SummaryBackground: The mechanisms behind development of tolerance to nitrate effects during sustained, asymmetric isosorbide dinitrate (ISDN) therapy are not fully understood.Hypothesis: The study was undertaken to investigate the changes of the relationships between left ventricular (LV) function and plasma concentrations of ISDN and its vasoactive metabolites (2-and 5-ISMO) during acute and sustained, asymmetric ISDN therapy.Methods: Left ventricular function and plasma concentrations of ISDN, 2-and 5-isosorbide mononitrates (P-ISDN, P-2-and 5-ISMO) were measured at rest and at supine exercise before and for 4 h after peroral 30 mg ISDN in 15 patients with coronary artery disease, all with initial exercise pulmonary artery wedge pressure (PAWP) >25 mmHg. Seven patients were untreated (acute group), while eight received 30 mg ISDN b.i.d. for 2 weeks before the invasive study. P-ISDN and the concentration of available isosorbide-bound nitrate (N02) in