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

Abstract

AIMS/HYPOTHESIS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION/INTERPRETATION:

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.

• Authors: L B Esberg, J Ren
• Journal: Diabetologia (Diabetologia) Vol. 46 Issue 10 Pg. 1419-27 (Oct 2003) ISSN: 0012-186X [Print] Germany
• PMID: 12898015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Free Radical Scavengers
• Peroxynitrous Acid
• Biopterins
• omega-N-Methylarginine
• Nitric Oxide
• Nitric Oxide Synthase
• Superoxide Dismutase
• sapropterin
• Glucose
• Calcium

Topics

• Animals
• Biopterins (analogs & derivatives, metabolism)
• Calcium (metabolism)
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Free Radical Scavengers (pharmacology)
• Glucose (poisoning)
• Intracellular Membranes (metabolism)
• Male
• Myocardial Contraction (drug effects)
• Myocytes, Cardiac (drug effects, metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Peroxynitrous Acid (metabolism)
• Rats
• Rats, Sprague-Dawley
• Superoxide Dismutase (pharmacology)
• Ventricular Dysfunction (metabolism, physiopathology)
• omega-N-Methylarginine (pharmacology)