Influence of glyceryl trinitrate on venous and arterial effects of chronic,asymmetric isosorbide dinitrate treatment in patients with ischemic heart disease

Asymmetric dosage regimes have been introduced to circumvent development of nitrate tolerance. This study assessed invasively the hemodynamics during supine rest and exercise before and after 4 weeks treatment with 30 mg isosorbide dinitrate (ISDN) or placebo asymmetrically b.i.d. in 14 randomized patients with stable ischemic heart disease in a double-blinded study. An intravenous infusion of glyceryl trinitrate (GTN) was used to assess possible nitrate tolerance. During the initial, medication-free exercise all patients had increased pulmonary arterial wedge pressure (PAWP) 31.4 ± 5.56 mmHg (mean ± SD), showing impaired left ventricular function, while mean arterial pressures (MAP) rose from 112 ± 16.3 mmHg at rest to 141 ± 15.9 mmHg during exercise. After 4 weeks ISDN treatment, mean exercise PAWP and MAP, 3 h after morning dose, were reduced to 22.4 ± 7.09 mmHg and 127 ± 18.2 mmHg, respectively. Before the ISDN treatment, GTN reduced exercise PAWP to 13.9 ± 5.27 mmHg and MAP to 119 ± 11.2 mmHg, whereas after 4 weeks ISDN treatment, the addition of GTN did not reduce exercise PAWP and MAP to the same low levels. Thus, the applied ISDN regimen improved the hemodynamics, but induced a definite, partial nitrate tolerance.