The Scavenging Illusion: Why Thirty Years of Clinical iNO Dosing Reflects Scavenging Burden, Not Receptor-Activation Calibration

Abstract Background: Three decades of inhaled nitric oxide (iNO) dose-response data have been generated almost entirely in populations with elevated cell-free hemoglobin, elevated plasma NO consumption, and disrupted erythrocyte compartmentalization: acute respiratory distress syndrome (ARDS), sepsis, and cardiopulmonary bypass (CPB). Persistent pulmonary hypertension of the newborn (PPHN) is included as a provisional extension: scavenging burden in this population is inferred from perinatal oxidative and hemolytic pathophysiology rather than direct plasma measurement. Plasma hemoglobin scavenges NO 100 to 1,000-fold faster than intra-erythrocytic hemoglobin. The pulmonary NO receptor, soluble guanylate cyclase (sGC), binds NO with picomolar affinity and activates at sub-nanomolar to low-nanomolar concentrations in vascular smooth muscle.Synthesis: Integrating these facts yields a structural argument: clinical iNO dose-response curves were generated almost exclusively in scavenging-elevated populations and are therefore calibrated to the scavenging burden of those populations, not to the intrinsic activation threshold of sGC. They are scavenging-compensation curves, not receptor-activation calibration curves, and the field has read them as if they were the latter. Predictions: From this reframing I derive five predictions: (1) iNO dose-response should be steeper in clean-corridor populations than in ARDS or sepsis; (2) the magnitude of endogenous nasal NO-mediated pulmonary effects should vary inversely with scavenging burden; (3) iNO non-responder variability should track scavenging-environment severity; (4) re-stratifying existing iNO trial data by cell-free hemoglobin-related covariates should reveal leftward dose-response shifts in low-scavenging subgroups; (5) plasma NO consumption rate, measured directly by reductive chemiluminescence, should predict iNO dose-response threshold more accurately than cell-free hemoglobin concentration alone (Dony 2023). Contribution: The components of this synthesis are established in the prior literature; the integration is, to my knowledge, unstated. An extensive literature search conducted in May 2026 across PubMed, Semantic Scholar, Consensus, Scite, and Scholar Gateway identified no prior paper explicitly assembling these four nodes, erythrocyte compartmentalization kinetics, sGC receptor pharmacology, the scavenging-calibrated provenance of the clinical iNO dose-response record, and direct plasma NO consumption measurement as the operative scavenging variable, into a unified reframing of clinical iNO dosing as scavenging-compensation rather than receptor-activation calibration. Specifically, the synthesis links direct plasma NO consumption measurement to sGC receptor pharmacology and predicts that plasma NO consumption should outperform cell-free hemoglobin concentration alone in stratifying iNO dose-response thresholds.