Effect of dosage regimen on the development of tolerance to nitroglycerin in rats

The recent introduction of several sustained delivery systems of nitroglycerin (NTG) raises the question whether the mode of drug input (e.g., sustained versus intermittent) may be a critical determinant in the development of nitrate tolerance. This hypothesis was tested in an animal model. Sixty male Sprague-Dawley rats (weighing 240-260 g) were administered a total intravenous dose of 2.5 mg NTG either as a continuous 6-h infusion (6.8 micrograms/min) or as six hourly pulse injections of 425 micrograms each. Animals were sacrificed 5 min following the termination of the infusion and 65 min following the last injection. A blood sample was taken from a central vein for plasma NTG determination, and the aorta and portal vein were isolated. Dose-response curves to NTG were determined on some of these blood vessels and on controls using an isolated tissue bath apparatus. Other blood vessels were incubated with 94 ng [14C]NTG for 60 min, and the incorporation of [14C]NTG into these tissues was determined after thin-layer chromatographic separation of NTG from its metabolites. There was no difference between the plasma NTG concentration measured at the time of sacrifice following either regimen. For the artery preparation, there was also no difference in the dose response to NTG or in the incorporation of [14C]NTG into the blood vessel from rats treated by either regimen. For the portal vein preparation, however, rats treated by continuous infusion had a similar sensitivity to NTG as controls, but there was a marked downward shift in the dose response to NTG in the veins of rats treated by the intermittent regimen.(ABSTRACT TRUNCATED AT 250 WORDS)