Lipopolysaccharides Up-regulate Kir6.1/SUR2B Channel Expression and Enhance Vascular KATP Channel Activity via NF-κB-dependent Signaling

Sepsis is a severe medical condition causing a large number of deaths worldwide. Recent studies indicate that the septic susceptibility is attributable to the vascular ATP-sensitive K+ (K-ATP) channel. However, the mechanisms underlying the channel modulation in sepsis are still unclear. Here we show evidence for the modulation of vascular K-ATP channel by septic pathogen lipopolysaccharides (LPS). In isolated mesenteric arterial rings, phenylephrine (PE) produced concentration-dependent vasoconstriction that was relaxed by pinacidil, a selective K-ATP channel opener. The PE response was disrupted with a LPS treatment. In acutely dissociated aortic smooth myocytes the LPS treatment augmented K-ATP channel activity, and hyperpolarized the cells. Quantitative PCR analysis showed that LPS raised Kir6.1 and SUR2B transcripts in a concentration-dependent manner, which was suppressed by transcriptional inhibition. Consistently, the same LPS treatment did not affect Kir6.1/SUR2B channels in a heterologous expression system. The LPS effect on Kir6.1 and SUR2B expression was abolished in the presence of NF-kappa B inhibitors. Several other Toll-like receptor ligands also stimulated Kir6.1 and SUR2B expression to a similar degree as LPS. Thus, the effect of LPS on vasodilation involves up-regulation of K-ATP channel expression, in which the NF-kappa B-dependent signaling plays an important role.