© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
The molecular site of action of KATP channel inhibitors determines their ability to inhibit iNOS-mediated relaxation in rat aorta
Centre for Clinical Pharmacology and Therapeutics, Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK
* Corresponding author. Tel.: +44-20-7679-6203; fax: +44-20-7691-2838 andrew.wilson{at}ucl.ac.uk
This work has previously been presented at the British Pharmacological Society Autumn and Winter Meetings, 2001.
Objective: ATP-sensitive potassium (KATP) channels are important modulators of vascular tone. Abnormal activation of these channels via over production of nitric oxide (NO) has been implicated in endotoxin-induced hypotension. However, based on studies with the sulphonylurea KATP channel inhibitor, glibenclamide, there is little evidence to support their role in mediating vasorelaxation to endotoxin in isolated blood vessels. In the present study, we investigated whether NO derived from inducible NO synthase (iNOS) modulates KATP channel function in rat aorta. Methods: Using standard organ bath techniques, the effects of structurally unrelated KATP channel inhibitors on the vasorelaxant responses to L-arginine (iNOS substrate), NO, levcromakalim (KATP channel opener) and forskolin were investigated in endothelium-denuded aortic rings exposed to endotoxin (lipopolysaccharide) for 4 h. Results: Relaxation evoked by L-arginine was unaffected by glibenclamide and the pinacidil-derived inhibitor, PNU-99963, but was significantly attenuated by the iNOS inhibitor, 1400W, as well as by PNU-37883A, Ba2+, 4-aminopyridine and tetraethylammonium, all known inhibitors of the KATP channel pore. In addition, endotoxin potentiated responses to levcromakalim and markedly reduced the efficacy of glibenclamide, and to a much lesser extent, PNU-37883A. Forskolin responses were unaffected by glibenclamide or PNU-37883A under control conditions, but were significantly potentiated following endotoxin treatment, an effect reversed by PNU-37883A, but not glibenclamide. Conclusion: KATP channels contribute to iNOS-mediated relaxation. However, the ability of sulphonylurea receptor-binding agents, but not those binding directly to the pore, to inhibit KATP channels, is greatly diminished in the presence of endotoxin.
KEYWORDS Endotoxins; K-ATP channel; Nitric oxide; Smooth muscle
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