Induction and circumvention of nitrate tolerance applying different dosage intervals

There is increasing evidence that constant nitrate plasma levels, as induced by at least three-times-daily ingestions of isosorbide dinitrate in sustained-release form, lead to an attenuation or even complete loss of the anti-ischemic effects (nitrate tolerance). Therefore, the dependence of tolerance development on dosage intervals according to once-daily and twice-daily ingestions was assessed. Tablets of isosorbide dinitrate (80 mg) in sustained-release form were administered once-daily at 8 A.M. (dosage interval 24 hours) or twice-daily at 8 A.M. and 8 P.M. (dosage interval 12 hours), as well as at 8 A.M. and 2 P.M., respectively (maximal dosage interval 18 hours). A total of 34 patients with angiographically proven coronary artery disease, a history of stable, exercise-dependent angina pectoris, and a reproducible, exercise-induced ST-segment depression of at least 0.15 mV (1.5 mm), who initially showed a response to 80 mg of isosorbide dinitrate, were enrolled. The anti-ischemic effects of isosorbide dinitrate on exercise-induced ischemia were objectively determined by the measurement of exercise-induced ST-segment depression before as well as two, six, and 12 hours after the ingestion at the first and the 15th day of the studies. Since the dosage interval of 12 hours resulted in constant plasma levels, the initially beneficial anti-ischemic effects of isosorbide dinitrate were considerably attenuated after two weeks of treatment. In contrast, the once-daily regimen with its intermittent peaks and valleys of nitrate plasma levels showed identical anti-ischemic effects at the 15th day as compared with the first day. Ingestions at 8 A.M. and 2 P.M. also circumvented the development of nitrate tolerance, however, combined with an even more pronounced anti-ischemic effect after 12 hours as compared with the once-daily regimen. Thus, the circumvention of nitrate tolerance requires a daily "nitrate-poor" interval. The best compromise between a maximal possible anti-ischemic effect and the circumvention of tolerance development was found for the "eccentric" dosage regimen in which the tablets were ingested in the morning and early afternoon.