Prevention of diabetes-induced myocardial dysfunction in rats by methyl palmoxirate and triiodothyronine treatment

Diabetes results in myocardial functional alterations which are accompanied by a depression of biochemical parameters such as myosin ATPase and calcium uptake in the sarcoplasmic reticulum. Methyl palmoxirate, a fatty acid analog, is reported to decrease circulating glucose levels by inhibiting fatty acid metabolism, thus forcing carbohydrate utilization. In the present study, we attempted to prevent streptozotocin diabetes-induced myocardial alterations in the rat. Using the isolated working heart preparation, we observed a depression of myocardial function in rats 6 weeks after the induction of diabetes, which was characterized by the inability of these hearts to develop left ventricular pressures and rates of ventricular contraction and relaxation as well as control hearts at higher left atrial filling pressures. Methyl palmoxirate treatment (25 mg kg−1 day−1 po daily) was unable to control diabetes-induced changes in plasma glucose, triglycerides, insulin, and total lipids. Also, the functional depression seen in diabetic rat hearts was present despite the treatment. However, depression of calcium uptake and elevation of long chain acyl carnitines seen in sarcoplasmic reticulum (SR) prepared from diabetic rat hearts could be prevented by the treatment. As triiodothyronine (T3) treatment has been shown to normalize depression of cardiac myosin ATPase in diabetic rats, we repeated the study using a combination of T3 (30 μg kg−1 day−1 sc daily) and methyl palmoxirate. While diabetic rats treated with T3 alone did not show significant improvement of myocardial function when compared with untreated diabetics, the function of those treated with both T3 and methyl palmoxirate was not significantly different from that in control rat hearts. These results suggest that while the combination of T3 and methyl palmoxirate may have other effects which result in improved function, preventing the depression of myosin ATPase and the SR calcium uptake can account at least in part for the functional depression.

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Prevention and reversal of altered myocardial function in diabetic rats by insulin treatment

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y83-079 ◽

1983 ◽

Vol 61 (5) ◽

pp. 516-523 ◽

Cited By ~ 26

Author(s):

Arun G. Tahiliani ◽

Rao V. S. V. Vadlamudi ◽

John H. McNeill

Keyword(s):

Insulin Treatment ◽

Myocardial Function ◽

Diabetic Rats ◽

Left Ventricular ◽

Diabetic Rat ◽

Myocardial Performance ◽

Perfused Heart ◽

Rat Hearts ◽

Heart Preparation ◽

Developed Pressure

Isolated perfused hearts from diabetic rats exhibit a decreased responsiveness to increasing work loads. However, the precise time point at which functional alterations occur is not clearly established. Previous observations in our laboratory have suggested that the alterations in myocardial function are not apparent at 30 days whereas they are clearly seen 100 days after streptozotocin-induced diabetes. We studied the cardiac function of 6-week diabetic rats using the isolated perfused heart preparation. The 6-week time period was found to be sufficient to cause depression of myocardial function in these animals. We also studied the effect of insulin treatment on myocardial performance of diabetic rats. Insulin treatment was initiated 3 days and 6 weeks after injection of streptozotocin (STZ). The treatment was continued for 6 and 4 weeks in the respective groups. Hearts from 6-week diabetic animals exhibited a depressed left ventricular developed pressure (LVDP) and positive and negative dP/dt at higher filling pressures when compared with 6-week control animals. However, the depression was not seen in the 6-week insulin-treated diabetic animals. Ten-week diabetic rat hearts also showed a depression of LVDP and positive and negative dP/dt when compared with 10-week controls. The group of animals that had been diabetic for 6 weeks and then treated for 4 weeks with insulin exhibited a reversal of the depressed myocardial function. These results demonstrate that depression of myocardial performance, which is evident 6 weeks after diabetes is induced, can be prevented if insulin treatment is initiated as the disease is induced. Further, insulin treatment is capable of reversing the abnormalities after they have occurred.

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Cardiac sarcoplasmic reticulum function in insulin- or carnitine-treated diabetic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1983.245.6.h969 ◽

1983 ◽

Vol 245 (6) ◽

pp. H969-H976 ◽

Cited By ~ 18

Author(s):

G. D. Lopaschuk ◽

A. G. Tahiliani ◽

R. V. Vadlamudi ◽

S. Katz ◽

J. H. McNeill

Keyword(s):

