title: Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans.
abstract: Nitric oxide (NO) is crucial for the microvascular homeostasis, but its role played in the microvascular alterations during sepsis remains controversial. We investigated NO-dependent vasodilation in the skin microcirculation and plasma levels of asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of the NO synthases, in a human model of sepsis. In this double-blind, randomized, crossover study, microvascular NO-dependent (local thermal hyperemia) and NO-independent vasodilation (post-occlusive reactive hyperemia) assessed by laser Doppler imaging, plasma levels of ADMA, and l-arginine were measured in seven healthy obese volunteers, immediately before and 4 h after either a i.v. bolus injection of Escherichia coli endotoxin (LPS; 2 ng/kg) or normal saline (placebo) on two different visits at least 2 weeks apart. LPS caused the expected systemic effects, including increases in heart rate (+43%, P < 0.001), cardiac output (+16%, P < 0.01), and rectal temperature (+1.4°C, P < 0.001), without change in arterial blood pressure. LPS affected neither baseline skin blood flow nor post-occlusive reactive hyperemia but decreased the NO-dependent local thermal hyperemia response, l-arginine, and, to a lesser extent, ADMA plasma levels. The changes in NO-dependent vasodilation were not correlated with the corresponding changes in the plasma levels of ADMA, l-arginine, or the l-arginine/ADMA ratio. Our results show for the first time that experimental endotoxemia in humans causes a specific decrease in endothelial NO-dependent vasodilation in the microcirculation, which cannot be explained by a change in ADMA levels. Microvascular NO deficiency might be responsible for the heterogeneity of tissue perfusion observed in sepsis and could be a therapeutic target.
authors.affiliation: Division of Clinical Pathophysiology, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, Switzerland.
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Engelberger
authors.forename: Yann K
authors.initials: YK
authors.lastname: Pittet
authors.forename: Hugues
authors.initials: H
authors.lastname: Henry
authors.forename: Frederik
authors.initials: F
authors.lastname: Delodder
authors.forename: Daniel
authors.initials: D
authors.lastname: Hayoz
authors.forename: René L
authors.initials: RL
authors.lastname: Chioléro
authors.forename: Bernard
authors.initials: B
authors.lastname: Waeber
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Mette M
authors.initials: MM
authors.lastname: Berger
authors.forename: François
authors.initials: F
authors.lastname: Feihl
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
chemical_list: D004731:Endotoxins; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli