups, i.e. control group, diabetic group, diabetic treated with low doses of exenatide (2 μg · kg−1.d−1) and diabetic treated with high doses of exenatide (10 μg · kg−1.d−1). Diabetes was induced by intraperitoneal injection of streptozotocin (65 mg/kg body weight). At the termination after exenatide treatment for eight weeks, following anesthesia of the rats, a catheter was inserted into the left ventricle through the right common carotid artery for measurement of left ventricular pressure, which included left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and the maximal rate of rise and decline of ventricular pressure (±dp/dt[max]). Plasma and myocardial adiponectin levels, and the expressions of myocardial adiponectin receptor 1, p22phox, NADPH oxidase 4 (NOX4), glucose transporter type 4 (Glut4), AMPK-α, phosphorylated-AMPK-α, connective tissue growth factor (CTGF) and copper zinc superoxide dismutase (Cu-Zn-SOD) were assayed.ResultsHeart function, plasma adiponectin levels, the protein expression of myocardial phosphorylated-AMPK-α, the mRNA expression of myocardial Glut4, and the positive expression of myocardial Cu-Zn-SOD were significantly decreased in diabetic. The protein expression of myocardial adiponectin receptor 1, the mRNA expression of myocardial p22phox and NOX4, and the positive expression of myocardial CTGF were significantly increased in diabetic. Low and high doses of exenatide treatment significantly attenuated these changes in diabetic rats.ConclusionsThese results suggest that exenatide may contribute to the improvement of the heart function in diabetic rats by down-regulating the expression of myocardial adiponectin receptor 1, p22phox and NOX4, and up-regulating plasma adiponectin level and the expression of myocardial AMPK-α, Glut4 and Cu-Zn-SOD.

VASONATRIN PEPTIDE ATTENUATES MYOCARDIAL ISCHAEMIA/REPERFUSION INJURY THROUGH INHIBITING THE ENDOPLASMIC RETICULUM STRESS AND THUS ENHANCING THE CELL SURVIVAL SIGNALS IN DIABETIC RATS

ObjectivesPeople with diabetes mellitus (DM) have a risk of ischaemic heart disease (IHD) two to five times greater than that in nondiabetic individuals. Diabetic patients have significantly more severe and...

Effect of telmisartan on the expression of adiponectin receptors and nicotinamide adenine dinucleotide phosphate oxidase in the heart and aorta in type 2 diabetic rats

BackgroundDiabetic cardiovascular disease is associated with decreased adiponectin and increased oxidative stress. This study investigated the effect of telmisartan on the expression of adiponectin receptor 2 (adipoR2) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits in the heart and the expression of adiponectin receptor 1 (adipoR1) in aorta in type 2 diabetic rats.MethodsType 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ). Heart function, adipoR2, p22phox, NOX4, glucose transporter 4(GLUT4), monocyte chemoattractant protein-1(MCP-1) and connective tissue growth factor (CTGF)in the heart, and adipoR1, MCP-1 and nuclear factor kappa B (NF-κB) in aorta were analyzed in controls and diabetic rats treated with or without telmisartan (5mg/kg/d) by gavage for 12 weeks.ResultsHeart function, plasma and myocardial adiponectin levels, the expression of myocardial adipoR2 and GLUT4 were significantly decreased in diabetic rats (P <0.05). The expression of myocardial p22phox, NOX4, MCP-1, and CTGF was significantly increased in diabetic rats (P <0.05). The expression of adipoR1 was decreased and the expression of MCP-1 and NF-κB was increased in the abdominal aorta in diabetic rats (P <0.05). Telmisartan treatment significantly attenuated these changes in diabetic rats (P <0.05).ConclusionsOur results suggest that telmisartan upregulates the expression of myocardial adiponectin, its receptor 2 and GLUT4. Simultaneously, it downregulates the expression of myocardial p22phox, NOX4, MCP-1, and CTGF, contributing so to the improvement of heart function in diabetic rats. Telmisartan also induces a protective role on the vascular system by upregulating the expression of adipoR1 and downregulating the expression of MCP-1 and NF-κB in the abdominal aorta in diabetic rats.

