Pharmacodynamic tolerance during continuous nitroglycerin (NTG) infusion is a significant limitation of nitrate therapy. The mechanism of this phenomenon is not well-understood but may involve physiologic compensation which involves vasoconstriction. We have obtained pharmacodynamic data on NTG-induced hemodynamic tolerance in a rat model of congestive heart failure (CHF), which we have shown to mimic human behavior toward NTG in vivo. In this report, we developed two mechanism-based pharmacokinetic/pharmacodynamic models to describe the time-dependent effects of NTG infusion on left ventricular end-diastolic pressures (LVEDP) in CHF rats and compared their abilities to describe the observed hemodynamic data. Both mathematical models introduced a counter-regulatory vasoconstrictive effect as a result of NTG-induced vasodilation and assumed the magnitude of this effect to be driven by the extent of the initial hemodynamic effect produced by NTG. The decay of this counter-regulatory effect was described by a first-order process in both models. A model that assumed vasoconstriction to develop via two sequential first-order processes was statistically superior in describing the data, when compared to one that assumed a single first-order process and a lag phase. Both models provided similar estimates of the half-life for the disappearance of the vasoconstriction (t1/2 of vasoconstriction: 128min vs. 182min, respectively), and both predicted rebound elevation of LVEDP after abrupt NTG withdrawal. These results are consistent with a counter-regulatory mechanism of NTG-induced hemodynamic tolerance and suggest that such an approach may be useful for modeling other tolerance phenomena as well.