Hepatic necrosis induced by norepinephrine in rabbits

Extensive hepatic necrosis was produced in rabbits 48 hr following infusion of a cardiopathogenic dose of norepinephrine (NE, 2 micrograms/kg/min for 90 min). Livers had necrotic areas of varying sizes and gross appearances. Histologically, the lesions were areas of varying sizes and gross appearances. Histologically, the lesions were areas of lytic-coagulative necrosis with massive mineralization by calcium. In addition, the serum glutamate-pyruvate transaminase (GPT) was significantly elevated (P less than 0.001). Pretreatment with the alpha 1-adrenoceptor blocker prazosin (200 micrograms/kg) 15 min prior to the standard NE infusion prevented both liver necrosis and serum GPT elevation. It is concluded that large doses of NE produce tissue injury in the liver. This may be the result of excessive activation of the alpha 1-adrenoceptor system, which leads to hepatic ischemia and necrosis.     

Metabolic disturbances in diabetic cardiomyopathy

It has been established that diabetes results in a cardiomyopathy, and increasing evidence suggests that an altered substrate supply and utilization by cardiac myocytes could be the primary injury in the pathogenesis of this specific heart muscle disease. For example, in diabetes, glucose utilization is insignificant, and energy production is shifted almost exclusively towards -oxidation of free fatty acids (FFA). FFA's are supplied to cardiac cells from two sources: lipolysis of endogenous cardiac triglyceride (TG) stores, or from exogenous sources in the blood (as free acid bound to albumin or as TG in lipoproteins). The approximate contribution of FFA from exogenous or endogenous sources towards -oxidation in the diabetic heart is unknown. In an insulin-deficient state, adipose tissue lipolysis is enhanced, resulting in an elevated circulating FFA. In addition, hydrolysis of the augmented myocardial TG stores could also lead to high tissue FFA. Whatever the source of FFA, their increased utilization may have deleterious effects on myocardial function and includes the abnormally high oxygen requirement during FFA metabolism, the intracellular accumulation of potentially toxic intermediates of FFA, a FFA-induced inhibition of glucose oxidation, and severe morphological changes. Therapies that target these metabolic aberrations in the heart during the early stages of diabetes could potentially delay or impede the progression of more permanent sequelae that could ensue from otherwise uncontrolled derangements in cardiac metabolism.     

Mitochondrial dysfunction in diabetic cardiomyopathy

Cardiovascular disease is common in patients with diabetes and is a significant contributor to the high mortality rates associated with diabetes. Heart failure is common in diabetic patients, even in the absence of coronary artery disease or hypertension, an entity known as diabetic cardiomyopathy. Evidence indicates that myocardial metabolism is altered in diabetes, which likely contributes to contractile dysfunction and ventricular failure. The mitochondria are the center of metabolism, and recent data suggests that mitochondrial dysfunction may play a critical role in the pathogenesis of diabetic cardiomyopathy. This review summarizes many of the potential mechanisms that lead to mitochondrial dysfunction in the diabetic heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.     

Cholinesterases in dexrazoxane-treated daunorubicin cardiomyopathy in rabbits

Changes in cholinesterases activities in daunorubicin cardiomyopathy and in dexrazoxane (DRZX)-treated daunorubicin cardiomyopathy were investigated in rabbits. Acetyl- and butyrylcholinesterase (AChE and BuChE) were determined using Ellman's method. In the serum, a significant decrease of BuChE was observed in the daunorubicin group (9.05 at the beginning and 7.15 microcat/l at the end of the experiment). After DRZX, no significant changes were found and a significant increase in BuChE was observed in the control group (10.26-12.38 microcat/l). AChE activity in the left and right cardiac ventricles was not significantly different between the groups while in the septum there was a significantly lower AChE activity found in the daunorubicin group only. BuChE activity was significantly decreased in the left (15.64 ncat/g) and right (19.27 ncat/g) heart ventricles, in the septum and in the liver in the daunorubicin group. A significant decrease in serum total protein and albumin was demonstrated only in the daunorubicin group. Our results support the hypothesis about the influence of daunorubicin on protein (and enzyme) synthesis in the liver and heart. A protective effect of DRZX on cholinesterases activity was observed. The changes in cholinesterase activities may thus reflect their possible role in cardiomyopathy.     

