Nitrate cross-tolerance: effect of sublingual isosorbide dinitrate and nitroglycerin during sustained nitrate therapy

In a randomized, single-blind, crossover study, 10 patients with stable, exercise-induced angina pectoris were studied during sustained therapy with oral isosorbide dinitrate (ISDN). Circulatory changes and exercise performance were evaluated before and 6 hours after therapy with oral ISDN. One-half hour after this therapy, sublingual ISDN or nitroglycerin (NTG) was administered and exercise testing repeated. Treadmill walking time 6 hours after oral ISDN was similar to the control value. Subsequent administration of sublingual ISDN improved walking time from 429 +/- 156 to 513 +/- 166 seconds (p less than 0.005), whereas after NTG improved from 411 +/- 159 to 480 +/- 158 second (p less than 0.005). The improvement in walking time with ISDN (23%) and NTG (18%) and the absolute walking times were not different. The standing systolic blood pressure decreased from 124 +/- 23 to 112 +/- 22 mm Hg (p less than 0.02) after therapy with sublingual ISDN and 122 +/- 23 to 110 +/- 24 mm Hg (p less than 0.005) after administration of NTG. This study demonstrates that (1) during sustained ISDN therapy, walking time returns to control values by 6 hours; (2) administration of either sublingual ISDN or NTG results in significant circulatory changes and improvement in walking time; and (3) the changes in circulatory and exercise variables after administration of NTG in patients taking sustained ISDN therapy cannot be taken as evidence of an absence of cross-tolerance between these agents.