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The development and reversal of tolerance to the hemodynamic and anti-anginal effects of isosorbide dinitrate in a sustained release form (ISDN-SR) were investigated in 11 male patients (mean age 58.9 y.o.) with stable effort angina. Treadmill exercise test, evaluation of hemodynamic parameters and measurement of plasma ISDN concentrations were performed during the control period, on the 1st, 7th and 14th days of therapy with 40 mg of ISDN-SR orally every 8 h and, subsequently, on the day when ISDN-SR was re-administered after a 72 h placebo period (17th day). Initially, exercise tolerance time (ETT) was prolonged significantly (p less than 0.001) by ISDN-SR from 257 +/- 50 sec in the control period to 434 +/- 55 sec on day 1. This prolongation was significantly reduced with sustained therapy and ETT was shortened to 332 +/- 69 sec on the 7th day (p less than 0.01 vs day 1) and 326 +/- 73 sec on the 14th day (p less than 0.01 vs day 1). The effects of ISDN-SR initially observed were restored after a 72 h placebo period and ETT was prolonged to 432 +/- 57 sec on the 17th day. The resting heart rate was increased significantly (p less than 0.01 vs control) and systolic blood pressure was decreased (p less than 0.001 vs control) by ISDN-SR on day 1. These changes were also diminished significantly (p less than 0.01 vs day 1) with sustained therapy and were restored after a 72 h nitrate-free interval.(ABSTRACT TRUNCATED AT 250 WORDS)

The development and reversal of tolerance to antianginal effect of isosorbide dinitrate in patients with effort angina.