Role of nitric oxide, tetrahydrobiopterin and peroxynitrite in glucose toxicity-associated contractile dysfunction in ventricular myocytes
- L. B. EsbergAffiliated withDivision of Pharmaceutical Sciences, University of Wyoming College of Health Sciences
- , J. RenAffiliated withDivision of Pharmaceutical Sciences, University of Wyoming College of Health Sciences Email author
Local overproduction of nitric oxide is seen in early stages of diabetes, which can react with superoxide (O2 −) to form peroxynitrite (ONOO−). The aim of this study was to examine the effect of scavengers for nitric oxide, O2 −, ONOO− and NOS cofactor tetrahydrobiopterin (BH4) 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 µmol/l), the NOS inhibitor L-NMMA (100 µmol/l), superoxide dismutase (SOD, 500 U/ml), the ONOO− scavengers urate (100 µmol/l), MnTABP (100 µmol/l), BH4 (10 µmol/l) and its inactive analogue NH4 (10 µmol/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 (TR90) and normal shortening duration (TPS) associated with reduced cytosolic Ca2+ rise compared to normal myocytes. The high glucose-induced abnormalities were abrogated or attenuated by urate, MnTBAP, L-NMMA, BH4, and SOD, whereas unaffected by haemoglobin, PTIO and NH4. L-NMMA reduced peak shortening while PTIO and DAHP depressed ± dL/dt and prolonged TPS or TR90 in normal myocytes. High glucose increased NOS activity, protein expression of eNOS but not iNOS, which were attenuated by L-NMMA and BH4, 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.
KeywordsGlucose contraction nitric oxide NOS tetrahydrobiopterin peroxynitrite
- Role of nitric oxide, tetrahydrobiopterin and peroxynitrite in glucose toxicity-associated contractile dysfunction in ventricular myocytes
Volume 46, Issue 10 , pp 1419-1427
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