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.

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.

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.

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.

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 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.

Effect of perfusate Ca2+ on the relation between metabolism and mechanical performance in the rat heart

1980 ◽  
Vol 58 (5) ◽  
pp. 570-573 ◽  
Author(s):  
T. Russell Snow ◽  
Gabor Rubanyi ◽  
Tunde Dora ◽  
Eörs Dora ◽  
Arisztid G. B. Kovach
Keyword(s):  
Respiratory Chain ◽  
Mechanical Performance ◽  
Left Ventricular ◽  
Perfused Heart ◽  
Exogenous Substrate ◽  
Rat Hearts ◽  
Nadh Fluorescence ◽  
Perfused Rat Hearts ◽  
Developed Pressure ◽  
Contractile Performance

Langendorf perfused rat hearts (n = 25) were used to study the effects of changes in perfusate Ca2+ concentration ([Ca2+p]) on the relation between metabolism and mechanical performance with either glucose or pyruvate as the exogenous substrate. Increased [Ca2+p] (from 1.3 to 3.9 mM) produced an increase (243 ± 38%) in left ventricular developed pressure regardless of the substrate. With glucose as the substrate, the NADH fluorescence intensity increased by 11.8 ± 1.2% (n = 17) relative to control indicating a more reduced state of the respiratory chain. Increasing [Ca2+p] in the pyruvate perfused heart produced the expected NADH oxidation (−6.2 ± 1.1%; n = 8). Hence the change in NADH fluorescence associated with increased [Ca2+p] is substrate dependent. The data show that, with glucose as the substrate but not with pyruvate, increases in [Ca2+p] increase the availability of reducing equivalents to the respiratory chain above the level necessary to compensate for the increased demand resulting from the greater contractile performance.

Reduced activity of mtTFA decreases the transcription in mitochondria isolated from diabetic rat heart

2002 ◽  
Vol 282 (4) ◽  
pp. E778-E785 ◽  
Author(s):  
Akio Kanazawa ◽  
Yoshihiko Nishio ◽  
Atsunori Kashiwagi ◽  
Hidetoshi Inagaki ◽  
Ryuichi Kikkawa ◽  
...  
Keyword(s):  
Insulin Treatment ◽  
Mitochondrial Protein ◽  
Mitochondrial Respiratory Chain ◽  
Binding Activity ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Mitochondrial Transcription Factor ◽  
Loop Region ◽  
Rat Hearts ◽  
D Loop

To evaluate abnormalities in the mitochondrial transcription factor A (mtTFA) function as a cause of mitochondrial dysfunction in diabetes, we measured the mRNA contents of the proteins consisting of the mitochondrial respiratory chain as well as transcriptional and translational activities in the mitochondria isolated from controls and streptozotocin-induced diabetic rat hearts. Using Northern blot analysis, we found 40% reduced mRNA contents of mitochondrial-encoded cytochrome b and ATP synthase subunit 6 in diabetic rat hearts compared with control rats ( P< 0.05). These abnormalities were completely recovered by insulin treatment. Furthermore, the mitochondrial activities of transcription and translation were decreased significantly in mitochondria isolated from diabetic rats by 60% ( P < 0.01) and 71% ( P < 0.01), respectively, compared with control rats. The insulin treatment also completely normalized these abnormalities in diabetic rats. Consistently, gel retardation assay showed a reduced binding of mtTFA to the D-loop of mitochondrial DNA in diabetic rats, although there was no difference in the mtTFA mRNA and protein content between the two groups. On the basis of these findings, a reduced binding activity of mtTFA to the D-loop region in the hearts of diabetic rats may contribute to the decreased mitochondrial protein synthesis.

Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction

2007 ◽  
Vol 292 (6) ◽  
pp. H2921-H2926 ◽  
Author(s):  
Z. Zhu ◽  
P. A. Hofmann ◽  
J. K. Buolamwini
Keyword(s):  
Infarct Size ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Nucleoside Transport ◽  
Total Risk ◽  
Risk Area ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Cardioprotective Effects ◽  
Developed Pressure

We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 μM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 ± 4.0% ( P < 0.001) and 14.1 ± 2.0 mmHg ( P < 0.03) for compound 2-treated hearts and 79.2 ± 5.9% ( P < 0.002) and 7.5 ± 2.7 mmHg ( P < 0.01) for compound 4-treated hearts compared with 41.6 ± 5.2% and 42.5 ± 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg for hearts treated with 1 μM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 μM, with LVDP recovery and EDP increase of 76.0 ± 4.9% ( P < 0.003) and 14.1 ± 1.0 mmHg ( P < 0.03). At 1 μM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 ± 3.17 ( P < 0.001) for compound 4 and 37.5 ± 3.42 ( P < 0.01) for NBMPR vs. 51.08 ± 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR ( P < 0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.

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.

Sign in / Sign up

Export Citation Format

Share Document