Tissue norepinephrine concentration in spontaneously diabetic Chinese hamsters

There is some controversy concerning a possible effect of diabetes mellitus on the sympathetic nervous system in humans with spontaneous diabetes mellitus and in animals with experimental diabetes mellitus. In this study we compared the tissue norepinephrine (NE) concentration of normal and diabetic Chinese hamsters in the untreated state and after treatment with insulin. Diabetes resulted in a 128% increase in the NE concentration of the kidney in female but not male hamsters. The NE concentration was increased in the liver (133%) and in the cerebral cortex (118%) of both male and female hamsters. There was no significant increase in the NE concentration of hypothalamus, acinar pancreas, pancreatic islets, or heart of diabetic hamsters. Three days of insulin therapy reduced the elevated NE concentration in kidney, liver and cerebral cortex of diabetic hamsters to the levels found in normal hamsters. However, insulin therapy of normal hamsters did not reduce the tissue NE concentration of the kidney, liver, and cerebral cortex below the normal levels found in these animals. Insulin therapy reduced the hypothalamic concentration of NE in both diabetic and normal hamsters. The increase in kidney NE concentration in female diabetic hamsters was not due to a reduction in renal size, for the kidneys of both female and male diabetic hamsters were larger than those of normal hamsters. When synthesis of NE was inhibited with alpha-methyltyrosine, there was a comparable rate of fall in the tissue NE concentration in the four experimental groups, suggesting that the increased tissue NE concentration in the tissues of diabetic hamsters was not due to a decreased rate of disappearance of this compound.(ABSTRACT TRUNCATED AT 250 WORDS)     

High fat diet induced diabetic cardiomyopathy

In response to a chronic high plasma concentration of long-chain fatty acids (FAs), the heart is forced to increase the uptake of FA at the cost of glucose. This switch in metabolic substrate uptake is accompanied by an increased presence of the FA transporter CD36 at the cardiac plasma membrane and over time results in the development of cardiac insulin resistance and ultimately diabetic cardiomyopathy. FA can interact with peroxisome proliferator-activated receptors (PPARs), which induce upregulation of the expression of enzymes necessary for their disposal through mitochondrial β-oxidation, but also stimulate FA uptake. This then leads to a further increase in FA concentration in the cytoplasm of cardiomyocytes. These metabolic changes are supposed to play an important role in the development of cardiomyopathy. Although the onset of this pathology is an increased FA utilization by the heart, the subsequent lipid overload results in an increased production of reactive oxygen species (ROS) and accumulation of lipid intermediates such as diacylglycerols (DAG) and ceramide. These compounds have a profound impact on signaling pathways, in particular insulin signaling. Over time the metabolic changes will introduce structural changes that affect cardiac contractile characteristics. The present mini-review will focus on the lipid-induced changes that link metabolic perturbation, characteristic for type 2 diabetes, with cardiac remodeling and dysfunction.     

Impaired in vivo myocardial reactivity to norepinephrine in diabetic rats

The effects of long-term diabetes with and without insulin treatment on in vivo myocardial contractile activity were studied under basal conditions and as a function of intravenously infused norepinephrine. Diabetes was induced by iv injection of streptozotocin (50 mg/kg). Insulin-treated diabetic rats received 5 units per day of isophane insulin suspension. The duration of the study was 8 weeks. In vivo myocardial contractility measurements were performed in ketamine-xylazine-anesthetized rats using a miniature catheter-tip pressure transducer advanced through the right carotid artery into the left ventricle. Peak positive dP/dt and intraventricular developed pressure were comparable among the groups when measured under basal conditions; however, the magnitude of the response to variable doses of norepinephrine (6 X 10(-12) to 6 X 10(-8) mole/kg body wt) were significantly diminished in diabetic rats, but the sensitivity was unchanged. Negative dP/dt was decreased under basal conditions and in response to norepinephrine in diabetic rats. Insulin treatment to diabetic rats prevented these changes, but heart rate was elevated. These results demonstrate that the in vivo cardiovascular reactivity of diabetic rats to norepinephrine is significantly attenuated.     

Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy

Phospholipase C (PLC) activity is known to influence cardiac function. This study was undertaken to examine the status of PLC beta3 in the cardiac cell plasma membrane (sarcolemma, SL) in an experimental model of chronic diabetes. SL membrane was isolated from diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mg/kg body weight). The total SL PLC was decreased in diabetes and was associated with a decrease in SL PLC beta3 activity, which immunofluorescence in frozen diabetic left ventricular tissue sections revealed to be due to a decrease in PLC beta3 protein abundance. In contrast, the SL abundance of Gqalpha was significantly increased during diabetes. These changes were associated with a loss of contractile function (+/- dP/dt). A 2-week insulin treatment of 6-week diabetic animals partially normalized all of these parameters. These findings suggest a defect in PLC beta3-mediated signaling processes may contribute to the cardiac dysfunction seen during diabetes.     

Defective phosphatidic acid-phospholipase C signaling in diabetic cardiomyopathy

The effects of exogenous phosphatidic acid (PA) on Ca2+ transients and contractile activity were studied in cardiomyocytes isolated from chronic streptozotocin-induced diabetic rats. In control cells, 25 microM PA induced a significant increase in active cell shortening and Ca2+ transients. PA increased IP3 generation in the control cardiomyocytes and its inotropic effects were blocked by a phospholipase C inhibitor. In cardiomyocytes from diabetic rats, PA induced a 25% decrease in active cell shortening and no significant effect on Ca2+ transients. Basal and PA-induced IP3 generation in diabetic rat cardiomyocytes was 3-fold lower as compared to control cells. Sarcolemmal membrane PLC activity was impaired. Insulin treatment of the diabetic animals resulted in a partial recovery of PA responses. Our results, therefore, identify an important defect in the PA-PLC signaling pathway in diabetic rat cardiomyocytes, which may have significant implications for heart dysfunction during diabetes.     

Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy

Phospholipase C (PLC) activity is known to influence cardiac function. This study was undertaken to examine the status of PLC 3 in the cardiac cell plasma membrane (sarcolemma, SL) in an experimental model of chronic diabetes. SL membrane was isolated from diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mg/kg body weight). The total SL PLC was decreased in diabetes and was associated with a decrease in SL PLC 3 activity, which immunofluorescence in frozen diabetic left ventricular tissue sections revealed to be due to a decrease in PLC 3 protein abundance. In contrast, the SL abundance of Gq was significantly increased during diabetes. These changes were associated with a loss of contractile function (±dP/dt). A 2-week insulin treatment of 6-week diabetic animals partially normalized all of these parameters. These findings suggest a defect in PLC 3-mediated signaling processes may contribute to the cardiac dysfunction seen during diabetes. (Mol Cell Biochem 261: 193–199, 2004)     

The role of NADPH oxidases in diabetic cardiomyopathy

Systemic changes during diabetes such as high glucose, dyslipidemia, hormonal changes and low grade inflammation, are believed to induce structural and functional changes in the cardiomyocyte associated with the development of diabetic cardiomyopathy. One of the hallmarks of the diabetic heart is increased oxidative stress. NADPH-oxidases (NOXs) are important ROS-producing enzymes in the cardiomyocyte mediating both adaptive and maladaptive changes in the heart. NOXs have been suggested as a therapeutic target for several diabetic complications, but their role in diabetic cardiomyopathy is far from elucidated. In this review we aim to provide an overview of the current knowledge regarding the understanding of how NOXs influences cardiac adaptive and maladaptive processes in a “diabetic milieu”. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.     

Sorbitol accumulation in heart: implication for diabetic cardiomyopathy

Sorbitol levels in heart were determined in streptozotocin-induced diabetic rats. Significantly higher levels were found in hearts of diabetic rats compared to normal rats. The findings are compatible with either significantly higher de novo synthesis of sorbitol in heart than is generally believed or uptake of circulating sorbitol by heart as previously indicated by nuclear magnetic resonance (NMR) in vivo metabolic imaging. Sorbitol accumulation in heart tissue may play a role in the pathogenesis of diabetic cardiomyopathy as has been implicated in cataract formation.     

AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy

We have recently shown that in diabetic OVE26 mice (type I diabetes), the AMP-activated protein kinase (AMPK) is reduced along with cardiac dysfunction and decreased cardiac autophagy. Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. More importantly, we have found chronic AMPK activation with metformin, one of the most used antidiabetes drugs and a well-characterized AMPK activator, significantly enhances autophagic activity, preserves cardiac function and prevents most of the primary characteristics of diabetic cardiomyopathy in OVE26 mice, but not in dominant negative-AMPK diabetic mice. We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart.     