Sarcoplasmic Reticulum ◽

Calcium Transport ◽

Heart Function ◽

Diabetic Rats ◽

Left Ventricular ◽

Diabetic Rat ◽

Cardiac Sarcoplasmic Reticulum ◽

Rat Hearts ◽

Developed Pressure ◽

Heart Apparatus

Cardiac sarcoplasmic reticulum (SR) function and SR levels of long-chain (LC) acylcarnitines were determined in streptozotocin-induced diabetic rats treated with insulin or D,L-carnitine. ATP-dependent calcium transport was significantly depressed in cardiac SR isolated from untreated diabetic rats compared with control rats. Diabetic rat cardiac SR levels of LC acylcarnitines were also significantly elevated. Various parameters of heart function (left ventricular developed pressure, +dP/dT, and -dP/dT), as determined on an isolated working heart apparatus, were found to be depressed in untreated diabetic rats. Cardiac SR isolated from diabetic rats treated throughout the study period with insulin or D,L-carnitine did not have elevated levels of LC acylcarnitines associated with SR membrane nor was SR calcium transport activity depressed. Heart function in the diabetic rats treated with insulin was similar to control rat hearts but heart function remained depressed in diabetic rats treated with D,L-carnitine. The data suggest that the LC acylcarnitines are involved in the observed impairment of cardiac SR function in diabetic rats. Other factors, however, must be contributing to the depression in heart function noted in these animals.

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Interaction of Halogenated Anesthetics with α- and β-Adrenoceptor Stimulations in Diabetic Rat Myocardium

Anesthesiology ◽

10.1097/00000542-200411000-00014 ◽

2004 ◽

Vol 101 (5) ◽

pp. 1145-1152 ◽

Cited By ~ 11

Author(s):

Julien Amour ◽

Jean-Stéphane David ◽

Benoît Vivien ◽

Pierre Coriat ◽

Bruno Riou

Keyword(s):

Sarcoplasmic Reticulum ◽

Positive Inotropic Effect ◽

Diabetic Rats ◽

Left Ventricular ◽

Inotropic Effect ◽

Diabetic Rat ◽

Inotropic Effects ◽

Beta Adrenoceptor ◽

Alpha Adrenoceptor ◽

Positive Inotropic Effects

Background Halogenated anesthetics potentiate the positive inotropic effects of alpha- and beta-adrenoceptor stimulations. Although diabetes mellitus induces significant myocardial abnormalities, the interaction of halogenated anesthetics and adrenoceptor stimulation in diabetic myocardium remains unknown. Methods Left ventricular papillary muscles were provided from healthy and streptozotocin-induced diabetic rats. Effects of 1 minimum alveolar concentration halothane, isoflurane, and sevoflurane on the inotropic and lusitropic responses of alpha (phenylephrine)- and beta (isoproterenol)-adrenoceptor stimulations were studied at 29 degrees C with 12 pulses/min. Data shown are mean percentage of baseline active force +/- SD. Results Phenylephrine induced comparable positive inotropic effects in healthy and diabetic rats (143 +/- 8 vs. 136 +/- 18%; not significant), but the potentiation by halogenated anesthetics was abolished in the diabetic rats (121 +/- 20, 130 +/- 20, and 123 +/- 20% for halothane, isoflurane, and sevoflurane, respectively; not significant). In diabetic rats, the positive inotropic effect of isoproterenol was markedly diminished (109 +/- 9 vs. 190 +/- 18%; P < 0.05), but its potentiation was preserved with isoflurane (148 +/- 21%; P < 0.05) and sevoflurane (161 +/- 40%; P < 0.05) but not with halothane (126 +/- 16%; not significant). Halothane induced a deleterious effect on the sarcoplasmic reticulum, as shown by its impairment in the lusitropic effect of isoproterenol, compared with isoflurane and sevoflurane. Conclusion Potentiation of the positive inotropic effect of alpha-adrenoceptor stimulation by halogenated anesthetics is abolished in diabetic rats. In contrast, potentiation of beta-adrenoceptor stimulation is preserved with isoflurane and sevoflurane but not with halothane, probably because of its deleterious effects on sarcoplasmic reticulum.

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The effect of chronic alloxan- and streptozotocin-induced diabetes on isolated rat heart performance

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y82-127 ◽

1982 ◽

Vol 60 (7) ◽

pp. 902-911 ◽

Cited By ~ 92

Author(s):

Rao V. S. V. Vadlamudi ◽

Robert L. Rodgers ◽

John H. McNeill

Keyword(s):

