Coadministration of hydralazine during continuous nitroglycerin infusion maintained a 45% reduction in left ventricular end-diastolic pressure at 10 hours, preventing hemodynamic tolerance in CHF rats.
Does hydralazine coadministration prevent nitroglycerin-induced hemodynamic tolerance in a rat model of congestive heart failure?
In a rat model of heart failure, coadministration of hydralazine prevents the rapid development of hemodynamic tolerance to continuous nitroglycerin infusion.
Absolute Event Rate: 45% vs 0%
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.
Bauer et al. (Mon,) conducted a other in Congestive heart failure (experimental rat model). Hydralazine coadministration with continuous nitroglycerin vs. Continuous nitroglycerin alone was evaluated on Reduction in left ventricular end-diastolic pressure. Coadministration of hydralazine during continuous nitroglycerin infusion maintained a 45% reduction in left ventricular end-diastolic pressure at 10 hours, preventing hemodynamic tolerance in CHF rats.