Abstract
The development and reversal of tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate in a sustained release from (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 re-administered after a 72 h placebo period (17th day). Initially, exercise tolerance time (ETT) was prolonged significantly (p<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<0.01 vs day 1) and 326±73 sec on the 14th day (p<0.01 vs day 1). The effects of ISDN-SR initially observed were restored after a 72 h placebo period and ETT was increased significantly (p<0.01 vs control) and systolic blood pressure was decreased (p<0.001 vs control) by ISDN-SR on day 1. These changes were also diminished significantly (p<0.01 vs day 1) with sustained therapy and were restore after a 72 h nitrate-free interval. The average plasma ISDN concentration was significantly higher during sustained than during acute therapy (p<0.01). It is concluded that partial tolerance to hemodynamic and antianginal effects developed during sustained (1 week) therapy with ISDN-SR and was reversed after a 72 h nitrate-free interval.
