Endothelial Dysfunction in Heart Failure and Ischemic Heart Disease: Rationale for the Clinical use of Mononitrates

Abstract

The clinical observation that heart failure can progress independently of the patient's hemodynamic status has focused interest on new, potential mechanisms underlying the progression of cardiac insufficiency It has been shown that in both ischemic and non-ischemic heart failure, endothelial dysfunction and reduced bioavailability of NO can contribute to the process of left ventricular remodelling. The endothelial dysfunction contributes to increasing peripheral vascular resistance, limiting blood flow to skeletal muscles, particularly during exercise, and compromising the regulation of pulmonary blood flow, leading to a flow-perfusion mismatch. The nitroderivates are a heterogeneous class of compounds that have in common their pharmacodynamic action, which is mediated through the production of NO. Isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) are the two main metabolites of isosorbide dinitrate (ISDN) and both act on the smooth muscle cells of vessel walls, causing generalized peripheral vasodilation, which is more marked in the venous system, reduced venous return to the heart and a reduction in peripheral resistance. The shorter half-life of IS-2-MN compared to that of IS-5-MN allows greater fluctuation of the blood levels of the drug; it can, therefore, be hypothesized that tolerance would develop more slowly. In the light of the important role of oxidative stress in the progression of heart failure, reduced occupation of the receptors for NO by IS-2-MN could have important implications for the bioavailability of the sulphydryl groups otherwise involved in the denitrification of the organic nitrates.