Effect of intermittent exposure and drug-free intervals on the [formula omitted] vascular tolerance to nitroglycerin

Abstract

Recent reports suggest that intermittent nitroglycerin (NTG) treatment, incorporating a daily nitrate-free interval, can avoid the tolerance associated with continuous NTG therapy. This study has investigated whether an in vitro model of NTG tolerance could be used to examine the mechanisms of tolerance avoidance (by intermittent NTG exposure) and tolerance reversal. Isolated rat abdominal aortic rings were exposed to 55 μM NTG at varying intervals over a 60 min period, and the concentration-relaxation curves to NTG were subsequently determined. Intermittent NTG exposure (either 12 × 0.5 min or 3 × 2 min) significantly reduced NTG tolerance compared to continuous exposure over the same period of time (60 min). The diminished tolerance was apparently due to the reduced total exposure time, since the NTG responsiveness of aortic rings exposed to NTG intermittently or continuously for 6 min of the incubation period was not significantly different. Under the present conditions, in vitro NTG tolerance could be reversed if sufficient washout time was allowed. Thus, aortic rings exposed to NTG for the initial, but not the final, 6 min of incubation were not tolerant to NTG. In addition, rings exposed to NTG for 3 min exhibited near-maximal tolerance after 5 min washout, but no tolerance after 60 or 120 min washout. It appears, therefore, that the isolated vessel retains the “repair” mechanism responsible for tolerance reversal under the present conditions. This study suggests that the in vitro model of NTG tolerance may be useful for investigating the characteristics and mechanisms of tolerance avoidance and reversal, as well as tolerance induction.