ALTERED CA2+ HANDLING IN VENTRICULAR MYOCYTES ISOLATED FROM DIABETIC RATS

It has been suggested that alterations in intracellular Ca2+ homeostas is may be responsible for the development of diabetic cardiomyopathy. We have studied the effects of streptozotocin-induced diabetes on intr acellular Ca2+ concentration ([Ca2+](i)) in enzymically isolated rat v entricular myocytes. [Ca2+](i) was measured using indo 1 or fluo 3. Bo th diastolic and peak systolic [Ca2+](i) were reduced in diabetic comp ared with normal myocytes (by 52 and 43%, respectively). The decay pha se of the systolic [Ca2+](i) transient was slower in the diabetic myoc yte compared with normal (time constant = 89.6 +/- 3.4 ms, n = 23, nor mal 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 di abetic myocyte. In both normal and diabetic myocytes, increasing the f requency of electrical stimulation decreased peak systolic [Ca2+](i). The relationship between stimulation frequency and normalized peak sys tolic [Ca2+](i) was the same for both normal and diabetic myocytes. We also found that the caffeine-induced Ca2+ release [used as an index o f sarcoplasmic reticulum (SR) Ca2+ content] was significantly reduced in diabetic myocytes. These data indicate that SR Ca2+ content is decr eased by diabetes. In the presence of thapsigargin (2.5 mu M, an inhib itor of SR Ca2+-adenosinetriphosphatase), the magnitude and time cours e of stimulus-evoked [Ca2+](i) transients were identical in both group s of myocytes, suggesting that Ca2+ influx and/or efflux across the pl asma membrane is not significantly affected in diabetes. We conclude t hat 1) diabetes is associated with significant alterations in [Ca2+](i ) homeostasis and 2) the decrease in systolic [Ca2+](i) and lengthenin g of the systolic [Ca2+](i) transient result primarily from dysfunctio n of the SR.