Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts

Am J Physiol. 1999 Jun;276(6):H1861-7. doi: 10.1152/ajpheart.1999.276.6.H1861.


We examined the mechanism of the time- and protein synthesis-dependent decline in cardiac mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer for 120 min in the presence or absence of the protein synthesis inhibitor cycloheximide (CX; 10 microM). Cardiac work remained stable for 60 min and then spontaneously decreased during 60-120 min of perfusion. This was accompanied by an increase in myocardial inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) activities and enhanced dityrosine formation in the perfusate, an indicator of peroxynitrite generation. CX markedly attenuated the loss in contractile function and prevented the increase in iNOS and XO activities and dityrosine level. Despite the decline in cardiac work in control hearts, the coupling between tricarboxylic acid (TCA) cycle activity and oxygen consumption remained constant in both groups. ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion. We concluded that the delayed and spontaneous loss in myocardial mechanical function in isolated working rat hearts is 1) attenuated by CX treatment, 2) accompanied by a concomitant increase in both iNOS and XO activities and peroxynitrite generation in the heart, and 3) not dependent on a direct impairment in myocardial ATP production, myocardial oxygen consumption, or TCA cycle acetyl-CoA production but may be due to an inefficiency of the heart to utilize ATP for contractile work.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cycloheximide / pharmacology
  • Energy Metabolism / physiology
  • Heart / drug effects
  • Heart / physiopathology*
  • In Vitro Techniques
  • Male
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Nitrates / metabolism
  • Nitrates / physiology*
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Protein Synthesis Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Xanthine Dehydrogenase / metabolism
  • Xanthine Oxidase / metabolism


  • Nitrates
  • Protein Synthesis Inhibitors
  • peroxynitric acid
  • Cycloheximide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Xanthine Dehydrogenase
  • Xanthine Oxidase