NITRITE CONTRIBUTES TO THE FRANK-STARLING RESPONSE

The heterometric regulation (Frank-Starling response) of the vertebrate heart allows the myocardium to respond to increased filling pressure with a more vigorous contraction of its lengthened fibres, performing more work through augmented stroke volume (SV) and consequent cardiac output. Evidence from both mammalian and non-mammalian vertebrates indicates that intracardiac NO synthase (NOS)-dependent nitric oxide (NO) facilitates myocardial relaxation, ventricular diastolic distensibility and hence the Frank-Starling response (Casadei and Sears, Prog. Biophys. Mol. Biol. 2003; Garofalo et al., Proc. R. Soc. B. 2009). Nitrite ion (NO2-), the major storage pool of bioactive NO and endogenous modulator, has been recently recognized as a cardioprotective principle. We demonstrated that, like NO, exogenous nitrite improves the Frank-Starling response of the isolated and perfused eel, frog and rat hearts, used as paradigms of fish, amphibians and mammals. This is indicated in the eel and frog working hearts by increased SV and Stroke Work and in the Langendorff rat heart preparation by increased Left Ventricular Pressure (LVP) and LVdP/dtmax, all indexes of inotropism. While in frog and rat, the nitrite-increased heterometric response is unaffected by NOS inhibition, in eel it resulted NOS-dependent. In all species, nitrite signalling is cGMP/PKG-dependent and involves an increase of S-nitrosylation of lower molecular weight proteins in cytosolic (frog and rat) and membrane (eel) fractions. In conclusion, the demonstration that in representatives of more than one group of vertebrates nitrite is an important positive heterometric modulator of heart performance provides evidence on its ubiquitous cardiotropic role.