Modification of cardiac oxidative stress in alloxan-induced diabetic rabbits with repaglinide treatment

The aim of this study was to analyze the antioxidative effect of repaglinide in the heart of alloxan-induced diabetic rabbits. The activities of superoxide dismutase (Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione (GSH), ascorbic acid (AA), products of lipid peroxidation (LPO) and protein carbonyl groups (PCG) were estimated after 4 and 8 weeks of repaglinide treatment (1 mg daily). At significance level p<0.05, in diabetic heart the activities of Cu,Zn-SOD and CAT were elevated as compared to control values (by 60.7% and 55.3% for Cu,Zn-SOD, and by 89.7% and 77.4% for CAT after 4 and 8 weeks, respectively). The level of AA was diminished by 52.5% and 41.5% while GSH-Px and GSSG-R activities were decreased after 4 weeks of experiment (by 11.5% and 14.4%, respectively). GSH level was diminished by 33.2% after 8 weeks. Simultaneously, in diabetic heart the levels of LPO and PCG were elevated as compared to control values (by 51.6% and 111.3% for LPO, and by 72.0% and 132.9% for PCG after 4 and 8 weeks, respectively). In diabetic animals, repaglinide normalized GSH-Px activity and GSH level. It modified the activities of Cu,Zn-SOD, CAT and AA as compared to diabetic non-treated animals. In diabetic-treated rabbits the level of LPO was diminished as compared to diabetic non-treated animals, while the level of PCG was not affected. In the present study, repaglinide did not affect blood glucose and plasma insulin concentrations in diabetic rabbits. Nevertheless, the drug showed some beneficial antioxidative properties in the heart tissue.     

AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy

We have recently shown that in diabetic OVE26 mice (type I diabetes), the AMP-activated protein kinase (AMPK) is reduced along with cardiac dysfunction and decreased cardiac autophagy. Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. More importantly, we have found chronic AMPK activation with metformin, one of the most used antidiabetes drugs and a well-characterized AMPK activator, significantly enhances autophagic activity, preserves cardiac function and prevents most of the primary characteristics of diabetic cardiomyopathy in OVE26 mice, but not in dominant negative-AMPK diabetic mice. We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart.     

Myocardial content of selected elements in experimental anthracycline-induced cardiomyopathy in rabbits

Cardiotoxicity represents the main drawback of clinical usefulness of anthracycline antineoplastic drugs. In this study, a content of selected elements (Ca, Mg, K, Se, Fe) in the post-mortem removed samples of the myocardial tissue was studied in three groups of rabbits: 1) control group (i.v. saline; n = 10); 2) daunorubicin-receiving animals (DAU; 3 mg/kg, i.v; n=11); 3) animals receiving cardioprotective iron-chelating agent dexrazoxane (DEX; 60 mg/kg, i.p.; n=5) prior to DAU. Drugs were administered once weekly for 10 weeks. 5–7 days after the last administration, cardiac left ventricular contractility (dP/dt_max) was significantly decreased in DAU-treated animals (745 ± 69 versus 1245 ± 86 kPa/s in the control group; P < 0.05), while in the DEX+DAU group it was insignificantly increased (1411 ± 77 kPa/s). Of the myocardial elements content studied, a significant increase in total Ca against control (16.2 ± 2.4 versus 10.6 ± 0.9 g/g of dry tissue; P < 0.05) was determined in the DAU-group, which was accompanied with significant decreases in Mg and K. In the heart tissue of DEX-pretreated animals, no significant changes of elements content were found as compared to controls, while the Ca content was in these animals significantly lower than in the DAU group (9.1 ± 0.4 versus 16.2 ± 2.4 g/g; P < 0.05). Hence, in this study we show that systolic heart failure induced by chronic DAU administration is primarily accompanied by persistent calcium overload of cardiac tissue and the protective action of DEX is associated with the restoration of normal myocardial Ca content.Published online: March 2005     

胰岛素信号损伤对糖尿病心肌病的影响

糖尿病心肌病(diabetic cardiomyopathy,DCM)是糖尿病患者的一种慢性并发症,目前已成为糖尿病患者心力衰竭和死亡的主要原因之一.该病是指糖尿病患者在没有其他心血管疾病如冠状动脉疾病、高血压、瓣膜病和先天性心脏病的情况下发生的心功能障碍,其潜在病因尚不清楚.其特征是早期表现为左心室肥厚和舒张功能受损...