on May 12, 2003
Published online before print May 12, 2003, doi: 10.1161/01.HYP.0000072010.54901.DE
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Submitted on January 2, 2003
From the Department of Pharmacology, Monash University, Melbourne, Victoria, Australia. * To whom correspondence should be addressed. E-mail: barbara.kemp{at}med.monash.edu.au.
Abstract--Nitric oxide (NO) plays an important role in the control of vascular tone. Traditionally, its vasorelaxant activity has been attributed to the free radical form of NO (NO•), yet the reduced form of NO (NO-) is also produced endogenously and is a potent vasodilator of large conduit arteries. The effects of NO- in the resistance vasculature remain unknown. This study examines the activity of NO- in rat small isolated mesenteric resistance-like arteries and characterizes its mechanism(s) of action. With the use of standard myographic techniques, the vasorelaxant properties of NO• (NO gas solution), NO- (Angeli's salt), and the NO donor sodium nitroprusside were compared. Relaxation responses to Angeli's salt (pEC50=7.51±0.13, Rmax=95.5±1.5%) were unchanged in the presence of carboxy-PTIO (NO• scavenger) but those to NO• and sodium nitroprusside were inhibited. L-Cysteine (NO- scavenger) decreased the sensitivity to Angeli's salt (P<0.01) and sodium nitroprusside (P<0.01) but not to NO•. The soluble guanylate cyclase inhibitor ODQ (3 and 10 µmol/L) concentration-dependently inhibited relaxation responses to Angeli's salt (41.0±6.0% versus control 93.4±1.9% at 10 µmol/L). The voltage-dependent K+ channel inhibitor 4-aminopyridine (1 mmol/L) caused a 9-fold (P<0.01) decrease in sensitivity to Angeli's salt, whereas glibenclamide, iberiotoxin, charybdotoxin, and apamin were without effect. In combination, ODQ and 4-aminopyridine abolished the response to Angeli's salt. In conclusion, NO- functions as a potent vasodilator of resistance arteries, mediating its response independently of NO• and through the activation of soluble guanylate cyclase and voltage-dependent K+ channels. NO- donors may represent a novel class of nitrovasodilator relevant for the treatment of cardiovascular disorders such as angina.
Revised on January 23, 2003
NO- Activates Soluble Guanylate Cyclase and Kv Channels to Vasodilate Resistance Arteries
Jennifer C. Irvine;
Key words: nitric oxide • nitroxyl anion • potassium channels • vasorelaxation • vasculature • mesenteric arteries
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