Dose dependence of tolerance during treatment with mononitrates

In order to test the clinically supposed development of tolerance during chronic high-dose nitrate therapy, we studied a total of 24 patients with angiographically proven coronary heart disease at rest and during ergometric exercise (supine position, 50 w for 3 min). Pulmonary arterial pressure (PAP, floating catheter), arterial blood pressure (cuff method), cardiac output (Fick principle), heart rate, and exercise capacity (w X min) were measured at rest and exercise before and during chronic (4 weeks) oral therapy with 5-isosorbide mononitrate (5-ISMN), 3 X 20 mg/day (n = 14) and 3 X 50 mg/day (n = 10). After acute administration, both doses of 5-ISMN decreased mean PAP at rest and during exercise (rest: by 25% with 20 mg and by 29% with 50 mg; exercise: by 30% with 20 mg and by 45% with 50 mg), whereas cardiac output and stroke volume were only reduced by 5-ISMN at rest. During chronic treatment with 60 mg and 150 mg 5-ISMN, and additional administration of 20 mg or 50 mg respectively lowered PAP at rest by 15% and 19%; during ergometric exercise PAP was 22% and 14% lower than during ergometry before any drug treatment. The exercise capacity slightly increased during treatment to 60 mg 5-ISMN, whereas it decreased by 25% on chronic treatment with 150 mg 5-ISMN per day. Our results show that acute administration of 5-ISMN in either dose (20 mg and 50 mg) exerts unloading effects on the heart and will increase the exercise tolerance. In contrast to the higher dose of 150 mg 5-ISMN per day, chronic treatment with the lower dose of 60 mg 5-ISMN daily will not result in drug tolerance.