title: Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure.
abstract: Enhanced iNOS (inducible nitric oxide synthase) activity may contribute to vascular dysfunction in patients with heart failure. In the present study, we aimed to determine whether iNOS activity contributes to the maintenance of vascular tone in patients with symptomatic heart failure with the use of the highly selective iNOS inhibitor 1400W {N-[3-(aminomethyl)benzyl] acetamidine}. Bilateral forearm blood flow was measured using venous occlusion plethysmography in 12 patients with New York Heart Association class II-IV heart failure and eight matched healthy control subjects during intra-brachial infusion of 1400W (0.1-1 micromol/min), L-NMMA (N(G)-monomethyl-L-arginine; a non-selective NOS inhibitor; 2-8 micromol/min) and noradrenaline (control vasoconstrictor; 60-480 pmol/min). In both patients and controls, intra-brachial infusion of L-NMMA and noradrenaline caused a dose-dependent reduction in infused forearm blood flow (P<0.05 for both): peak reduction of 32+/-6% and 37+/-4% during L-NMMA and 52+/-6% and 49+/-5% during noradrenaline respectively (P values were not significant when patients were compared with controls). In contrast, 1400W had no effect on blood flow at 1 micromol/min [-3+/-4% in patients (95% confidence intervals, -11 to 5%) and 3+/-8% in controls; P value was not significant]. In conclusion, we have demonstrated that intrabrachial selective iNOS inhibition does not influence forearm blood flow in patients with heart failure. We conclude that iNOS activity does not contribute to peripheral vascular tone in patients with symptomatic heart failure.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Anna.Dover@ed.ac.uk
authors.forename: Anna R
authors.initials: AR
authors.lastname: Dover
authors.forename: Stanley
authors.initials: S
authors.lastname: Chia
authors.forename: James W
authors.initials: JW
authors.lastname: Ferguson
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Cruden
authors.forename: Ian L
authors.initials: IL
authors.lastname: Megson
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010991:Plethysmography / Q000379:methods; D012039:Regional Blood Flow; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine