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 (ET A R) during endotoxemia remain unknown. We hypothesized that selective ET A R 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 ET A R 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 dosedependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ET A R blockade. We conclude that ET A R 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.

Enhanced Endothelin A and B Receptor Expression and Receptor-Mediated Vasoconstriction in Rat Mesenteric arteries after Lipopolysaccharide Challenge

“…Despite of the calculated pEC 50 values that might not be reliable owing to lack of response to S6c in the NS group, the markedly increased E Max values indicated the enhanced vasoreactivity to ETR agonists. This is in concern with a previous finding that intraperitoneal injection of a very high dose of LPS (20 mg/kg body weight) for 6 hrs induced pulmonary hypertension in rats [29]. Intraperitoneal administration of LPS could increase the TNF- α production by peritoneal macrophages and hence mediate severe liver damage in pancreatitis rats, leading to development of multiple organ failure [9, 10].…”

Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice

“…The observed leukocytic pan-alveolitis in our model was suppressed to a large extent by highly selective ETA inhibition, following preventive sitaxentan administration, thus highlighting the role of ETA in driving inflammation. This is in apparent contrast with sitaxentan's inefficacy in a rat model of lipopolysaccharide (LPS) administration, which may be explained by the acute (LPS) versus subacute (BLM) time-course of the models [46]. Furthermore, in agreement with our findings, Hocher et al [18] showed that ET-1 overexpression in the lungs of transgenic mice was related to inflammatory cell recruitment (mainly mononuclear cells) around pulmonary arteries, and was associated with pulmonary fibrosis development.…”

Pulmonary embolism and pulmonary hypertension in the setting of negative computed tomography

“…PH involves changes in nitric oxide, endothelin, thromboxane, and prostacyclin pathways, among other possible cellular and biological pathways of pulmonary endothelial dysfunction (20)(21)(22)(23)(24)(25). Proinflammatory signals such as during infection affect these pathways (26).…”