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INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a peroxynitrite decomposition catalyst, protects the heart against reperfusion injury in mice.

Abstract
Oxidative/nitrative stress caused by peroxynitrite, the reaction product of superoxide (O2(.-)) and nitric oxide (NO), is the primary cause of myocardial ischemia/reperfusion injury. The present study determined whether INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a new peroxynitrite decomposition catalyst, may provide cellular protection and protect heart from myocardial ischemia/reperfusion injury. Adult male mice were subjected to 30 min of ischemia and 3 or 24 h of reperfusion. Mice were randomized to receive vehicle, INO-4885 without catalytic moiety, or INO-4885 (3-300 microg/kg i.p.) 10 min before reperfusion. Infarct size, apoptosis, nitrotyrosine content, NO/O2(.-) production, and inducible nitric-oxide synthase (iNOS)/NADPH oxidase expression were determined. INO-4885 treatment reduced ischemia/reperfusion-induced protein nitration and caspase 3 activation in a dose-dependent fashion in the range of 3 to 100 microg/kg. However, doses exceeding 100 microg/kg produced nonspecific effects and attenuated its protective ability. At the optimal dose (30 microg/kg), INO-4885 significantly reduced infarct size (p < 0.01), decreased apoptosis (p < 0.01), and reduced tissue nitrotyrosine content (p < 0.01). As expected, INO-4885 had no effect on ischemia/reperfusion-induced iNOS expression and NO overproduction. To our surprise, this compound significantly reduced superoxide production and partially blocked NADPH oxidase overexpression in the ischemic/reperfused cardiac tissue. Additional experiments demonstrated that INO-4885 provided better cardioprotection than N-(3-(aminomethyl)benzyl)acetamidine (1400W, a selective iNOS inhibitor), apocynin (an NADPH oxidase inhibitor), or Tiron (a cell-permeable superoxide scavenger). Taken together, our data demonstrated that INO-4885 is a cardioprotective molecule that attenuates myocardial reperfusion injury by facilitating peroxynitrite decomposition and inhibiting NADPH oxidase-derived O2(.-) production.
AuthorsXiang-Ying Jiao, Erhe Gao, Yuexin Yuan, Yajing Wang, Wayne Bond Lau, Walter Koch, Xin-Liang Ma, Ling Tao
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 328 Issue 3 Pg. 777-84 (Mar 2009) ISSN: 1521-0103 [Electronic] United States
PMID19033557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • (5,10,15,20-tetrakis(N-(benzyl-4'-carboxylate)-2-pyridinium)-21H,23H-porphine)iron(III)
  • Metalloporphyrins
  • Peroxynitrous Acid
  • Nitric Oxide Synthase Type II
  • NADPH Oxidase
  • Caspase 3
Topics
  • Animals
  • Apoptosis (drug effects)
  • Caspase 3 (metabolism)
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Heart (drug effects, physiology, physiopathology)
  • Male
  • Metalloporphyrins (therapeutic use)
  • Mice
  • Myocardial Infarction (prevention & control)
  • NADPH Oxidase (drug effects, genetics)
  • Nitric Oxide Synthase Type II (drug effects, genetics)
  • Oxidative Stress (drug effects, physiology)
  • Peroxynitrous Acid (therapeutic use)
  • Reperfusion Injury (prevention & control)

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