Organic nitrates in cardiovascular disease

Therapeutic activation of the vascular NO/cGMP pathway is induced by a variety of stimuli/mediators including physical activity, supplementation with the precursor L-arginine and organic nitrates which generate NO in the vasculature. The necessity of an enzymatic reduction for NO generation from these drugs as well as differences in the activity of the NO/cGMP pathway within the vascular tree determine the unique hemodynamic changes elicited by organic nitrates. These changes include preferential venodilation, vessel-size specific arterial dilation and improvement of the aortic distensibility and Windkessel-function. Some animal experiments and clinical investigations suggest that nitrates may also be endowed with cardioprotective and/or vasoprotective effects. "Early entry" therapy with nitrates do not significantly improve survial in myocardial infarction but increases the beneficial effects of the ACE-inhibitor enalapril by 50%. Furthermore, nitrates have been shown to improve survival in heart failure, but prognostic effects in stable angina pectoris are unknown. Short-term experimental and clinical investigations suggest that nitrate tolerance induced by nitroglycerin is associated with toxic effects in the vasculature, but this is not true for pentaerythrityl tetranitrate and isosorbide mononitrate. The observed endothelial dysfunction induced by a continuous treatment with nitroglycerin may be an additional risk for patients who receive continuous nitroglycerin to treat conditions such as unstable angina and acute heart failure. In general, nitrates are remarkably safe drugs and are well tolerated. Appropriate clinical trials are needed to answer the question whether nitrates can do more than symptomatic relief in cardiovascular disease.