Circulation, Vol 84, 35-39, Copyright © 1991 by American Heart Association
JA Bauer and HL Fung
BACKGROUND. Organic nitrates such as nitroglycerin and isosorbide dinitrate
are useful in the treatment of congestive heart failure (CHF), but
tolerance develops rapidly during continuous administration. Because
combination therapy of nitrate and hydralazine has been shown to provide
both short- and long-term benefit but nitrate alone produces hemodynamic
tolerance, we questioned whether hydralazine can preserve the favorable
preload effects of nitroglycerin. METHODS AND RESULTS. Using an in vivo
model of nitroglycerin tolerance in the CHF rat, we examined the effects of
hydralazine bolus dosing during continuous nitroglycerin infusion.
Continuous infusion of nitroglycerin alone (10 micrograms/min) produced
initial reductions in left ventricular end- diastolic pressure of 40-50%,
which returned to baseline by 8 hours (tolerance development).
Coadministration of hydralazine (2 x 0.1 mg) maintained the effects of
nitroglycerin infusion on left ventricular end-diastolic pressure (45%
reduction at 10 hours). This hydralazine dose alone reduced left
ventricular peak systolic pressure by approximately 12 +/- 3% but had no
effect on left ventricular end- diastolic pressure. Hydralazine dosing did
not affect steady-state plasma concentrations of nitroglycerin or
metabolites, and hydralazine was unable to prevent nitroglycerin tolerance
induced in vitro. CONCLUSIONS. The beneficial interaction of hydralazine on
the preload effects of nitroglycerin may explain the long-term clinical
efficacy of hydralazine/nitrate combination in CHF. Our results also
suggest that the mechanism of in vivo nitrate tolerance in CHF may be
systemic rather than vascular in origin.
ARTICLES
Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
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