EFFECTS OF THE UROTENSIN-II RECEPTOR ANTAGONIST SB-710411 ON REMOTE ISCHEMIC PRECONDITIONING IN A RAT MODEL OF LPS-INDUCED ENDOTOXIC SHOCK: CARDIOVASCULAR RESPONSE, INFLAMMATORY INJURY, AND SURVIVAL.

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.