Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats.

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.