On the expression of cardiac adiponectin and its receptor 1 by telmisartan tn diabetic rats

Objective To observe the effects of telmisartan on the expression of cardiac adiponectin and its receptor 1 in diabetic rats.and to investigate the protective roles and mechanisms of telmisartan on cardiomyopathy of diabetic rats.Methods Thirty male Wistar rats were randomly divided inlo control group.diabetic group,and telmisartan group.Diabetes mellitus was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin.After establishment of diabetes model.telmisartan(5 mg·kg~(-1)·d~(-1))was administered by lavage for 12 weeks in telmisartan group.At termination,the cardiac function was detected.Plasma and myocardial adiponectin levels were assayed by enzyme immunoassay.mRNA expression of adiponectin receptor 1(adipoR1)was assayed by RT-PCR,and protein expression of adipoR1,phosphorylated-AMPK-α,and glucose transporter 4(GluT4)were determined by Western blotting in myocardium.Results After12 weeks,the ratio of heart to body weight was increased[(4.38±0.07 vs 2.99±0.67)g/kg,P<0.05],but adiponectin levels in plasma and myocardium were decreased[(1.09±0.03 vs 1.87±0.05)μg/ml,(0.12±0.02vs 0.21±0.02)μg/mg protein,both P<0.05]in diabetic rats.In myocardium of diabetic rats,the protein and mRNA of adipoR1 were also decreased(0.35±0.08 vs 0.78±0.11,0.34±0.07 vs 0.77±0.08,both P<0.05).so were the expressions of phosphorylated-AMPK-α and GluT_4(0.47±0.12 vs 0.72±0.10,0.41±0.09 vs 0.79±0.08.both P<0.05).The cardiac function was also significantly decreased in diabetic group.The ratio of heart to body weight was significantly decreased in telmisartan group[(3.49±0.39 vs 4.38±0.07)g/kg,P<0.05].Both of plasma and myocardial adiponectin levels were increased[(1.4±0.02 vs 1.09±0.03)μg/ml,(0.16±0.01 vs 0.12±0.02)μg/mg protein,P<0.05],as well as mRNA(0.48±0.06 vs 0.35±0.08)and protein expression of adipoR1(0.47±0.09 vs 0.34±0.07),phosphorylated-AMPK-α(0.57±0.10 vs 0.47±0.12),and GluT_4(0.52±0.10 vs 0.41 ±0.09,all P<0.05)in myocardium.The cardiac function was obviously improved after telmisartan treatment(P < 0.05).Conclusion The levels of myocardial adiponectin and its receptor 1 are decreased in diabetic rats.Telmisartan up-regulates the levels of myocardial adiponectin and its receptor 1 and may promote myocardial glucose oxidation,resulting in the improvement of heart function in diabetic rats. Key words: Telmisartan; Diabetes mellitus,experimental; Adiponectin receptor 1 ; Cardiomyopathy

Preservation of heart function in diabetic rats by the combined effects of muscle cell implantation and insulin therapy

Diabetic cardiomyopathy is a common cause of heart failure in diabetic patients, but current treatments do not directly improve ventricular function. Cell transplantation can prevent cardiac dilatation after injury, and may also prevent congestive heart failure in diabetic cardiomyopathy. This study evaluated the functional effects of smooth muscle cells (SMCs) implanted into the myocardium of insulin- and non insulin-treated diabetic rats. Four weeks after streptozotocin infusion, adult Wistar rats were implanted with BrdU-labelled SMCs or culture media (N=12/group). Six rats in each group were also treated with insulin. Echocardiograms were performed at 0, 4 and 8 weeks after streptozotocin injection, and histology and heart function were evaluated at 4 weeks after implantation. Blood glucose levels decreased after insulin treatment. Among cell-injected rats, histology indicated that those that did not receive insulin retained fewer surviving BrdU+ SMCs, and a smaller volume of myocardial tissue positive for alpha-smooth muscle actin. Cardiac function was preserved in the insulin-treated groups relative to those that did not receive insulin. Among insulin-treated rats, the cell-injected group functioned better than the media-injected group. Diabetic cardiomyopathy is partially treatable with insulin; however, a combination of SMC transplantation and insulin treatment produced the best functional result. Cell transplantation may prevent the progression of diabetic cardiomyopathy in patients whose glucose levels are controlled with insulin.

Effects of Insulin Replacements, Inhibitors of Angiotensin, and PKCβ's Actions to Normalize Cardiac Gene Expression and Fuel Metabolism in Diabetic Rats

High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)beta inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and (13)C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.

Effects of high levels of fatty acids on functional recovery of ischemic hearts from diabetic rats.

