Hypertensive pulmonary edema often occurs acutely and is typically associated with normal left ventricular performance. Factors other than simple Starling forces may contribute to the molecular mechanisms by which increased blood pressure leads to acute endothelial barrier failure and lung edema.MethodsTo mimic an adrenergically‐mediated hypertensive crisis, we administered norepinephrine (NE) to rats and assessed indices of edema development. Rats were anesthetized with isoflurane and mechanically‐ventilated; subjects received an infusion of NE to target a MAP = 150mmHg. Lung wet/dry ratio, ΔPaO2, plasma hematocrit, lung MPO activity, BAL protein and cell analysis were assessed. Inhibition of nitric oxide synthase (NOS) by L‐NAME was used to test the contribution of endothelial mechanotransduction on changes in permeability. In parallel studies, rat lung microvascular endothelial cells were stimulated with norepinephrine in the presence or absence of propranolol (10−5M, β‐adrenoceptor antagonist), phentolamine (10−5M, α‐adrenoceptor antagonist), PP2 (10−5M, Src inhibitor), apocynin (3×10−5M, ROS scavenger), or L‐NIO (10−4M, NOS inhibitor). Reactive oxygen species (ROS) production was determined by DHE fluorescence. Albumin uptake was assessed by ELISA and albumin transport was measured by fluorimetry.ResultsNE‐treated rats had a decrease in PaO2, an increase in lung albumin content, MPO activity and wet/dry ratio. BAL fluid had increased protein content and number of macrophages indicative of inflammation. L‐NAME significantly attenuated NE‐induced pulmonary edema. In vitro, albumin uptake and transport was increased by NE in a time‐dependent manner. ROS production was augmented by NE. Phentolamine, PP2 and apocynin decreased NE‐induced albumin uptake and ROS generation, effects not altered by L‐NIO.SummaryWe describe a novel pathway whereby norepinephrine stimulates albumin uptake and potentially endothelial permeability which might be important in hypertensive pulmonary edema.Support or Funding InformationDepartment of Anesthesiology, University of Illinois at Chicago