Nitrite exerts potent negative inotropy in the isolated heart via eNOS-independent nitric oxide generation, cGMP-PKG pathway activation and inhibition of mitochondrial respiration

The ubiquitous anion nitrite (NO2−) has recently emerged as an endocrine storage form of nitric oxide (NO)and a signalling molecule that mediates a number of biological responses. Although the role of NO inregulating cardiac function has been investigated in depth, the physiological signalling effects of nitrite oncardiac function have only recently been explored. We now show that remarkably low concentrations ofnitrite (1 nM) significantly modulate cardiac contractility in isolated and perfused Langendorff rat heart. Inparticular, nitrite exhibits potent negative inotropic and lusitropic activities as evidenced by a decrease in leftventricular pressure and relaxation, respectively. Furthermore, we demonstrate that the nitrite-dependenteffects are mediated by NO formation but independent of NO synthase (NOS) activity. Specifically, nitriteinfusion in the Langendorff system produces NO and cGMP/PKG-dependent negative inotropism, asevidenced by the formation of cellular iron–nitrosyl complexes and inhibition of biological effect by NOscavengers and by PKG inhibitors. These data are consistent with the hypothesis that nitrite represents aneNOS-independent source of NO in the heart which modulates cardiac contractility through the NO–cGMP/PKG pathway. The observed high potency of nitrite supports a physiological function of nitrite as a source ofcardiomyocyte NO and a fundamental signalling molecule in the heart.