Hearts from diabetic rats are more resistant to in vitro ischemia: possible role of altered Ca2+ metabolism.

Abstract

The effects of whole heart ischemia were studied in isolated perfused rat hearts from control and diabetic animals. When whole heart ischemia was maintained for 30 minutes at 37 degrees C, diabetic hearts recovered 100% whereas hearts from normal animals recovered 30% of their preischemic function. Reperfusion Ca2+ uptake was about 2.5 microM/g dry wt in diabetic hearts compared with 10 microM/g dry wt in control hearts. When the ischemic period was extended to 40, 50, and 60 minutes, diabetic hearts had depressed recovery of ventricular function, and greater Ca2+ overload but reperfusion function was still significantly higher and Ca2+ overload significantly less than in control hearts. Depressed function and increased Ca2+ uptake were both linearly related to low tissue levels of residual high energy phosphates and inversely related to the amount of lactate that accumulated in the tissue during ischemia. However, regression lines relating these metabolic changes to depressed function and increased Ca2+ uptake showed that for any level of residual high energy phosphate or ischemic lactate, diabetic hearts performed much better and had less Ca2+ uptake than control hearts. These effects of diabetes were due to the diabetogenic action of the drugs used since both streptozotocin and alloxan had the same effect and in vivo insulin treatment reversed the effect. Diabetic hearts had a reduced maximum inotropic effect to increased extracellular Ca2+ under control aerobic perfusion conditions. The improved recovery of ventricular function during reperfusion of ischemic hearts from diabetic animals was highly correlated with reduced Ca2+ uptake, and regression lines relating depressed ventricular function to Ca2+ overload showed that data from control and diabetic hearts fell on the same line; that is, when depressed function occurred it was related to increased Ca2+ uptake to the same extent in both control and diabetic hearts. The resistance to ischemia in diabetic hearts was not related to higher tissue levels of high energy phosphates during reperfusion nor to lactate accumulation during ischemia. The observations suggest a role of increased reperfusion Ca2+ influx in ischemic damage and that alterations of sarcolemmal Ca2+ transport systems in diabetic myocardium may account for the greater resistance of these hearts to ischemia.

The Insulin Sensitizer Pioglitazone Improves the Deterioration of Ischemic Preconditioning in Type 2 Diabetes Mellitus Rats

“…[4][5][6][7][8][9][10][11][12][13][14] However, there was no significant difference in the incidence and duration of RVT between CIP(-) and DIP(-) in this study, suggesting that the diabetic heart used in this study does not have tolerance against reperfusion arrhythmias. Moreover, in diabetic rats there was no significant difference in the incidence and duration of RVT between DIP(+) and DIP(-).…”

“…The heart was promptly removed and perfused by the Langendolff method, and then converted to a working heart method (preload 10 cmH 2 O, afterload 80 cmH 2 O) as previously described. 24) Modified Krebs-Henseleit bicarbonate buffer (K-H buffer, mM: NaCl 118, KCl 4.7, CaCl 2 2.0, MgSO 4 7.4, 37°C, 95%O 2 +5%CO 2 gas mixture) was used as the perfusion buffer. A oneway ball valve in the cannula inserted into the aorta was used to block coronary perfusion during diastole in order to produce ischemia.…”

Ischaemic preconditioning does not protect the heart in obese and lean animal models of Type 2 diabetes

“…The impact of diabetes on myocardial infarct size after an ischaemic insult in experimental Type 1 diabetes has shown variable results [9,10,11,12,13]. The discrepancies can be explained by different experimental conditions.…”

Phosphorylated heat shock protein 27 is involved in enhanced heart tolerance to ischemia in short-term type 1 diabetic rats1

“…The reduction of phospho-hsp27 in correlation to hyperglycemia was effective in abrogating heart tolerance to ischemia in diabetes. Although there is controversy over the effects of hyperglycemia on cardiovascular outcomes, it is important to note that increased tolerance to ischemia is almost exclusively found in type 1 diabetic hearts [8,9,15,16] . In contrast to decreased sensitivity to ischemia of type 1 diabetic hearts, increased sensitivity to myocardial ischemia was found in type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats [17] .…”

“…Studies of animals with type 1 diabetes demonstrate either increased or decreased sensitivity of diabetic hearts to ischemia [5][6][7] . Suggested mechanisms for decreased sensitivity include attenuated Na + -H + exchanger activity, inhibited glycolysis, and reduced Ca 2+ overload during reperfusion [7][8][9] . Studies demonstrating the detrimental effects of hyperglycemia on ischemia suggest roles of pseudohypoxia and reactive oxygen species [6] .…”