[Nitrates in the treatment of heart failure]

Organic nitrates were the first peripherally-active vasodilators to be used for the treatment of heart failure. Currently, three nitrate derivatives, glycerol trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate as well as the nitrate-like substance molsidomine are employed clinically. For treatment of heart failure, the decisive hemodynamic effect is a meaningful reduction in ventricular filling pressures with maintenance or even a slight increase in cardiac output. The individual response to nitrates is variable. An important indicator for the effect achievable for a certain dose or for the necessary dosage to affect a defined reduction in ventricular filling pressures, is the magnitude of right atrial pressure. It can be assumed that the latter statement is also valid for the nitrate-like substance molsidomine. An inherent problem with any long-term treatment with nitrates is the incurrence of tolerance. This can be expected with any dosing regimen which leads to nitrate cumulation in the plasma or to nearly-constant, high, plasma concentrations as rendered by multiple daily administration of orally-active nitrates or with continuous transdermal or intravenous nitrate administration. The cause of nitrate tolerance is regarded as an insufficient or absent stimulation of guanylate cyclase and, consequently, inadequate generation of cyclic GMP due to availability of thiol substrate. Since the nitrate-like substance molsidomine appears to be able to stimulate guanylate cyclase independent of thiol groups, tolerance development may not be a limiting factor with this agent. Comparable reduction of diastolic pulmonary artery pressure after acute administration and at the end of one week of treatment with 4 mg molsidomine four times daily has been reported.(ABSTRACT TRUNCATED AT 250 WORDS)