title: Ascorbic acid and N-acetyl cysteine prevent uncoupling of nitric oxide synthase and increase tolerance to ischemia/reperfusion injury in diabetic rat heart.
abstract: Oxidative stress may cause a loss of tetrahydrobiopterin (BH4), a co-factor of nitric oxide synthase (NOS), decrease the bioavailability of NO and aggravate ischemia/reperfusion (I/R) injury in diabetic heart. We hypothesized that ascorbic acid (AA) and N-acetyl cysteine (NAC) protect the diabetic heart from I/R injury by increasing BH4/dihydrobiopterin (BH2) ratio and inhibiting uncoupling of NOS. Diabetes mellitus was induced in rats by streptozotocin treatment, and the hearts were isolated and perfused. BH4 and BH4/BH2 ratio decreased in the diabetic heart associated with increased production of superoxide and nitrotyrosine (NT). Treatment with AA or NAC significantly increased BH4/BH2 ratio in the diabetic heart associated with decreased production of superoxide and NT and increased generation of nitrate plus nitrite (NOx). Pre-treatment with AA or NAC before 30 min ischemia followed by 120 min reperfusion improved left ventricular (LV) function and reduced infarct size in the diabetic but not non-diabetic hearts. The NOS inhibitor, L-NAME, inhibited the increase in the generation of superoxide, NT and NOx, but aggravated LV function and increased infarct size in the diabetic heart. L-NAME also abrogated the increase in NOx and improvement of LV function and the infarct size-limiting effect induced by AA or NAC in the diabetic heart. These results suggest that AA and NAC increase BH4/BH2 ratio and prevent NOS uncoupling in the diabetic heart. Resultant increase in the bioavailability of NO renders the diabetic heart toleratant to I/R injury.
authors.affiliation: Second Department of Internal Medicine, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Okazaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shimazu
authors.forename: Kei
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism
chemical_list: D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin; D001205:Ascorbic Acid; D000111:Acetylcysteine