Hydralazine does not ameliorate nitric oxide resistance in chronic heart failure.
OBJECTIVE
The A-HeFT trial demonstrated incremental survival with hydralazine/isosorbide dinitrate combination in African-American patients with chronic heart failure (CHF). It has been suggested that hydralazine might enhance nitric oxide (NO)-mediated effects of organic nitrates by decreasing superoxide (O (2) (-) ) formation, one of the factors inducing NO resistance. We evaluated whether hydralazine therapy potentiates nitrate-induced vasodilation and inhibition of platelet aggregation by ameliorating NO resistance.


METHODS
Patients (n = 14) with NYHA class II-III CHF were studied in a randomised, double-blind, placebo-controlled, crossover study of the effects of hydralazine therapy (25 mg b.d., for 1 week) on physiological responsiveness to glyceryl trinitrate (GTN). Vascular response to GTN was assessed via applanation tonometry, as change in augmentation index (AIx) over time. Platelet responsiveness to GTN and sodium nitroprusside (SNP) was determined, as inhibition of ADP-induced platelet aggregation. O (2) (-) release was evaluated during aggregation via lucigenin-derived chemiluminescence.


RESULTS
Platelet responsiveness to the NO donors GTN and SNP was impaired, denoting the presence of severe NO resistance. Hydralazine therapy decreased systolic blood pressure by 6.8 +/- 10.5 (S.D.) mmHg (p = 0.02), and caused a reduction in AIx by 15 +/- 24% (p = 0.03). However, there were no significant changes in platelet aggregability and associated O (2) (-) release, or in platelet or vascular responses to NO donor.


CONCLUSIONS
The results of the present study do not support the assumption that hydralazine could be viewed as a "NO enhancer"; there is no evidence of attenuation of NO resistance by hydralazine treatment.
Chirkov
Yuliy Y
YY
Cardiology Unit, Vascular Disease and Therapeutics Research Group, Basil Hetzel Institute, The Queen Elizabeth Hospital, School of Medicine, The University of Adelaide, Adelaide, Australia.
De Sciscio
Michele
M
Sverdlov
Aaron L
AL
Leslie
Sue
S
Sage
Peter R
PR
Horowitz
John D
JD
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004351:Drug Resistance / Q000187:drug effects*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008365:Manometry; D008875:Middle Aged; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011674:Pulse; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D020030:Nitric Oxide Donors; D013481:Superoxides; D009599:Nitroprusside; D006830:Hydralazine; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D005996:Nitroglycerin