title: The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts.
abstract: OBJECTIVE
  Nitric oxide (NO) is known to act as a mediator of tissue injury as well as being a potent endogenous vasodilator. The functional and metabolic effects of NO on ischemia-reperfusion injury are still controversial. The aim of this study was to clarify the relationship between the degree of NO synthase (NOS) inhibition and the effects on ischemia-reperfusion injury.
  
  
  RESULTS
  Langendorff-perfused rat hearts were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP), creatine kinase (CK) release, and myocardial high energy phosphates were measured in hearts perfused with or without NOS inhibitors, L-N(G)-monomethyl arginine (L-NMMA) or N(G)nitro-L-arginine methylester (L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial adenosine triphosphate content after reperfusion. In contrast, the high dose of L-NMMA had adverse effects. L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of L-NMMA were abolished by excessive co-administration of L-arginine and the same doses of D-N(G)-monomethyl arginine (D-NMMA) showed no effect on ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition, L-NMMA suppressed the myocardial malondialdehyde accumulation, an indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose L-NMMA significantly decreased coronary fl ow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress.
  
  
  CONCLUSIONS
  The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the ischemia-reperfusion injury.
authors.affiliation: Second Dept. of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Takeda
authors.forename: Akiko
authors.initials: A
authors.lastname: Mano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Jun
authors.initials: J
authors.lastname: Shiraishi
authors.forename: Natsuya
authors.initials: N
authors.lastname: Keira
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Jun
authors.initials: J
authors.lastname: Asayama
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
mesh_terms: D000227:Adenine Nucleotides / Q000032:analysis; D000818:Animals; D003401:Creatine / Q000032:analysis; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000032:analysis; D006003:Glycogen / Q000032:analysis; D006321:Heart / Q000187:drug effects; D019344:Lactic Acid / Q000032:analysis; D008315:Malondialdehyde / Q000032:analysis; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012107:Research Design; D016277:Ventricular Function, Left / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000227:Adenine Nucleotides; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D019344:Lactic Acid; D008315:Malondialdehyde; D006003:Glycogen; D019001:Nitric Oxide Synthase; D003402:Creatine Kinase; D005947:Glucose; D003401:Creatine; D019331:NG-Nitroarginine Methyl Ester