Pharmacodynamics of in vivo nitrate action

We have used animal models to examine the dynamic events associated with the hemodynamic and antiaggregatory actions of nitroglycerin. For the study of hemodynamics, we utilized a rat model of congestive heart failure and showed that the major features of nitrate tolerance and withdrawal rebound could be reproduced in this model. We showed that both phenomena can be described quantitatively by a pharmacokinetic/pharmacodynamic model that incorporated rate constants for a number of physiologic rate processes. The model assumes that tolerance is produced by the development of a counterregulatory vasoconstriction, the magnitude of which is dependent on the extent of the vasodilative component of nitrate action. Dissipation of the vasoconstrictive process is shown to be slower than that of nitrate- induced vasodilation. We further showed, in a normal conscious rat model, that the time-courses of the antiaggregatory actions of nitroglycerin are dissociated from those of hemodynamic tolerance, indicating that sustained antiaggregatory action from nitrates is present despite the observation of hemodynamic tolerance. Our experimental findings are generally consistent with clinical results obtained by other investigators. These results indicate that useful information can be gained from pharmacodynamic examination of in vivo nitrate tolerance in experimental animals.