Premium
The pore‐forming subunit of the K ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro
Author(s) -
O'Brien Alastair J,
Thakur Gita,
Buckley James F,
Singer Mervyn,
Clapp Lucie H
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706065
Subject(s) - glibenclamide , phenylephrine , chemistry , pharmacology , nitric oxide synthase , yohimbine , vascular smooth muscle , thromboxane a2 , nitric oxide , mesenteric arteries , prostaglandin , biophysics , antagonist , endocrinology , medicine , biochemistry , receptor , biology , artery , smooth muscle , blood pressure , diabetes mellitus
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 K ATP channel inhibitors. 3 The pore‐forming subunit inhibitors barium chloride (BaCl 2 ; 300 μ M ) and PNU‐37883A (1 μ M ) significantly reversed hyporeactivity at both time points, although less so at 20 h. In contrast, the SUR inhibitors, Glib (10 μ M ), tolbutamide (Tolb) (1 m M ) and PNU‐99963 (1 μ M ) were ineffective. In LPS‐incubated tissues, Glib and Tolb antagonised contractions to the thromboxane A2 mimetic, U46619 (9,11‐dideoxy‐9 α , 11 α ‐methanoepoxy prostaglandin F 2 α ) (10 −7 M ), whereas the pinacidil‐derived inhibitor, PNU‐99963, did not. 4 Contractions to 60 m M 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 μ M ) and Tolb inhibited the production of nitrite induced by LPS, whereas BaCl 2 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.British Journal of Pharmacology (2005) 144 , 367–375. doi: 10.1038/sj.bjp.0706065