Investigations into the development of tolerance to organic nitrates in conscious dogs

The role of doses and dose intervals in the development of tolerance towards organic nitrates was investigated. It was studied whether the decrease in systolic blood pressure (SBP) induced by i.v. injection of 30 micrograms/kg glyceryl trinitrate (GTN) is influenced by the simultaneous i.v. infusion of GTN or isosorbide-5-mononitrate (IS-5-MN) - two dose levels each - at doses that lower the SBP by 20-35 mmHg. Although infusion of the lower dose of IS-5-MN caused a constant plasma concentration that was about 100 times more than that required for the anti-anginal effects, the acute GTN response was not reduced. However, the acute response was diminished at the other groups. In additional investigations incremental doses of IS-5-MN were injected i.v. at different dose intervals. It was observed that the responsiveness was nearly identical at dose intervals of 24, 4 and 2 h (= 1.3 half-lives in the dog, which is equivalent to a t.i.d. dose schedule in man), whereas it was markedly reduced at intervals of 10 min.