Heart International

Nitric oxide (NO), a highly unstable gas with a half-life of a few seconds, is the most important mediator produced by endothelial cells and has several important protective functions concerning the control of vascular tone, thrombogenesis, fibrinolysis, cell proliferation, inflammation and endothelial permeability, which are crucial for the maintenance of an anti-inflammatory anti-atherogenic and anti-thrombotic state. The exogenous administration of NO with nitrates has been proposed as possible NO exogenous sources in endothelial dysfunction therapy and coronary artery disease because of their anti-atherosclerotic effect, through a reduction in oxidative stress, on low-density lipoprotein (LDL) oxidation, chemotactic molecules and growth factors, which mediate leukocytal adhesion and proliferation of vascular smooth cells. Moreover, nitrates show a vasodilatant effect on the venous, arterial and coronary region with a consequent reduction in preload, afterload and an improvement in myocardial energetic metabolism. Due to these favorable effects nitrates are indicated not only in angina pectoris, acute myocardial infarction and pulmonary hypertension or hypertension crisis, but also in systolic and diastolic heart failure, in the prevention of ischemic and reperfusion damage after IMA or PCI and in the prevention of post-infarctual remodeling. Moreover, recent data concerning the protective effects of nitrates on endothelial function, suggest their possible use in the prevention of endothelial damage and atherogenesis.

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.

The endothelium plays a key role in the regulation of numerous physiological functions, including fibrinolysis, thrombosis, inflammation, cell growth and the maintenance of vascular tone. Several studies have shown that endothelial dysfunction is an early event in the course of the heart failure and changes in vascular reactivity have a series of hemodynamic consequences, including increases in total peripheral resistance and afterload, worsening of cardiac performance and a reduction in tolerance to exercise.

Organic nitrates are the oldest drugs used in patients with coronary artery disease and heart failure and are able to deliver nitric oxide (NO) directly to the vascular wall inducing the well known vasodilator effects.

Therefore, it is likely that the release of NO by organic nitrates is associated with antiaggregatory, antiadhesive, antiproliferative and antioxidative effects, all of which are considered to be vasoprotective.

Recent data from animal models suggest that treatment with high doses of isosorbide mononitrate (ISMN) reduce the progression of atherosclerosis and this reduction of morphologic changes is associated with an improvement of the endothelial function. Organic nitrates and recent mononitrates (IS-5-MN and IS-2-MN) appear useful to protect arterial endothelium and inhibit the progression of the disease in heart failure and ischemic heart disease.

Isosorbide-5-mononitrate is one of the two pharmacologically active metabolites of isosorbide dinitrate. At variance from its parent drug, it has a longer elimination half-life, no metabolic first-pass, and greater bioavailability, allowing once-daily administration as standard or as sustained-release formulations. Several trials have shown that isosorbide-5-mononitrate, in the form of sustained-released capsules administered once daily at doses ranging between 50 and 100 mg, is an effective symptomatic drug for the treatment of stable angina and chronic heart failure (CHF), and is now indicated for these conditions by American and European guidelines. In particular, at 80 mg once-daily sustained-release isosorbide-5-mononitrate has been shown to have trough plasma levels below the minimum therapeutic concentration (100 ng/mL), ensuring a nitrate-free period as sufficient as to avoid nitrate tolerance. This 80 mg dosage is the only high dose sustained-release formulation of isosorbide-5-mononitrate currently marketed in Italy. Isosorbide-5-mononitrate also exerts positive hemodynamic effects (reduction in filling pressure and systemic vascular resistance, with increase in cardiac output) in heart failure in association with standard medical therapy and hydralazine, with a positive impact on patient prognosis.

Nitrates are a cornerstone in the treatment of coronary heart disease and heart failure. Although they are widely used in clinical practice, their therapeutic value is partially compromised by the rapid development of tolerance. The effect of different nitrates, nitroglycerin (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-mononitrate (2MN) and the mechanism responsible for nitrate tolerance were investigated on isolated rabbit hearts and aortic strips. Preparation was stimulated by different spasmogenic agents: KCl, angiotensin II (A) and noradrenaline (NA); nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. Nitrates produced the following maximum inhibitions on NA-induced contraction: NTG 90% (10–⁶ M), ISDN 60% (10^-4 M), 5MN 55% (10–⁴ M) and 2MN 80% (10–⁴ M). In another series of experiments, preparations were pre-incubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance. After incubation a loss of vasodilator effect of nearly 50–60% was observed for all the nitrates considered except 2MN, in which the loss of effect was significantly lower (36%). The cyclic GMP (cGMP) levels measured in the preparations were lower in the presence of 2MN than in the other compounds. These data suggest that 2MN is able to induce a lesser cGMP increase and a lesser tolerance induction; since these observations seem to be correlated the vasodilator effect of 2MN probably involves mechanisms other than guanylyl cyclase stimulation.

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.