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.