In this study we determined the effects of high levels of fatty acids on recovery of heart function when present either during or after ischemia. Isolated working hearts from 6-wk streptozotocin diabetic and control rats perfused with 11 mM glucose were subjected to 25 min of global ischemia followed by 30 min of aerobic reperfusion. Four groups were studied: 1) 1.2 mM palmitate present before, during, and after ischemia; 2) 1.2 mM palmitate present before and during ischemia, followed by reperfusion in the absence of palmitate; 3) no palmitate before and during ischemia, followed by 1.2 mM palmitate during reperfusion; and 4) no palmitate before and during ischemia or during reperfusion. In control hearts, palmitate during reperfusion depressed recovery of function regardless of whether palmitate was present or absent during ischemia. In contrast, palmitate present during reperfusion did not depress recovery of mechanical function in the diabetic rat hearts. However, the presence of palmitate during ischemia itself in diabetic rat hearts was detrimental to recovery of mechanical function. The presence of palmitate during ischemia resulted in an accelerated rate of ATP loss and a decreased rate of lactate accumulation during ischemia, although this effect was similar in control and diabetic rat hearts. Our results demonstrate that high concentrations of fatty acids depress functional recovery of control rat hearts during the reperfusion period but depress recovery of function in diabetic rat hearts when present during ischemia itself.

Depression of compartmentalized creatine kinase activity and the consequence on diastolic function in diabetic rat hearts

Depression of compartmentalized creatine kinase activity and the consequence on diastolic function in diabetic rat hearts

L-carnitine increases glucose metabolism and mechanical function following ischaemia in diabetic rat heart

Stimulation of glucose oxidation by L-carnitine improves mechanical recovery of ischaemic hearts from non-diabetic rats perfused with high levels of fatty acids. The aim of this study was to determine whether L-carnitine also increases glucose oxidation and function in diabetic rat hearts, which have suppressed glucose metabolism. Isolated working hearts from six week streptozotocin diabetic and control rats were perfused with 11 mM (5-3H/U-14C)-glucose, 1.2 mM palmitate. Hearts were paced at 260 beats.min-1 during 60 min of low flow ischaemia, and were then subjected to 30 min of aerobic reperfusion. Total myocardial carnitine content in these hearts was first increased by a 60 min aerobic perfusion with 10 mM L-carnitine. Steady state glucose oxidation rates (measured as 14CO2 production) were depressed in diabetic rat hearts compared to control hearts during the initial aerobic period. However, L-carnitine treatment dramatically increased glucose oxidation rates in the diabetic rat hearts, as well as in control hearts. Glycolysis was also lower in diabetic rat hearts compared to control hearts, although L-carnitine treatment significantly increased glycolysis only in the diabetic animals. During reperfusion, steady state rates of glucose oxidation and glycolysis returned to preischaemic values in both the control and diabetic groups. L-carnitine treatment stimulated glucose oxidation during reperfusion in control and diabetic rat hearts. Mechanical function of control hearts returned to 38(SEM 9)% of preischaemic values, whereas in L-carnitine treated hearts function returned to 90(7)% of preischaemic values. Recovery of function was 80(15)% of preischaemic in the diabetic rat hearts, and was increased to 100% of preischaemic function with L-carnitine. Carnitine improves recovery of function of ischaemic non-diabetic rats by stimulating glucose oxidation during reperfusion, whereas it may be beneficial in diabetic rat hearts by stimulating both glycolysis during ischaemia and glucose oxidation during reperfusion.

Islet transplantation improves glucose oxidation and mechanical function in diabetic rat hearts.

In poorly controlled diabetes an impairment of glucose use can contribute to a depression in mechanical function of rat hearts. In this study we determined the effects of islet transplantation on glucose use and heart function in streptozotocin-induced diabetic rats. Myocardial function, glycolysis, and glucose oxidation were measured in isolated working hearts obtained from control, diabetic, and islet-transplanted diabetic Wistar-Furth rats. Islets (1200) were transplanted beneath the kidney capsule 2 weeks after a single i.v. dose of streptozotocin (55 mg/kg). The study consisted of three groups: (i) islet-transplanted diabetic rats, (ii) untreated diabetic controls, and (iii) normal controls. Following 11 weeks of monitoring, working hearts were perfused at a 11.5-mmHg (1 mmHg = 133.3 Pa) preload and 80-mmHg afterload, with buffer containing 11 mM [5-3H,14C(U)]glucose, 1.2 mM palmitate, and 100 microU/mL insulin. In untreated diabetic rat hearts, glucose oxidation rates were markedly depressed compared with control hearts (30.4 +/- 4 and 510 +/- 68 nmol.g-1 dry wt..min-1, respectively). Low glucose oxidation rates in diabetic rats were significantly improved in islet-transplanted animals (234 +/- 39 nmol.g-1 dry wt..min-1). The low glucose oxidation rates in untreated diabetic rat hearts were accompanied by an impaired mechanical function compared with control hearts, which was improved by islet transplantation (heart rate x developed pressure x 10(-3) was 10.6 +/- 0.9, 14.8 +/- 1.3, and 14.8 +/- 1.5 beats.mmHg.min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of high levels of fatty acids on functional recovery of ischemic hearts from diabetic rats

