The biological effects of nitric oxide (NO) are in large part mediated by S-nitrosylation of peptides and proteins to produce bioactive S-nitrosothiols (SNOs). 1–3 The observation of abnormal SNO levels in numerous pathophysiological states2 suggests that dysregulation of SNO homeostasis may contribute to disease pathogenesis. For example, the hypotension of human sepsis is accompanied by increases in circulating levels of vasodilatory SNOs. 3 Although such altered SNO levels may simply mirror NO production (eg, induction of inducible NO synthase in sepsis), they may also reflect changes specific to SNO biosynthesis and metabolism. Indeed, mice lacking a SNO-metabolizing enzyme are profoundly hypotensive under anesthesia. 3 Thus, blood pressure is evidently regulated by both synthesis and turnover of SNOs. In this issue of Hypertension, Gandley et al4 extend this paradigm by proposing that a defect in SNO turnover contributes to the hypertension of preeclampsia. In the blood, S-nitrosoalbumin (SNO-albumin) and S-nitrosohemoglobin (SNO-Hb) constitute the major conduits for circulating NO bioactivity. Although both SNOs may influence blood pressure, they operate within distinct signaling circuits. SNO-Hb can be viewed as a principal regulator of SNO homeostasis, adaptively modulating NO chemistry to control NO bioactivity. SNO-Hb is formed by transfer of NO from heme-iron to Cysß93 thiol on T to R structural transition (oxygenation) of the hemoglobin tetramer. 5 SNO-Hb associates with the red blood cell (RBC) membrane via an interaction with the cytoplasmic domain of anion-exchanger 1 protein (CDAE1, Band 3); on deoxygenation (R3T) transfer of the NO group from SNO-Hb to a cysteine thiol within CDAE1 supports export of RBC vasodilatory activity. 6 SNO-Hb thus serves as an O2 sensor and O2-dependent transducer of NO bioactivity. In contrast, it appears that rather than transducing a specific signal, albumin operates as a buffer to maintain NO homeostasis. 7 S-nitrosylation of albumin occurs at Cys347 via reactions—with NO or nitrosothiols—that are favored by design: specifically, both hydrophobic pockets in albumin (NO/O2 coupling) and bound copper (NO/metal redox coupling) may serve to generate nitrosylating species. 8–10 Gandley et al4 make the case that the buffering function of SNO-albumin is impaired in preeclamptic patients, where the thiol of albumin acts as a sink for NO and thus, raises blood pressure. Nudler and colleagues9 have previously demonstrated that albumin can raise blood pressure independently of its oncotic effects: Redistribution of NO, from the tissues into the hydrophobic core of the protein, subserves S-nitrosylation and lowers the steady-state level of vasodilatory NO within the vascular smooth muscle. 9 Accumulating evidence strongly suggests a role of SNO-albumin in mitigating cardiovascular risk. Elevated (2 μmol/L) concentrations of plasma SNOs (of which SNO-albumin is the major constituent) portend adverse cardiovascular outcomes in patients with end-stage renal disease and correlate with elevated blood pressures. 11 Plasma SNOs are also elevated in patients with hypercholesterolemia. 12 Increases in SNO are correlated with an increase in plasma ceruloplasmin, a protein that is known to support SNO synthesis, 13 and with a decline in ascorbate, a compound known to promote SNO degradation. 14 Gandley et al4 proffer compelling evidence that SNO throughput, not level, is the key measure of NO bioactivity in plasma. They observe elevated levels of SNO-albumin in preeclamptic versus normal pregnancy plasma (7 μmol/L versus 2 μmol/L, respectively) and link reduced …