Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation.
Non-insulin-dependent diabetic (NIDD) male Wistar rats develop a cardiomyopathy approximately 9 mo after the onset of the diabetic condition. This cardiomyopathy is characterized by reduced contractility, relaxation, cardiac work, and diastolic compliance. Although the basis for these defects is not completely understood, altered cellular Ca2+ regulation appears to play a major role in their development. In both isolated sarcolemmal membrane and cardiomyocytes, significant diabetes-linked defects in Ca2+ metabolism were observed. A small, but significant, decrease in the rate of sarcolemmal ATP-dependent Ca2+ transport of the diabetic heart was observed. Also evident was a major defect in sarcolemmal Na(+)-Ca2+ exchange as determined by reduced Na(+)-dependent Ca2+ transport into vesicles and Na(+)-dependent Ca2+ efflux from 45Ca(2+)-loaded cardiomyocytes from diabetic rats. In isolated cardiomyocytes, it was observed that the relative fluorescence of fura-2 at 502 nm was higher in cells from NIDD hearts, suggestive of a higher cytosolic free Ca2+. Consistent with diabetes-linked defects in Ca(2+)-transporter activities, the accumulation of Ca2+ after depolarization with KCl was greater in the diabetic. This study demonstrates that diabetes-induced defects in Ca2+ movement by the various Ca2+ transporters lead to abnormal cytosolic Ca2+ regulation by the diabetic cardiomyocytes. This observation supports the notion that abnormal Ca2+ regulation contributes to the development of the NIDD cardiomyopathy.
Allo
S N
SN
Department of Pharmacology, College of Medicine, University of South Alabama, Mobile 36688.
Lincoln
T M
TM
Wilson
G L
GL
Green
F J
FJ
Watanabe
A M
AM
Schaffer
S W
SW
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D016257:Fura-2; D006321:Heart / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger; D013050:Spectrometry, Fluorescence
D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D000252:Calcium-Transporting ATPases; D011188:Potassium; D002118:Calcium; D016257:Fura-2