Endothelial dysfunction in heart failure and ischemic heart disease: rationale for the clinical use of mononitrates
Abstract
Overview
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.
(Heart International 2007; 3: 86-97)
Keywords
Nitrates, Endothelial dysfunction, Heart failure, Ischemic heart disease
Article Information
Correspondence
Prof. Oberdan Parodi, CNR Clincal Physiology Institute of Milan, Cardiology Department, Niguarda CÃ Granda Hospital, Piazza Ospedale Maggiore, 3, 20162 Milan – Italy, ifcnig@tin.it
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