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

1983 ◽  
Vol 245 (6) ◽  
pp. H969-H976 ◽  
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.

Lack of effect of thyroid hormone on diabetic rat heart function and biochemistry

1984 ◽  
Vol 62 (6) ◽  
pp. 617-621 ◽  
Author(s):  
Arun G. Tahiliani ◽  
John H. McNeill
Keyword(s):  
Heart Function ◽  
Myocardial Dysfunction ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Chain Acyl ◽  
Uptake Activity ◽  
Streptozotocin Diabetic Rats ◽  
Developed Pressure

Cardiac functional abnormalities are frequently seen in diabetics and diabetes is also known to produce a state of mild hypothyroidism. To study the degree of involvement of diabetes-induced hypothyroidism on altered myocardial function, thyroid replacement therapy was carried out in streptozotocin-diabetic rats. Triiodothyronine (T3) treatment was initiated 3 days after the rats were made diabetic and was carried out for 6 weeks thereafter. Isolated perfused hearts from diabetic rats exhibited a depression in left ventricular developed pressure and positive and negative dP/dt at higher filling pressures as compared with controls. The depression could not be prevented by thyroid treatment. Calcium uptake activity in the cardiac sarcoplasmic reticulum (SR) was also depressed as a result of diabetes and this depression also was not prevented by thyroid treatment. Long chain acyl carnitine levels were found to be elevated in diabetic cardiac SR and could not be lowered by T3 treatment. The results indicate that the myocardial dysfunction observed in diabetic rats is due to factors other than the induced hypothyroidism.

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

1983 ◽  
Vol 61 (5) ◽  
pp. 516-523 ◽  
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.

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

1985 ◽  
Vol 63 (8) ◽  
pp. 925-931 ◽  
Author(s):  
Arun G. Tahiliani ◽  
John H. McNeill
Keyword(s):  
Fatty Acid ◽  
Sarcoplasmic Reticulum ◽  
Calcium Uptake ◽  
Myocardial Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Myosin Atpase ◽  
Diabetic Rat ◽  
Carbohydrate Utilization ◽  
Rat Hearts

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.

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

1993 ◽  
Vol 71 (12) ◽  
pp. 896-903 ◽  
Author(s):  
G. D. Lopaschuk ◽  
J. R. T. Lakey ◽  
R. Barr ◽  
R. Wambolt ◽  
A. B. R. Thomson ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Glucose Oxidation ◽  
Heart Function ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Mechanical Function ◽  
Oxidation Rates ◽  
Rat Hearts ◽  
Low Glucose ◽  
Developed Pressure

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 μU/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 × developed pressure × 10−3 was 10.6 ± 0.9, 14.8 ± 1.3, and 14.8 ± 1.5 beats∙mmHg∙min−1, respectively). In the presence of insulin, steady-state rates of glycolysis were only slightly depressed in untreated diabetic rat hearts compared with control (1944 ± 436 and 2720 ± 265 nmol∙g−1 dry wt.∙min−1, respectively). However, during a reduction of coronary flow to 0.5 mL∙min−1, glycolytic rates accelerated in control and islet-transplanted rat hearts, but not in untreated diabetic rat hearts. These data show that the decrease in glucose use that occurs in untreated diabetic rats under both aerobic and ischemic conditions can be significantly alleviated by islet transplantation. The increase in glucose oxidation in aerobic hearts supports our previous studies, which suggest that increasing glucose oxidation can improve function in diabetic rat hearts.Key words: glucose oxidation, glycolysis, diabetes, islet transplantation.

Metformin improves cardiac function in isolated streptozotocin-diabetic rat hearts

1994 ◽  
Vol 266 (2) ◽  
pp. H714-H719 ◽  
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.

