Efficacy and rebound phenomenon related to intermittent nitroglycerin therapy for the prevention of nitrate tolerance

Intermittent transdermal therapy of nitroglycerin (NTG) has been recommended for the prevention of nitrate tolerance, but a rebound phenomenon has been reported to occur following removal of the NTG tape. The present study investigated the effects of intermittent NTG therapy on vasodilatory response and the intracellular production of cyclic GMP (cGMP). The study group comprised 12 healthy adults and measurements were taken of the platelet cGMP level, the venous volume (VV) (by forearm plethysmography) and the plasma levels of neurohormonal factors before and 5 min after administration of 0.3 mg of sublingual nitroglycerin (NTG) during the following 4 phases: (i) the control phase (8.00 h); (ii) the continuous phase (8.00 h; 7 days after continuous application of a 10 mg/24 h NTG tape); (iii) the intermittent application phase (8.00 h; 7 days after intermittent application of NTG tape, applied at 21.00 h and removed at 9.00 h); and (iv) the intermittent removal phase (13.00 h; 4 h after removal of the NTG tape in the intermittent phase). The percentage increase in cGMP (%cGMP) and venous volume (%VV) were significantly lower in the continuous phase than the control phase, but there was no difference between the control and the intermittent application phases. However, in the intermittent removal phase, the cGMP level before sublingual NTG, the %cGMP and the %VV were unchanged, but the VV before sublingual NTG was significantly lower than in the control phase. Plasma renin activity and the plasma level of angiotensin II were significantly increased in the continuous phase, the intermittent application phase, and the intermittent removal phase. In conclusion, intermittent transdermal NTG therapy prevented nitrate tolerance in the production of cGMP and vasodilation, but induced a rebound phenomenon after removal of the NTG tape. The rebound phenomenon following the tape removal may be related to some other mechanism, such as activation of neurohormonal factors.