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Diabetologia. 2003 Oct;46(10):1419-27. Epub 2003 Jul 29.

Role of nitric oxide, tetrahydrobiopterin and peroxynitrite in glucose toxicity-associated contractile dysfunction in ventricular myocytes.

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Division of Pharmaceutical Sciences, University of Wyoming College of Health Sciences, Laramie, WY 82071-3375, USA.



Local overproduction of nitric oxide is seen in early stages of diabetes, which can react with superoxide (O(2)(-)) to form peroxynitrite (ONOO(-)). The aim of this study was to examine the effect of scavengers for nitric oxide, O(2)(-), ONOO(-) and NOS cofactor tetrahydrobiopterin (BH(4)) on high glucose-induced cardiac contractile dysfunction.


Ventricular myocytes were cultured for 24 h with either normal (N, 5.5 mmol/l) or high (25.5 mmol/l) glucose, with or without the nitric oxide scavengers haemoglobin (100 nmol/l), PTIO (100 micromol/l), the NOS inhibitor L-NMMA (100 micromol/l), superoxide dismutase (SOD, 500 U/ml), the ONOO(-) scavengers urate (100 micromol/l), MnTABP (100 micromol/l), BH(4) (10 micromol/l) and its inactive analogue NH(4) (10 micromol/l), and the GTP cyclohydrolase I inhibitor DAHP (1 mmol/l). Myocyte mechanics, NOS protein expression and activity were evaluated.


High glucose myocytes showed reduced peak shortening, decreased maximal velocity of shortening/relengthening (+/- dL/dt), prolonged relengthening (TR(90)) and normal shortening duration (TPS) associated with reduced cytosolic Ca(2+) rise compared to normal myocytes. The high glucose-induced abnormalities were abrogated or attenuated by urate, MnTBAP, L-NMMA, BH(4), and SOD, whereas unaffected by haemoglobin, PTIO and NH(4). L-NMMA reduced peak shortening while PTIO and DAHP depressed +/- dL/dt and prolonged TPS or TR(90) in normal myocytes. High glucose increased NOS activity, protein expression of eNOS but not iNOS, which were attenuated by L-NMMA and BH(4), respectively.


These results suggested that NOS cofactor, NO and ONOO(-) play a role in glucose-induced cardiomyocyte contractile dysfunction and in the pathogenesis of diabetic cardiomyopathy.

[Indexed for MEDLINE]

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