The effect of alloxan- and streptozotocin-induced diabetes on calcium transport in rat cardiac sarcoplasmic reticulum. The possible involvement of long chain acylcarnitines

1983 ◽  
Vol 61 (5) ◽  
pp. 439-448 ◽  
Author(s):  
Gary D. Lopaschuk ◽  
Sidney Katz ◽  
John H. McNeill
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Heart Function ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Microsomal Preparation ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Gradual Onset ◽  
Female Wistar Rats ◽  
Streptozotocin Induced Diabetes ◽  
Long Chain

Isolated working hearts from diabetic rats have a decreased ability to respond to increasing preload or afterload. The ability of cardiac sarcoplasmic reticulum to transport Ca2+ was examined in diabetic rats. Hearts were obtained from female Wistar rats 120 days or 7 days after the induction of diabetes by a single I.V. injection of either alloxan (65 mg/kg) or streptozotocin (60 mg/kg). At all Ca2+ concentrations tested (0.2–5.0 μM free Ca2+) cardiac sarcoplasmic reticulum from 120-day diabetic rats showed a significant decrease in the rate of ATP-dependent tris-oxalate facilitated Ca2+ transport (62–73% of control). This was accompanied by a decrease in Ca2+ ATPase activity. The levels of long chain acylcarnitines associated with the microsomal sarcoplasmic reticulum preparation from 120-day diabetic rats were significantly higher than those present in sarcoplasmic reticulum from control rats. Palmitylcarnitine, the most abundant of the long chain acylcarnitines, in concentrations < 7 μM was found to be a potent time-dependent inhibitor of Ca2+ transport in both control and diabetic rat sarcoplasmic reticulum preparations; inhibition of Ca2+ transport was found to be more marked in the control preparations. This would indicate that a degree of inhibition produced by the high endogenous levels of palmitylcarnitine may already be present in the diabetic rat preparations. Cardiac sarcoplasmic reticulum prepared from acutely diabetic rats (7 days) did not show any decrease in Ca2+ transport ability. Levels of long chain acylcarnitines associated with the microsomal preparation enriched in sarcoplasmic reticulum were also unchanged. These findings suggest that the alteration in heart function in 120-day diabetic rats may be due to the buildup of cellular long chain acylcarnitines which inhibit sarcoplasmic reticulum Ca2+ transport. The absence of any change in Ca2+-transport activity or levels of long chain acylcarnitines at 7 days suggests that the alterations seen in 120-day diabetic rats must be of gradual onset.

Cardiac function in spontaneously hypertensive diabetic rats

1986 ◽  
Vol 251 (3) ◽  
pp. H571-H580 ◽  
Author(s):  
B. Rodrigues ◽  
J. H. McNeill
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Myocardial Dysfunction ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Developed Pressure ◽  
Working Heart ◽  
Diabetes Induction

The isolated perfused working heart was used to study hypertensive diabetes-induced alterations in cardiac function at 6 and 12 wk after diabetes was induced. At 6 wk after diabetes induction, cardiac performance was depressed in the diabetic animals. However, there was no difference in cardiac function between normotensive Wistar and spontaneously hypertensive (SHR) diabetic rats. Wistar-Kyoto (WKY) rats were also included as normotensive controls in our 12-wk study. Hearts from 12-wk SHR and Wistar diabetic animals exhibited a depressed left ventricular developed pressure and positive and negative dP/dt when compared with control animals. However, this depression was not seen in the WKY diabetic animals. In addition, quantitation of various parameters of heart function revealed highly significant differences between SHR diabetic animals and all other groups associated with an increased mortality. Serum lipids were elevated in SHR and Wistar and were unaffected in WKY diabetic rats. Furthermore, thyroid hormone levels were not depressed in WKY diabetic rats as seen in the other two diabetic groups. This normal lipid metabolism and thyroid status could, in part, explain the lack of cardiac dysfunction in these animals. The data provide further evidence that the combination of hypertension and diabetes mellitus produces greater myocardial dysfunction than with either disease alone and is associated with a significant mortality.

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

2004 ◽  
Vol 101 (5) ◽  
pp. 1145-1152 ◽  
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 &lt; 0.05), but its potentiation was preserved with isoflurane (148 +/- 21%; P &lt; 0.05) and sevoflurane (161 +/- 40%; P &lt; 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.

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

1982 ◽  
Vol 60 (7) ◽  
pp. 902-911 ◽  
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.

Insulin reversal of biochemical changes in hearts from diabetic rats

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.

Sign in / Sign up

Export Citation Format

Share Document