In vitro tolerance of mononitrates and effects on aggregation of blood platelets

Overview

Long-term therapy with organic nitrates is frequently associated with a progressive
reduction of hemodynamic effects (nitrate tolerance) (4-7). This induces a major limitation in
terms of efficacy on nitrate therapy for myocardial infarction, stable angina and congestive heart
failure. Recent studies have demonstrated that the development of in vitro tolerance is mainly,
and quickly, induced by nitrates with high potency type and depends on the number of nitrate
groups present on the molecule, pentaerythritol tetranitrate (PETN) or glyceryl trinitrate (GTN)
are more potent than mononitrates (isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-
mononitrate (IS-2-MN)). Mononitrates have been used for many years in cardiovascular therapy
and they demonstrate a very interesting profile for better pharmacokinetic parameters in respect
of the old nitrates. In delivering the exogenous nitric oxide (NO), they are an attractive therapeutic
option, particularly with a view to slowing the progression of atherosclerosis and reducing the
risk of thrombosis. The multiple actions of nitrates are the summarized inhibition of vascular
smooth muscle cells (VSMCs) and migration, limiting the development of the complex plaque,
inhibition of platelet activation, aggregation and adhesion to the area of endothelial damage, reducing
the extent of thrombosis. In this study, the mononitrates induced tolerance in vitro as
documented for other nitrates but to a lesser degree. The antiplatelet effects were demonstrated
to be greater with IS-2-MN than IS-5-MN. Although the mononitrates induced tolerance, it
has been demonstrated that the anti-aggregatory effects are not reduced after chronic treatment,
and this is an important factor in protecting the ischemic patient from cardiac injury and
the high risk of thrombosis in acute coronary syndrome. (Heart International 2007; 3: 122-8)

Keywords

Nitrate tolerance, Platelet aggregation, Isosorbide-5-mononitrate, Isosorbide-2- mononitrate, Aortic rings, Nitric oxide

Correspondence

Dr. Enrico Lampa, Department of Experimental Medicine, Section of Pharmacology “Leonardo Donatelli”, Second University of Naples, 80100 Naples – Italy, enrico.lampa@unina2.it