title: Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite.
abstract: OBJECTIVE
  Nitrite (NO₂⁻) has recently been shown to represent a potential source of NO, in particular under hypoxic conditions. The aim of the current study was to compare the haemodynamic effects of NO₂⁻ in healthy volunteers and patients with stable congestive heart failure (CHF).
  
  
  METHODS
  The acute haemodynamic effects of brachial artery infusion of NO₂⁻ (0.31 to 7.8 μmol·min⁻¹) was assessed in normal subjects (n = 20) and CHF patients (n = 21).
  
  
  RESULTS
  NO₂⁻ infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF patients at NO₂⁻ infusion rates which induced no changes in normal subjects (ANOVA: F = 5.5; P = 0.02). Unstressed venous volume (UVV) increased even with the lowest NO₂⁻ infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (ANOVA: F = 6.2; P = 0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO₂⁻ infusion. Venous plasma NO₂⁻ concentrations were lower in CHF patients at baseline, and rose substantially less with NO₂⁻ infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF patients than normal subjects at baseline. This difference was attenuated during NO₂⁻ infusion. Prolonged NO₂⁻ exposure in vivo did not induce oxidative stress, nor did it induce tolerance in vitro.
  
  
  CONCLUSIONS
  The findings of arterial hyper-responsiveness to infused NO₂⁻ in CHF patients, with evidence of accelerated transvascular NO₂⁻ clearance (presumably with concomitant NO release) suggests that NO₂⁻ effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO₂⁻ as a therapeutic modality in CHF.
authors.affiliation: Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. abdul.r.maher@googlemail.com
authors.forename: Abdul R
authors.initials: AR
authors.lastname: Maher
authors.forename: Sayqa
authors.initials: S
authors.lastname: Arif
authors.forename: Melanie
authors.initials: M
authors.lastname: Madhani
authors.forename: Khalid
authors.initials: K
authors.lastname: Abozguia
authors.forename: Ibrar
authors.initials: I
authors.lastname: Ahmed
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.forename: A G
authors.initials: AG
authors.lastname: O'Sullivan
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sverdlov
authors.forename: Doan
authors.initials: D
authors.lastname: Ngo
authors.forename: Rustem
authors.initials: R
authors.lastname: Dautov
authors.forename: Philip E
authors.initials: PE
authors.lastname: James
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Frenneaux
mesh_terms: D000368:Aged; D001916:Brachial Artery; D015331:Cohort Studies; D004361:Drug Tolerance; D005260:Female; D005542:Forearm; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009569:Nitric Oxide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D005996:Nitroglycerin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012501:Saphenous Vein / Q000187:drug effects / Q000503:physiopathology; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D014665:Vasodilator Agents; D009569:Nitric Oxide; D005996:Nitroglycerin; D012977:Sodium Nitrite