[Development of tolerance with regard to the anti-ischemic effect of isosorbide dinitrate in regular multiple daily...

In previous studies it had been shown that during longterm treatment of coronary artery disease with isosorbide dinitrate (ISDN) in sustained-release form, there was no reduction in exercise-induced ST-segment depression, no decrease in the rate of anginal attacks or nitrate consumption and no changes in blood pressure or heart rate [1, 4]. To determine to what extent tolerance development is a fundamental property of longterm administration of ISDN, this study, carried out according to a randomized, double-blind, cross-over, placebo-controlled protocol (Figure 1), was undertaken. The anti-ischemic effects of 40 mg ISDN were analyzed after acute administration and during longterm treatment with 40 mg four times daily in eleven patients with stable angina pectoris and reproducible ST-segment depression. Additionally, the influence of this therapy on the anti-ischemic effects of 0.8 mg sublingually-administered nitroglycerin (GTN) was assessed in ten of the eleven patients. On acute administration, 40 mg ISDN led to a reduction in ST-segment depression at one hour from 2.05 to 0.18 mm (p less than 0.01), and at six hours from 2.35 to 1.20 mm (p less than 0.01) (Figure 2, Table 1). During chronic treatment, statistically significant changes were no longer detectable. In eight of the eleven patients there was a complete loss of effects; in the remaining three, a marked attenuation was observed (Figure 3). Acute administration of 40 mg ISDN resulted in plasma concentrations of 221 ng/ml 5-ISMN, 53 ng/ml 2-ISMN and 23 ng/ml ISDN (Figure 6, Table 2).(ABSTRACT TRUNCATED AT 250 WORDS)