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The pore-forming subunit of the K-ATP channel is an important molecular target for LPS-induced vascular hyporeactivity in vitro

O'Brien, AJ; Thakur, G; Buckley, JF; Singer, M; Clapp, LH; (2005) The pore-forming subunit of the K-ATP channel is an important molecular target for LPS-induced vascular hyporeactivity in vitro. BRIT J PHARMACOL , 144 (3) 367 - 375. 10.1038/sj.bjp.0706065. Gold open access

Abstract

1 ATP-sensitive K+ (K-ATP) 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 K-ATP channel pore could be effective.2 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.3 The pore-forming subunit inhibitors barium chloride (BaCl2; 300 muM) and PNU-37883A (1 muM) significantly reversed hyporeactivity at both time points, although less so at 20 h. In contrast, the SUR inhibitors, Glib (10 muM), tolbutamide (Tolb) (1 mM) and PNU-99963 (1 muM) were ineffective. In LPS-incubated tissues, Glib and Tolb antagonised contractions to the thromboxane A(2) mimetic, U46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F-2alpha) (10(-7) M), whereas the pinacidil-derived inhibitor, PNU-99963, did not.4 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.5 The inducible nitric oxide synthase ( iNOS) inhibitor, 1400 W (10 muM) and Tolb inhibited the production of nitrite induced by LPS, whereas BaCl2 and PNU-37883A had no effect.6 In conclusion, K-ATP 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 K-ATP channel suggests altered SUR function following LPS administration, which cannot be explained by thromboxane receptor inhibition.

Type: Article
Title: The pore-forming subunit of the K-ATP channel is an important molecular target for LPS-induced vascular hyporeactivity in vitro
Open access status: An open access publication
DOI: 10.1038/sj.bjp.0706065
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC15760...
Keywords: vascular hyporeactivity, endotoxin, K-ATP channel, phenylephrine, organ culture, nitric oxide, mesenteric artery, NITRIC-OXIDE SYNTHASE, SENSITIVE POTASSIUM CHANNELS, RAT AORTA, PHARMACOLOGICAL CHARACTERIZATION, ORGAN-CULTURE, SMOOTH-MUSCLE, L-ARGININE, ABNORMAL ACTIVATION, MESENTERIC-ARTERY, ENDOTOXIC-SHOCK
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Internal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Metabolism and Experi Therapeutics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: http://discovery.ucl.ac.uk/id/eprint/132867
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