SEQUENCE OF ALTERATIONS IN SUBCELLULAR ORGANELLES DURING THE DEVELOPMENT OF HEART DYSFUNCTION IN DIABETES

Although changes in different subcellular organelles such as myofibril s, sarcoplasmic reticulum (SR), mitochondria and sarcolemma (SL), as w ell as in heart function have been reported to occur in chronic diabet es, their inter-relationships and functional significance are poorly u nderstood, In order to gain information on this aspect, diabetes in ra ts was induced by an intravenous injection of streptozotocin and anima ls were assessed hemodynamically at 15-27 days. Ventricular tissue fro m several diabetic animals was pooled, subcellular organelles were iso lated and their biochemical activities determined. Significant depress ions in cardiac contractile and relaxation were observed to be associa ted with decreases in myofibrillar Ca2+- stimulated ATPase and SR Ca2-pump activities at 21 days from the induction of diabetes, Likewise, the SL Na+-Ca2+ exchange and Ca2+-channel density were decreased at 21 days but the affinity of SL Ca2+-channels was increased in the diabet ic heart. The SL Ca2+-pump and Na+-K+ ATPase activities were depressed at 18 and 24 days, respectively. Both alpha- and beta-adrenoceptor de nsities in SL were decreased at 27 days whereas no changes in mitochon drial function were observed at these early stages of diabetes. The SL low affinity Ca2+-binding was decreased while the low affinity Ca2+-A TPase activity was increased at 18 days following the induction of dia betes. These results indicate that SL defects precede those in SR, myo fibrils or mitochondria and suggest that abnormalities in Ca2+-handlin g as well as interaction of Ca2+ with myofilaments in cardiomyocytes m ay lead to the development of heart dysfunction in chronic diabetes.