Key result
SB-710411 prevents hypotension and tissue injury in LPS or RIPC rat models but fails combined.
Why the study?
Blockade of the urotensin II receptor confers protective effects against endotoxic shock or remote ischemic preconditioning, prompting investigation into whether the selective antagonist SB-710411 protects against remote ischemic preconditioning in endotoxic shock.
The selective urotensin II receptor antagonist SB-710411 protects against cardiovascular deterioration and inflammatory injury in LPS-induced endotoxic shock or RIPC in rats, though not in the combined RIPC/LPS model.
Hypothesis-generating for UT antagonism in endotoxic shock; leaves open translation to human sepsis.
BACKGROUND: Blockade of the urotensin II receptor (UT; G protein-coupled receptor [GPR]14) has been reported to confer protective effects against impaired cardiovascular response, inflammatory tissue injury, and mortality induced by lipopolysaccharide (LPS)-induced endotoxic shock or remote ischemic preconditioning (RIPC). This study aimed to test the hypothesis that SB-710411, a selective UT antagonist, has a protective effect on RIPC in a rat model of LPS-induced endotoxic shock. METHODS: The endotoxic shock model was established by injecting LPS into rats. RIPC was induced with three 10-minute ischemia/10-minute reperfusion cycles of both hind limbs of rats using tourniquets before saline or LPS injection. The rats were treated with SB-710411 (0.01 mg/kg) 1 hour after saline or LPS injection. The mean arterial pressure and heart rate values of the rats were measured during the experiments. RESULTS: SB-710411 prevented hypotensive and tachycardic responses to LPS or RIPC, but not to the RIPC/LPS. While RIPC ameliorated LPS-induced hypotension, but not tachycardia, it also caused a 33% mortality rate. The increase in the expression/activity of U-II, GPR14, nuclear factor-κB, inducible nitric oxide (NO) synthase, vasodilator-stimulated phosphoprotein, gp91 phox, p47 phox, 3-nitrotyrosine, and IL-1β as well as the decrease in endothelial NO synthase expression/activity in the arterial, cardiac, renal, pulmonary, and/or cerebral tissues of endotoxemic rats was prevented by SB-710411. SB-710411 also attenuated the elevation in scores for histopathological changes induced by LPS or RIPC/LPS in the heart, as well as LPS in the lung and brain. CONCLUSION: Our findings revealed that SB-710411 prevents deterioration of cardiovascular response and inflammatory tissue injury in rat models of LPS-induced endotoxic shock or RIPC, but not that of RIPC/LPS. It also seems that RIPC does not confer protection against LPS-induced endotoxic shock.
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Dıdanı et al. (2026) studied LPS-induced endotoxic shock. SB-710411 vs. Saline or LPS alone was evaluated on Cardiovascular response, inflammatory tissue injury, and survival. SB-710411 prevented hypotensive and tachycardic responses and inflammatory tissue injury in rat models of LPS-induced endotoxic shock or RIPC, but not in the combined RIPC/LPS model.
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