The predominant venodilator properties of the
nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the
nitrates to replenish the deficient
endothelium-derived relaxing factor (EDRF),
nitric oxide (NO), in patients with
coronary heart disease and also to inhibit platelet aggregation. In
stable angina pectoris, the antianginal and antiischemic effects of oral
nitrates are well established. Continuous administration of
nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral
nitrates without provocation of anginal attacks during periods of low
nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release
isosorbide-5-mononitrate in patients with
stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of
myocardial ischemia. In
unstable angina pectoris,
nitrates rapidly relieve
chest pain and ameliorate the electrocardiographic signs of
myocardial ischemia. In patients with acute
myocardial infarction, early treatment with
nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic
heart failure, oral
nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator
hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral
nitrates reduced
infarct size and morbidity and mortality in patients with acute
myocardial infarction. In the ISIS 4 post-
infarction study,
isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of
nitrates with an
angiotensin-converting enzyme (
ACE) inhibitor reduced mortality risks by 17% in patients with acute
myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with
nitrates for control of rest angina,
myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label
nitrates in the control groups may have diluted the true beneficial effects of
nitrates in both studies. Taken together, these many studies with oral
nitrate treatment in
coronary heart disease and
heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to
coronary artery disease.