Impaired nitroglycerin biotransformation in patients with chronic heart failure.
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.
Petersson
Magnus
M
Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden.
Rundqvist
Bengt
B
Bennett
Brian M
BM
Adams
Michael A
MA
Friberg
Peter
P
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
D014665:Vasodilator Agents; C014509:dinitroglycerol; D005996:Nitroglycerin