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Endothelin-A Receptor Blockade Attenuates Endotoxin-Induced Pulmonary Hypertension without Affecting Blood Pressure and Oxygenation

B Toney

A. J. Fisher

Robert Presson

I Petrache

Tim Lahm


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

BACKGROUND: Endothelin (ET)-1 is a potent vasoconstrictor and pro-inflammatory mediator of sepsis-induced pulmonary hypertension (PH). We have shown that selective ET(A)-receptor blockade using sitaxsentan improves vasoreactivity in isolated pulmonary artery (PA) rings from endotoxemic rats. However, the effects of selective ET(A)-receptor blockade on pulmonary and systemic hemodynamics, as well as parameters of acute lung injury (ALI) during lipopolysaccharide (LPS)-induced endotoxemia are unknown. We hypothesized that sitaxsentan attenuates endotoxin-induced PH without negatively affecting blood pressure and oxygenation. To test our hypothesis, we assessed cardiopulmonary hemodynamics, PA cytokine transcripts, as well as markers of oxygenation, acidosis, and ALI in a rat model of LPS-induced endotoxemia.

METHODS: Adult male Sprague Dawley rats (250-500 g) received LPS (S. typhimurium, 20 mg/kg intraperitoneally) or its vehicle (saline, 1 ml) 6h before hemodynamic assessment and tissue harvest. Sitaxsentan (10 mg/kg) or vehicle (1 ml saline) was injected intravenously 3h after LPS. Rats underwent assessment of right ventricular systolic pressure (RVSP; via 2F Millar catheter). Systemic hemodynamics were assessed using a carotid artery catheter for mean arterial pressure (MAP) measurement, and aortic flow probe (Transonic) for cardiac output (CO) determination. Arterial blood analysis was performed to measure oxygenation (P/F ratio) and serum bicarbonate. Full lung bronchioalveolar lavage (BAL) and lung wet-to-dry ratios were obtained at the conclusion of hemodynamic monitoring. BAL cell differentials were assessed via manual cell counting. IL-1β, IL-6, TNF-α, and iNOS mRNA was measured in harvested PAs. p<0.05 was considered statistically significant. Values are means±SEM.

RESULTS: LPS administration induced a septic phenotype (indicated by a statistically significant decrease in MAP, CO and serum bicarbonate), as well as PH (evidenced by increase in RVSP/MAP from 0.324±0.004 to 0.685±0.052). Interestingly, sitaxsentan significantly attenuated sepsis-induced PH (RVSP/MAP 0.361±0.03). These changes were not associated with a decrease in MAP or P/F ratio. On the contrary, sitaxsentan tended to increase MAP (74±8.8 for sitaxsentan vs 53±3.7 mmHg for LPS), indicating that its administration during experimental endotoxemia is safe and well-tolerated. LPS increased IL-1β, IL-6, TNF-α, and iNOS mRNA. Interestingly, there was a trend for sitaxsentan to attenuate the LPS-induced increase in IL-6 and TNF-α mRNA. Serum bicarbonate, though decreased by LPS, was unaffected by sitaxsentan. BAL cell counts or wet-to-dry ratios were neither affected by LPS nor by sitaxsentan, suggesting lack of significant ALI in our model.

CONCLUSIONS: Sitaxsentan treatment attenuates endotoxin-induced PH without negatively affecting systemic blood pressure or oxygenation, suggesting lack of systemic vasodilation or increase in ventilation/perfusion mismatch. Sitaxsentan’s effect does not appear to be mediated by attenuation of sepsis-induced acidosis, nor by attenuation of ALI, but may be mediated at least in part by anti-inflammatory effects in the PA. While ET-1 signaling may become a useful therapeutic target for the pulmonary vascular complications of sepsis, further investigations elucidating the mechanism in the pulmonary vasculature are currently ongoing in our laboratory.

FUNDING: Investigator-initiated research grant from Pfizer, Inc.; Indiana University Department of Medicine; Richard L. Roudebush VA Medical Center