title: Impaired nitroglycerin biotransformation in patients with chronic heart failure.
abstract: OBJECTIVE
  Patients with chronic heart failure (CHF) often require higher doses of nitroglycerin (glyceryl trinitrate, GTN) than patients with normal cardiac function to achieve a given haemodynamic goal. Two pathways leading to biotransformation of GTN have been characterized; a high-affinity pathway operative in nanomolar concentration ranges yielding predominantly 1,2-glyceryl dinitrate (1,2-GDN), and a low-affinity pathway operative at higher, micromolar concentrations of GTN associated with a greater proportion of 1,3-GDN formation. We tested the hypothesis that, at a given GTN-induced blood pressure reduction, the CHF group would present with: (i) higher concentrations of GTN; and (ii) decreased ratios of 1,2-GDN/GTN and 1,2-GDN/1,3-GDN compared with healthy subjects (HS).
  
  
  METHODS
  Twelve patients with CHF (left ventricular ejection fraction 20 +/- 5%, NYHA III) and nine HS were investigated during a right cardiac catheterization. GTN was titrated intravenously until mean arterial blood pressure (MAP) was reduced by 15%.
  
  
  RESULTS
  At arterial GTN concentrations of 27.2 [10.0-57.8] nmol l(-1) in CHF and 2.8 [2.5-3.5] nmol l(-1) in HS [median (quartile range), P<0.05 between groups], MAP and mean capillary wedge pressures were reduced similarly in both groups (approx. 15% and 65%, respectively, P = NS between groups). The ratios of 1,2-GDN/GTN and 1,2-GDN/1,3-GDN were lower in CHF (0.86 [0.28-1.58] and 5.8 [5.6-6.3]) compared with HS [1.91 (1.54-2.23) and 7.6 (7.2-10.2), P<0.05], with a negative correlation between the 1,2-GDN/1,3-GDN ratio and the arterial GTN concentrations in the CHF patients (R = -0.8, P<0.05).
  
  
  CONCLUSIONS
  Patients with CHF have attenuated GTN responsiveness and decreased relative formation of 1,2-GDN in comparison with HS, indicating an altered biotransformation of GTN.
authors.affiliation: Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Petersson
authors.forename: Bengt
authors.initials: B
authors.lastname: Rundqvist
authors.forename: Brian M
authors.initials: BM
authors.lastname: Bennett
authors.forename: Michael A
authors.initials: MA
authors.lastname: Adams
authors.forename: Peter
authors.initials: P
authors.lastname: Friberg
mesh_terms: D000328:Adult; D001711:Biotransformation; D002908:Chronic Disease; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D014665:Vasodilator Agents; C014509:dinitroglycerol; D005996:Nitroglycerin