title: Suppression of neutrophil superoxide generation by BNP is attenuated in acute heart failure: a case for 'BNP resistance'.
abstract: OBJECTIVE
  The release of the B-type natriuretic peptide (BNP) is increased in heart failure (HF), a condition associated with oxidative stress. BNP is known to exert anti-inflammatory effects including suppression of neutrophil superoxide (O2(-)) release. However, BNP-based restoration of homeostasis in HF is inadequate, and the equivocal clinical benefit of a recombinant BNP, nesiritide, raises the possibility of attenuated response to BNP. We therefore tested the hypothesis that BNP-induced suppression of neutrophil O2(-) generation is impaired in patients with acute HF.
  
  
  RESULTS
  We have recently characterized suppression of neutrophil O2(-) generation (PMA- or fMLP-stimulated neutrophil burst) by BNP as a measure of its physiological activity. In the present study, BNP response was compared in neutrophils of healthy subjects (n = 29) and HF patients (n = 45). Effects of BNP on fMLP-induced phosphorylation of the NAD(P)H oxidase subunit p47phox were also evaluated. In acute HF patients, the suppressing effect of BNP (1 µmol/L) on O2(-) generation was attenuated relative to that in healthy subjects (P < 0.05 for both PMA and fMLP). Analogously, BNP inhibited p47phox phosphorylation in healthy subjects but not in HF patients (P < 0.05). However, O2(-)-suppressing effects of the cell-permeable cGMP analogue (8-pCPT-cGMP) were preserved in acute HF. Conventional HF treatment for 5 weeks partially restored neutrophil BNP responsiveness (n = 25, P < 0.05), despite no significant decrease in plasma NT-proBNP levels.
  
  
  CONCLUSIONS
  BNP inhibits neutrophil O2(-) generation by suppressing NAD(P)H oxidase assembly. This effect is impaired in acute HF patients, with partial recovery during treatment.
authors: Department of Cardiology and Clinical Pharmacology, Basil Hetzel Institute, The Queen Elizabeth Hospital, The University of Adelaide, South Australia, Australia.
authors: Saifei
authors: S
authors: Liu
authors: Doan T M
authors: DT
authors: Ngo
authors: Cher-Rin
authors: CR
authors: Chong
authors: Anjalee T
authors: AT
authors: Amarasekera
authors: Nathan E K
authors: NE
authors: Procter
authors: Giovanni
authors: G
authors: Licari
authors: Rustem F
authors: RF
authors: Dautov
authors: Simon
authors: S
authors: Stewart
authors: Yuliy Y
authors: YY
authors: Chirkov
authors: John D
authors: JD
authors: Horowitz
mesh_terms: D000328:Adult; D000368:Aged; D004351:Drug Resistance; D005260:Female; D006333:Heart Failure / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D045283:Natriuretic Agents / Q000494:pharmacology*; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000097:blood; D013481:Superoxides / Q000378:metabolism*
chemical_list: D045283:Natriuretic Agents; D017382:Reactive Oxygen Species; D013481:Superoxides; D020097:Natriuretic Peptide, Brain; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases
keywords: Acute heart failure; BNP; Redox stress; Superoxide