Evidence Mounts That Nitrite Contributes to Hypoxic Vasodilation in the Human Circulation

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Hypoxic vasodilation is a conserved physiological response to hypoxia that matches blood flow and oxygen delivery to tissue metabolic demand. This fundamental physiological process has been characterized for >100 years since the initial description by Roy and Brown1 in 1880. Hypoxic vasodilation requires a sensor mechanism that can detect a divergence in the normal relationship between delivered blood oxygen and tissue oxygen consumption.2 This hypoxic sensor mechanism must be coupled to the feedback generation of vasodilatory effectors that increase blood flow to maintain adequate tissue oxygenation. In short, hypoxic vasodilation requires hypoxia and/or pH sensing coupled to the release of a vasodilating signal. In mammalian species, the set point for hypoxic vasodilation occurs as the hemoglobin desaturates from 60% to 40%, around a partial pressure of oxygen ranging from 40 to 20 mm Hg.3 Despite the fact that the hypoxic vasodilation response was discovered almost 150 years ago, the identities of the oxygen sensor mechanism and the specific feedback vasodilator effectors remain uncertain. Although a number of mediators have been considered, including adenosine, nitric oxide (NO), ATP-sensitive potassium (KATP) channels, endothelium-derived hyperpolarizing factor (candidates include CO, H2O2, or ONOO−), and prostacyclin,2,4 the specific blockade of many of these pathways fails to completely inhibit hypoxic vasodilation.2 Article p 670 The present study published by Maher and colleagues5 in this issue of Circulation provides compelling evidence in normal human volunteers that the circulating anion salt nitrite (NO2−) may be an effector of hypoxic vasodilation. They report that nitrite potently vasodilates the venous forearm circulation under resting conditions and potently vasodilates the arteriolar circulation during experimental hypoxia, achieved by systemic breathing of 11% oxygen. Their studies indicate that the vasodilatory effect of nitrite is maximal in the deoxygenated venous …