title: Selective endothelin-A receptor blockade attenuates endotoxin-induced pulmonary hypertension and pulmonary vascular dysfunction.
abstract: Endothelin-1 is a potent mediator of sepsis-induced pulmonary hypertension (PH). The pulmonary vascular effects of selective blockade of endothelin receptor subtype A (ETAR) during endotoxemia remain unknown. We hypothesized that selective ETAR antagonism attenuates endotoxin-induced PH and improves pulmonary artery (PA) vasoreactivity. Adult male Sprague-Dawley rats (250-450 g) received lipopolysaccharide (LPS; Salmonella typhimurium; 20 mg/kg intraperitoneally) or vehicle 6 hours before hemodynamic assessment and tissue harvest. The selective ETAR antagonist sitaxsentan (10 or 20 mg/kg) or vehicle was injected intravenously 3 hours after receipt of LPS. Right ventricular systolic pressure, mean arterial pressure (MAP), cardiac output (CO), oxygenation (P/F ratio), and serum bicarbonate were measured. Bronchoalveolar lavage (BAL) cell differential and lung wet-to-dry ratios were obtained. Endothelium-dependent and endothelium-independent vasorelaxations were determined in isolated PA rings. PA interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) were measured. LPS caused PH, decreased MAP, CO, and serum bicarbonate, and increased PA IL-1β, IL-6, TNF-α, and iNOS mRNA. Sitaxsentan attenuated sepsis-induced PH and increased MAP. The P/F ratio, CO, serum bicarbonate, and BAL neutrophilia were not affected by sitaxsentan. In isolated PA rings, while not affecting phenylephrine-induced vasocontraction or endothelium-dependent relaxation, sitaxsentan dose-dependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ETAR blockade. We conclude that ETAR blockade attenuates endotoxin-induced alterations in systemic and PA pressures without negatively affecting oxygenation. This protective effect appears to be mediated not by attenuation of sepsis-induced cardiac dysfunction, acidosis, or alveolar inflammation but rather by improved endothelium-independent vasorelaxation.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Brent M
authors.initials: BM
authors.lastname: Toney
authors.affiliation: Department of Anesthesiology, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fisher
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Albrecht
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Angelia D
authors.initials: AD
authors.lastname: Lockett
authors.affiliation: Department of Anesthesiology, Indiana University, Indianapolis, Indiana, USA ; Center for Immunobiology, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Presson
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University, Indianapolis, Indiana, USA ; Center for Immunobiology, Indiana University, Indianapolis, Indiana, USA ; Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University, Indianapolis, Indiana, USA ; Center for Immunobiology, Indiana University, Indianapolis, Indiana, USA ; Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
keywords: cytokines; endothelium; sepsis; sitaxsentan; vasoreactivity