Nitrite is a positive modulator of the Frank-Starling response in the vertebrate heart

Am J Physiol Regul Integr Comp Physiol. 2012 Jun;302(11):R1271-81. doi: 10.1152/ajpregu.00616.2011. Epub 2012 Apr 4.


Evidence from both mammalian and nonmammalian vertebrates indicates that intracardiac nitric oxide (NO) facilitates myocardial relaxation, ventricular diastolic distensibility, and, consequently, the Frank-Starling response, i.e., the preload-induced increase of cardiac output. Since nitrite ion (NO(2)(-)), the major storage pool of bioactive NO, recently emerged as a cardioprotective endogenous modulator, we explored its influence on the Frank-Starling response in eel, frog, and rat hearts, used as paradigms of fish, amphibians, and mammals, respectively. We demonstrated that, like NO, exogenous nitrite improves the Frank-Starling response in all species, as indicated by an increase of stroke volume and stroke work (eel and frog) and of left ventricular (LV) pressure and LVdP/dt max (rat), used as indexes of inotropism. Unlike in frog and rat, in eel, the positive influence of nitrite appeared to be dependent on NO synthase inhibition. In all species, the effect was sensitive to NO scavengers, independent on nitroxyl anion, and mediated by a cGMP/PKG-dependent pathway. Moreover, the nitrite treatment increased S-nitrosylation of lower-molecular-weight proteins in cytosolic and membrane fractions. These results suggest that nitrite acts as a physiological source of NO, modulating through different species-specific mechanisms, the stretch-induced intrinsic regulation of the vertebrate heart.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anguilla
  • Animals
  • Blotting, Western
  • Cardiac Output / drug effects*
  • Cyclic GMP / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Heart / drug effects
  • Heart / physiology*
  • Male
  • Myocardial Contraction / drug effects*
  • Myocardium / metabolism*
  • Nitric Oxide / metabolism*
  • Nitrites / metabolism
  • Nitrites / pharmacology*
  • Rana esculenta
  • Rats
  • Rats, Wistar
  • Stroke Volume / drug effects*


  • Nitrites
  • Nitric Oxide
  • Cyclic GMP