Left Ventricular Pressure ◽

Diabetic Rats ◽

Left Ventricular ◽

Isolated Rat Heart ◽

Cardiac Performance ◽

Diabetic Rat ◽

Heart Performance ◽

Rat Hearts ◽

Female Wistar Rats ◽

Streptozotocin Induced Diabetes

Cardiac disease is a common secondary complication appearing in chronic diabetics. Isolated perfused working hearts obtained from both acute and chronic diabetic rats have also been shown to exhibit cardiac functional abnormalities when exposed to high work loads. We studied cardiac performance at various time points after induction of diabetes in rats to determine exactly when functional alterations appeared and whether these alterations progressed with the disease state. Female Wistar rats were made diabetic by a single i.v. injection of either alloxan (65 mg/kg) or streptozotocin (STZ 60 mg/kg). Cardiac performance was assessed at 7, 30, 100, 180, 240, and 360 days after induction of diabetes using the isolated perfused working heart technique. No changes were observed in the positive and negative dP/dt development at various atrial filling pressures in the diabetic hearts 7 days after treatment. Alloxan diabetic rat hearts exhibited depressed left ventricular pressure and positive and negative dP/dt development when perfused at high atrial filling pressures, at 30. 100, and 240 days after treatment. STZ diabetic rat hearts exhibited depressed cardiac performance at high atrial filling pressures at 100, 180, and 360 days after treatment, but not at 30 days after treatment. Control hearts exhibited slight but significant depressions in cardiac function with age. These results suggest that cardiac functional alterations appear in diabetic rats about 30 days after induction and progress with the disease. These alterations may indicate the development of a cardiomyopathy.

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Insulin reversal of biochemical changes in hearts from diabetic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.251.3.h670 ◽

1986 ◽

Vol 251 (3) ◽

pp. H670-H675

Author(s):

S. Bhimji ◽

D. V. Godin ◽

J. H. McNeill

Keyword(s):

Insulin Treatment ◽

Serum Insulin ◽

Complete Recovery ◽

Magnesium Content ◽

Diabetic Rats ◽

Left Ventricular ◽

Biochemical Changes ◽

Diabetic Rat ◽

Lysosomal Hydrolase ◽

Rat Hearts

Reversal of myocardial biochemical changes with insulin treatment (4 and 8 wk) was studied in 8 and 12 wk streptozotocin (STZ)-diabetic rats. STZ-induced diabetes was characterized by elevations in blood glucose, serum cholesterol, and triglycerides and depressed serum insulin levels. Insulin treatment for 4 and 8 wk completely restored the serum alterations to control values. The polyuria, polydipsia, and polyphagia were also markedly diminished by the insulin treatment. Diabetic rats had pronounced decreases in body, heart, and left ventricular weights, all of which were completely reversed by the insulin treatment. Hydroxyproline accumulation in diabetic rat hearts was only reversed by the 8-wk and not by the 4-wk insulin treatment. STZ produced a significant depletion of left ventricular magnesium content as well as depression of K+-stimulated sarcoplasmic reticulum and myofibrillar ATPase activities. Both the 4- and 8-wk insulin treatment produced a complete recovery of the myocardial magnesium content. No significant changes in sarcolemmal Na+-K+-ATPase and K+-stimulated p-nitrophenyl phosphatase activities were observed in diabetic animals compared with control. The decreased latency of the lysosomal hydrolase, N-acetyl-beta-glucosaminidase, and the increased collagen deposition observed in the diabetic hearts were only partially reversed by the 4-wk insulin treatment, but completely reversed by the 8-wk treatment period.

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Triacylglycerol turnover in isolated working hearts of acutely diabetic rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y94-157 ◽

1994 ◽

Vol 72 (10) ◽

pp. 1110-1119 ◽

Cited By ~ 54

Author(s):

Maruf Saddik ◽

Gary D. Lopaschuk

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Diabetic Rats ◽

Diabetic Rat ◽

Acid Oxidation ◽

Atp Production ◽

Oxidation Rates ◽

Rat Hearts

Although myocardial triacylglycerol may be a potentially important source of fatty acids for β-oxidation in diabetes, few studies have measured triacylglycerol turnover directly in hearts from diabetic animals. In this study, myocardial triacylglycerol turnover was directly measured in isolated working hearts from streptozotocin-induced acutely diabetic rats. Hearts were initially perfused in the presence of 1.2 mM [14C]palmitate and 11 mM glucose for 1 h (pulse) to label the endogenous lipid pools, followed by a 10-min washout perfusion. Hearts were then perfused for another hour (chase) with buffer containing 11 mM glucose ± 1.2 mM [3H]palmitate. During the chase, both 14CO2 and 3H2O production (measures of endogenous and exogenous fatty acid oxidation, respectively) were determined. A second series of hearts were perfused using the same protocol, except that unlabeled palmitate was used during the pulse and 11 mM [14C(U),5-3H]glucose ± unlabeled palmitate was present during the chase. Both glycolysis (3H2O production) and glucose oxidation (14CO2 production) rates were measured in this series. Myocardial triacylglycerol levels were significantly higher in the diabetic rat hearts (77.5 ± 4.6 vs. 33.7 ± 4.1 μmol fatty acid/g dry mass in control hearts). In diabetic rat hearts chased with 1.2 mM palmitate, triacylglycerol lipolysis was increased, although endogenous [14C]palmitate oxidation rates were similar to control hearts and contributed 10.1% of overall ATP production. The majority of fatty acids derived from triacylglycerol lipolysis were released into the perfusate. In the absence of palmitate, both triacylglycerol lipolysis and endogenous [14C]palmitate oxidation rates were significantly increased in diabetic rat hearts, compared with control. Under these conditions, triacylglycerol fatty acid oxidation contributed 70% of steady-state ATP production in diabetic rat hearts, compared with 34% in control hearts. These results demonstrate that in diabetic rat hearts myocardial triacylglycerol lipolysis is significantly increased and can readily be used as a source of fatty acids for mitochondrial β-oxidation.Key words: heart, triacylglycerols, fatty acid oxidation, glucose oxidation, glycolysis.

