The pore-forming subunit of the KATP channel is an important molecular target for LPS-induced vascular hyporeactivityin vitro


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Abstract

ATP-sensitive K+ (KATP) channel activation is implicated in the vascular hyporeactivity occurring in septic shock. However, channel inhibition with the sulphonylurea receptor (SUR) antagonist, glibenclamide (Glib) fails to reverse lipopolysaccharide (LPS)-induced vascular hyporeactivity in vitro. We investigated whether inhibitors that act by binding to the KATP channel pore could be effective.Ring segments of endothelium-intact rat mesenteric artery were incubated with LPS in culture media for either 6 or 20 h before contractile responses to phenylephrine were assessed in the absence or presence of KATP channel inhibitors.The pore-forming subunit inhibitors barium chloride (BaCl2; 300 μM) and PNU-37883A (1 μM) significantly reversed hyporeactivity at both time points, although less so at 20 h. In contrast, the SUR inhibitors, Glib (10 μM), tolbutamide (Tolb) (1 mM) and PNU-99963 (1 μM) were ineffective. In LPS-incubated tissues, Glib and Tolb antagonised contractions to the thromboxane A2 mimetic, U46619 (9,11-dideoxy-9α, 11α-methanoepoxy prostaglandin F2α) (10−7 M), whereas the pinacidil-derived inhibitor, PNU-99963, did not.Contractions to 60 mM KCl were unaffected by LPS at 6 h, but were significantly depressed by LPS at 20 h, suggesting that K+-channel-independent pathways contribute to hyporeactivity at the later time point.The inducible nitric oxide synthase (iNOS) inhibitor, 1400 W (10 μM) and Tolb inhibited the production of nitrite induced by LPS, whereas BaCl2 and PNU-37883A had no effect.In conclusion, KATP channels contribute to LPS-induced vascular hyporeactivity via the iNOS pathway in rat mesenteric artery. The effectiveness of pore inhibitors over SUR inhibitors of the KATP channel suggests altered SUR function following LPS administration, which cannot be explained by thromboxane receptor inhibition.British Journal of Pharmacology (2005) 144, 367–375. doi:10.1038/sj.bjp.0706065

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