Tolerance does not occur equally with all nitric oxide donors. Nitroprusside, for example, retains activity over long periods. Other organic nitrates appear to be less susceptible than nitroglycerin to the development of tolerance. In cell-free systems, soluble guanylate cyclase is inhibited, possibly by nitrosylation of the enzyme, only after prolonged exposure to exceedingly high nitroglycerin concentrations. In contrast, treatment with antioxidants that protect ALDH2 and similar enzymes appears to prevent or reduce tolerance. This suggests that tolerance is a function of diminished bioactivation of organic nitrates and, to a lesser degree, a loss of soluble guanylate cyclase responsiveness to nitric oxide.
Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured. When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness (“Monday disease”). After a day or so, these symptoms disappear owing to the development of tolerance. Over the weekend, when exposure to the chemicals is reduced, tolerance disappears, so symptoms recur each Monday. Other hazards of industrial exposure, including dependence, have been reported. There is no evidence that physical dependence develops as a result of the therapeutic use of short-acting nitrates for angina, even in large doses.
C. Carcinogenicity of Nitrate and Nitrite Derivatives
Nitrosamines are small molecules with the structure R2–N–NO formed from the combination of nitrates and nitrites with amines. Some nitrosamines are powerful carcinogens in animals, apparently through conversion to reactive derivatives. Although there is no direct proof that these agents cause cancer in humans, there is a strong epidemiologic correlation between the incidence of esophageal and gastric carcinoma and the nitrate content of food in certain cultures. Nitrosamines are also found in tobacco and in cigarette smoke. There is no evidence that the small doses of nitrates used in the treatment of angina result in significant body levels of nitrosamines.
Mechanisms of Clinical Effect
The beneficial and deleterious effects of nitrate-induced vasodilation are summarized in Table 12–2.
A. Nitrate Effects in Angina of Effort
Decreased venous return to the heart and the resulting reduction of intracardiac volume are important beneficial hemodynamic effects of nitrates. Arterial pressure also decreases. Decreased intra-ventricular pressure and left ventricular volume are associated with decreased wall tension (Laplace relation) and decreased myocardial oxygen requirement. In rare instances, a paradoxical increase in myocardial oxygen demand may occur as a result of excessive reflex tachycardia and increased contractility.
Intracoronary, intravenous, or sublingual nitrate administration consistently increases the caliber of the large epicardial coronary arteries except where blocked by concentric atheromas.
TABLE 12–2 Beneficial and deleterious effects of nitrates in the treatment of angina.
Vasodilation of epicardial Relief of coronary artery spasm coronary arteries
Increased collateral flow Improved perfusion of ischemic myocardium
Coronary arteriolar resistance tends to decrease, though to a lesser extent. However, nitrates administered by the usual systemic routes may decrease overall coronary blood flow (and myocardial oxygen consumption) if cardiac output is reduced due to decreased venous return. The reduction in oxygen demand is the major mechanism for the relief of effort angina.
B. Nitrate Effects in Variant Angina
Nitrates benefit patients with variant angina by relaxing the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm.
C. Nitrate Effects in Unstable Angina