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Metformin improves cardiac function in isolated streptozotocin-diabetic rat hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.2.h714 ◽

1994 ◽

Vol 266 (2) ◽

pp. H714-H719 ◽

Cited By ~ 3

Author(s):

S. Verma ◽

J. H. McNeill

Keyword(s):

Isolated Heart ◽

Diabetic Rats ◽

Left Ventricular ◽

Diabetic Rat ◽

Metformin Hydrochloride ◽

Ventricular Contractility ◽

Glucose Levels ◽

Rat Hearts ◽

Plasma Insulin Levels ◽

Developed Pressure

The effects of metformin administration were studied in isolated perfused working hearts from control and diabetic rats. Control and streptozotocin-treated diabetic rats were treated for 8 wk with metformin hydrochloride. Treatment was initiated at 350 mg.kg-1 x day-1 and was gradually increased to a dose of 650 mg.kg-1 x day-1, which was maintained over a 6-wk period. Isolated heart performance was assessed under conditions of increasing preload to evaluate the performance of each heart to “stress.” Hearts from untreated diabetic rats exhibited a depressed response to increases in left atrial filling pressures from 17.5 to 22.5 cmH2O in terms of left ventricular developed pressure, ventricular contractility, and ventricular relaxation compared with age-matched untreated controls. The diabetic hearts also exhibited a delayed half time to relaxation at filling pressures from 15 to 22.5 cmH2O. The function curves were performed at a constant heart rate of 300 beats/min. These responses were restored to control values in diabetic rats treated with metformin. Metformin treatment did not affect the ventricular responses in control rats. Metformin reduced plasma glucose levels in the diabetic rats from 24.3 to 14.4 mM without any increase in the plasma insulin levels. The diabetic group had higher triglycerides than age-matched untreated control rats, and metformin administration in diabetic rats reduced triglyceride levels to control values but had no effect in control rats. In conclusion, metformin administration improves cardiac performance in streptozotocin-diabetic rats under conditions of increasing preload.

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The acute effects of different spironolactone doses on cardiac function in streptozotocin-induced diabetic rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0055 ◽

2017 ◽

Vol 95 (11) ◽

pp. 1343-1350

Author(s):

Aleksandra Vranic ◽

Stefan Simovic ◽

Petar Ristic ◽

Tamara Nikolic ◽

Isidora Stojic ◽

...

Keyword(s):

Diabetes Mellitus ◽

Systolic Function ◽

Diabetic Rats ◽

Diabetic Rat ◽

Albino Rats ◽

Acute Administration ◽

Rat Hearts ◽

Patients With Diabetes ◽

Streptozotocin Induced Diabetes ◽

Wistar Albino Rats

Currently, cardiovascular diseases are the leading cause of global mortality, while diabetes mellitus remains an important cause of cardiovascular morbidity. A recent study showed that patients with diabetes mellitus treated with mineralocorticoid receptor antagonists have improved coronary microvascular function, leading to improved diastolic dysfunction. In this study, we evaluated the influence of acute administration of spironolactone on myocardial function in rats with streptozotocin-induced diabetes mellitus, with special emphasis on cardiodynamic parameters in diabetic rat hearts. The present study was carried out on 40 adult male Wistar albino rats (8 weeks old). Rats were randomly divided into 4 groups (10 animals per group): healthy rats treated with 0.1 μmol/L of spironolactone, diabetic rats treated with 0.1 μmol/L of spironolactone, healthy rats treated with 3 μmol/L of spironolactone, and diabetic rats treated with 3 μmol/L of spironolactone. Different, dose-dependent, acute responses of spironolactone treatment on isolated, working diabetic and healthy rat heart were observed in our study. In healthy rats, better systolic function was achieved with higher spironolactone dose, while in diabetic rats, similar effects of low and high spironolactone dose were observed.

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