It has been suggested that alterations in intracellular Ca2+ homeostasis may be responsible for the development of diabetic cardiomyopathy. We have studied the effects of streptozotocin-induced diabetes on intracellular Ca2+ concentration ([Ca2+]i) in enzymically isolated rat ventricular myocytes. [Ca2+]i was measured using indo 1 or fluo 3. Both diastolic and peak systolic [Ca2+]i were reduced in diabetic compared with normal myocytes (by 52 and 43%, respectively). The decay phase of the systolic [Ca2+]i transient was slower in the diabetic myocyte compared with normal (time constant = 89.6 +/- 3.4 ms, n = 23, normal vs. 105.2 +/- 4.05 ms, n = 20, diabetic; P < 0.01). This led to a significant prolongation of the [Ca2+]i transient duration in the diabetic myocyte. In both normal and diabetic myocytes, increasing the frequency of electrical stimulation decreased peak systolic [Ca2+]i. The relationship between stimulation frequency and normalized peak systolic [Ca2+]i was the same for both normal and diabetic myocytes. We also found that the caffeine-induced Ca2+ release [used as an index of sarcoplasmic reticulum (SR) Ca2+ content] was significantly reduced in diabetic myocytes. These data indicate that SR Ca2+ content is decreased by diabetes. In the presence of thapsigargin (2.5 microM, an inhibitor of SR Ca(2+)-adenosinetriphosphatase), the magnitude and time course of stimulus-evoked [Ca2+]i transients were identical in both groups of myocytes, suggesting that Ca2+ influx and/or efflux across the plasma membrane is not significantly affected in diabetes. We conclude that 1) diabetes is associated with significant alterations in [Ca2+]i homeostasis and 2) the decrease in systolic [Ca2+]i and lengthening of the systolic [Ca2+]i transient result primarily from dysfunction of the SR.

Controversy exists as to whether the diabetic heart is more or less sensitive to ischemic injury. Although a considerable number of experimental studies have directly determined the effects of ischemia on the diabetic heart, there is still no general agreement as to whether metabolic changes within the myocardium contribute to the severity of ischemic injury. This paper reviews the evidence suggesting that the diabetic heart can actually be less sensitive to an episode of severe ischemia. Possible reasons for this decreased sensitivity to injury are discussed, which include a decreased accumulation of glycolytic products during ischemia (lactate and protons), as well as alterations in the regulation of intracellular pH in the diabetic heart. Based on existing studies, we suggest that although impaired glucose metabolism in the diabetic heart contributes to injury in hypoxic hearts or in hearts subjected to low-flow ischemia, diabetes-induced decreases in glycolysis can actually be beneficial to the diabetic heart during and following a severe ischemic episode. A decreased clearance of protons via the Na+/H+ exchanger may also contribute to the decreased sensitivity to ischemic injury in the diabetic heart.

SUMMARY1. The whole-cell voltage-clamp technique was applied to ventricular myocytes isolated from normal and streptozotocin-induced diabetic rat hearts to investigate the contribution of the calcium current and of the calcium-independent potassium currents to diabetes-induced alterations of the action potential.2. In single calcium-tolerant isolated myocytes diabetes induced a lengthening of the action potential similar to that previously described in intact ventricular muscles.3. Only L-type calcium current was present both in normal and diabetic cells. Inactivation of ICa was described in both preparations by two exponentials, whose time constants were not modified by diabetes.4. Calcium current density-voltage relationships and steady-state inactivation curves were not significantly affected by diabetes.5. Potassium background inward rectifier current was not modified by diabetes. 6. Calcium-independent outward potassium current inactivated, in both cell types, according to a biexponential process whose time constants were not affected by diabetes.7. The transient outward potassium current density was significantly reduced by diabetes whereas neither the voltage dependence of the inactivation nor the time dependence of recovery from inactivation was modified.8. A 4-aminopyridine-insensitive potassium current was also reduced by diabetes. 9. Our results show that in isolated ventricular myocytes the lengthening of the action potential induced by diabetes results mainly from a decrease of the transmembrane calcium-independent potassium permeability.