In this study we determined the effects of high levels of fatty acids on recovery of heart function when present either during or after ischemia. Isolated working hearts from 6-wk streptozotocin diabetic and control rats perfused with 11 mM glucose were subjected to 25 min of global ischemia followed by 30 min of aerobic reperfusion. Four groups were studied: 1) 1.2 mM palmitate present before, during, and after ischemia; 2) 1.2 mM palmitate present before and during ischemia, followed by reperfusion in the absence of palmitate; 3) no palmitate before and during ischemia, followed by 1.2 mM palmitate during reperfusion; and 4) no palmitate before and during ischemia or during reperfusion. In control hearts, palmitate during reperfusion depressed recovery of function regardless of whether palmitate was present or absent during ischemia. In contrast, palmitate present during reperfusion did not depress recovery of mechanical function in the diabetic rat hearts. However, the presence of palmitate during ischemia itself in diabetic rat hearts was detrimental to recovery of mechanical function. The presence of palmitate during ischemia resulted in an accelerated rate of ATP loss and a decreased rate of lactate accumulation during ischemia, although this effect was similar in control and diabetic rat hearts. Our results demonstrate that high concentrations of fatty acids depress functional recovery of control rat hearts during the reperfusion period but depress recovery of function in diabetic rat hearts when present during ischemia itself.

Islet tranplantation normalizes glucose oxidation and mechanical function in diabetic rat hearts: R. Barr, J.R.T. Lakey, R. Wambolt, A.B.R. Thomson, M.T. Clandinin, R. V. Rajotte, G.D. Lopaschuk, Faculty of Medicine, U. of Alberta, Edmonton, Canada

Islet tranplantation normalizes glucose oxidation and mechanical function in diabetic rat hearts: R. Barr, J.R.T. Lakey, R. Wambolt, A.B.R. Thomson, M.T. Clandinin, R. V. Rajotte, G.D. Lopaschuk, Faculty of Medicine, U. of Alberta, Edmonton, Canada

Glucose oxidation rates in fatty acid-perfused isolated working hearts from diabetic rats

The effect of fatty acids and the carnitine palmitoyltransferase I (CPT I) inhibitor, Etomoxir, on myocardial glucose oxidation in diabetes was studied. 14CO 2 production from 11 mM [ 14C]glucose was measured in control or 6-week streptozotocin-diabetic isolated working rat hearts perfused with or without 1.2 mM palmitate (bound to 3% albumin). In control hearts, addition of palmitate to the buffer resulted in a marked reduction (13-fold) in glucose oxidation rates. Glucose oxidation in diabetic rat hearts perfused with palmitate was almost abolished. Even though glucose oxidation rates were low, exogenous palmitate oxidation rates, measured as 14CO 2 production from [ 14C]palmitate, were not increased in diabetic versus control hearts. Addition of the CPT 1 inhibitor, Etomoxir (1 · 10 −6 M), resulted in a doubling of glucose oxidation rates in both control and diabetic rat hearts, in the presence or absence of palmitate. The effects of Etomoxir on glucose oxidation could not be explained by reduced exogenous palmitate oxidation or decreased levels of citrate. Cardiac function, as measured by the heart rate × peak systolic pressure product, was reduced in diabetic rat hearts. Etomoxir significantly increased heart function in palmitate-perfused hearts from both control and diabetic rats. These data suggest that fatty acids contribute to decreased glucose oxidation and cardiac function in diabetic rat hearts. These effects of fatty acids can be partially reversed with the CPT 1 inhibitor, Etomoxir.

Effect of experimental diabetes on isolated rat heart responsiveness to isoproterenol.

The isolated perfused working rat heart was used to study experimental diabetes-induced alterations in the sensitivity and responsiveness of the myocardium to the effects of isoproterenol. Experimental diabetes was induced by intravenous administration of either 65 mg/kg alloxan or 60 mg/kg streptozotocin. The positive inotropic and cardiac relaxant effects of isoproterenol were studied at various time points after the induction of diabetes. There were no changes either in the sensitivity or in the maximum responses of diabetic rat hearts to the positive inotropic effect of isoproterenol at any time point studied. However, the cardiac relaxant effect of isoproterenol was depressed in acute as well as chronic diabetic rat hearts when compared with age-matched controls. Ventricular noradrenaline content was unchanged in 180-day diabetic rat hearts indicating the absence of a diabetes-induced sympathetic neuropathy in the heart. The depressed relaxing effect of isoproterenol may have resulted from alterations in energy utilization and sarcoplasmic reticular function in diabetic rat hearts.