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Based on clinical studies of long-term treatment with orally administered nitrates indicating a reduction in the rate of anginal attacks, nitrate consumption, or ST-segment depression as well as an increased exercise capacity, this regimen has been considered useful in the prophylactic treatment of angina pectoris [2, 4, 8, 12]. Moreover, it has been reported that during chronic treatment with nitrates, acute administration of an additional dose, regardless of application form, favorably influences the rate of anginal attacks as well as ST-segment depression and the duration of exercise with maintained efficacy [1, 3, 9]. Apparently discrepant are the withdrawal symptoms, resulting from developed tolerance and observed in industrial workers chronically exposed to nitrates, the mechanism of which has been attributed to a resetting of vascular reactivity [7].

In 1980 a placebo-controlled double-blind study was published by us demonstrating a clear development of tolerance to the antiischemic effect of isosorbide dinitrate (ISDN) in slow-release (s.r.) form during long-term treatment with 20, 40, or 60 mg three times daily [1, 11]. These results were at that time actively discussed as they showed that the widely used — but at that time not proven — administration of ISDN s.r. t.i.d. is equivalent to a placebotreatment. This study induced us to make further investigations to assess the following: 1. whether tolerance, independent of the galenic formulation, is an inherent property of ISDN longterm treatment; 2. the temporal course of development and reversal of tolerance; 3. whether the antiischemic and hypotensive effects of ISDN show a different response in respect to tolerance development; 4. the interaction between nitrate plasma concentration and tolerance development; 5. the clinical significance of a possible cross-tolerance to the antiischemic effect of sublingually administered nitroglycerin (GTN); and 6. whether tolerance can be avoided by intermittent administration.

Auf Grund klinischer Studien, die bei Patienten mit koronarer Herzerkrankung eine Reduktion der Angina-pectoris-Anfallshaufigkeit, des Nitratverbrauchs und der ST-Streckensenkung sowie einen Anstieg der Belastungstoleranz unter Langzeittherapie mit oral verabreichten Nitraten nachwiesen, wurde diese Therapieform als effektiv zur Angina-pectoris-Prophylaxe angesehen [2, 4, 8, 12].