A reaction between nitric oxide and hydrogen sulfide to generate nitroxyl may be key to activating a biochemical pathway to lower blood pressure and improve heart contraction (Nat. Commun. 2014, DOI: 10.1038/ncomms5381). NO, H2S, and HNO are all long recognized to be important for cardiovascular signaling, with researchers looking for sources of HNO as possible treatments for heart failure. But the biochemical pathways for HNO generation and how it triggers release of a peptide that promotes blood-vessel dilation and heart contraction are largely unknown. A group led by Milos R. Filipović and Peter W. Reeh of Friedrich-Alexander University Erlangen-Nuremberg, in Germany, now finds that NO and H2S react to form HNO, which then oxidizes thiol side chains on a particular ion channel to promote disulfide bridge formation. The changes cause the ion channel to open, which in turn triggers release of the peptide. The chemistry may also play a role in migraines by stimulating the same ion channel in sensory neurons. Filipović also suggests that all physiological effects ascribed to H2S may go through HNO.