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Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control^,,,. Hydrogen peroxide (H₂O₂) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans^,,,,,. H₂O₂ causes the formation of a disulfide bond between the two α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO …