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. The mechanisms by which tolerance develops are not completely understood.As noted above,diminished release of nitric oxide resulting from depletion of tissue thiol compounds may be partly responsible for tolerance to nitroglycerin.Systemic compensation also plays a role in tolerance in the intact human.Initially,significant sympathetic discharge occurs and after one or more days of therapy with long-acting nitrates,retention of salt and water may reverse the favorable hemodynamic changes normally caused by nitroglycerin. C.CARCINOGENICITY OF NITRATE AND NITRATE 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.While 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 different 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 A.NITRATE EFFECTS IN ANGINA OF EFFORT Decreased venous return to the heart and the resulting reduction of intracardiac volume are the principal hemodynamic effects.Arterial pressure also decreases. Decreased intraventricular 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.Coronary arteriolar resistance tends to decrease,although to a lesser extent.However,nitrates administered by the usual systemic routes also consistently decrease overall coronary blood flow and myocardial oxygen consumption.The reduction in oxygen consumption 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 1111 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. The mechanisms by which tolerance develops are not completely understood. As noted above, diminished release of nitric oxide resulting from depletion of tissue thiol compounds may be partly responsible for tolerance to nitroglycerin. Systemic compensation also plays a role in tolerance in the intact human. Initially, significant sympathetic discharge occurs and after one or more days of therapy with long-acting nitrates, retention of salt and water may reverse the favorable hemodynamic changes normally caused by nitroglycerin. C. CARCINOGENICITY OF NITRATE AND NITRATE 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. While 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 different 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 A. NITRATE EFFECTS IN ANGINA OF EFFORT Decreased venous return to the heart and the resulting reduction of intracardiac volume are the principal hemodynamic effects. Arterial pressure also decreases. Decreased intraventricular 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. Coronary arteriolar resistance tends to decrease, although to a lesser extent. However, nitrates administered by the usual systemic routes also consistently decrease overall coronary blood flow and myocardial oxygen consumption. The reduction in oxygen consumption 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