title: Metabolic and functional protection by selective inhibition of nitric oxide synthase 2 during ischemia-reperfusion in isolated perfused hearts.
abstract: BACKGROUND
  Drugs that selectively block nitric oxide synthase (NOS) 2 enzyme activity by inhibiting dimerization of NOS2 monomers have recently been developed.
  
  
  RESULTS
  To investigate whether selective inhibition of NOS2 is cardioprotective, rats were pretreated for 2 days with BBS2, an inhibitor of NOS2 dimerization, at 15 mg/kg SC. Isolated buffer-perfused hearts from treated (n=9) and control (n=7) hearts were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion. NOS2 protein was upregulated in all hearts at the end of ischemia and of reperfusion; NOS2 enzyme activity was 60% lower in hearts from the treated animals. In the treated hearts, the increase in end-diastolic pressure was significantly attenuated at the end of ischemia, and the return of developed pressure at reperfusion was greater (P<0.05). Creatine kinase release at reperfusion was lower in treated hearts than in controls (P=0.02). At the end of ischemia and of reperfusion, myocardial ATP levels were significantly higher in the treated hearts than in controls (P<0.05). In the treated hearts under ischemic conditions, lactate content was higher and the lactate/pyruvate ratio was lower than in controls (P<0.05); GAPDH activity was higher; and G-3-P and aldose reductase activity were lower. At reperfusion, in the treated hearts, there was less histological damage and less apoptosis of cardiac muscle cells.
  
  
  CONCLUSIONS
  Pretreatment with BBS2, a selective inhibitor of NOS2, improves contractile performance, preserves myocardial ATP, and reduces damage and death of cardiac myocytes during ischemia and reperfusion of isolated buffer-perfused rat hearts.
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Yuying C
authors.initials: YC
authors.lastname: Hwang
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liu
authors.forename: Ni Huiping
authors.initials: NH
authors.lastname: Son
authors.forename: Ningsheng
authors.initials: N
authors.lastname: Ma
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
authors.forename: Robert
authors.initials: R
authors.lastname: Sciacca
authors.forename: Arline
authors.initials: A
authors.lastname: Albala
authors.forename: Niloo
authors.initials: N
authors.lastname: Edwards
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Szabolcs
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cannon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003402:Creatine Kinase / Q000378:metabolism; D052283:Creatine Kinase, MM Form; D019281:Dimerization; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011292:Premedication; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; C487929:N-((1,3-benzodioxol-5-yl)methyl)-1-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)-4-(methoxycarbonyl)piperazine-2-acetamide; D010879:Piperazines; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form