be only partially prevented or reversed with a sulfhydryl-regenerating agent. Increased generation of oxygen free radicals during nitrate therapy may be another important mechanism of tolerance. Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action,thus providing an additional mechanism for causing vasodilation. B.ORGAN SYSTEM EFFECTS Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone (Figure 3).It has practically no direct effect on cardiac or skeletal muscle. 1.Vascular smooth muscle All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin.Veins respond at the lowest concentrations,arteries at slightly higher ones.Arterioles and precapillary sphincters are dilated less than the large arteries and the veins,partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide.The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload.Pulmonary vascular pressures and heart size are significantly reduced.In the absence of heart failure,cardiac output is reduced.Because venous capacitance is increased,orthostatic hypotension may be marked and syncope can result.Dilation of some large arteries (including the aorta)may be significant because of their large increase in compliance.Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite.In heart failure,preload is often abnormally high;the nitrates and other vasodilators,by reducing preload,may have a beneficial effect on cardiac output in this condition. The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure; this consistently results in tachycardia and increased cardiac contractility.Retention of salt and water may also be significant,especially with intermediate-and long-acting nitrates.These compensatory responses contribute to the development of tolerance. In normal subjects without coronary disease,nitroglycerin can induce a significant,if transient,increase in total coronary blood flow.In contrast,there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease.However,some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin's therapeutic effect.Nitroglycerin also exerts a weak negative inotropic effect via nitric oxide. 77 be only partially prevented or reversed with a sulfhydryl-regenerating agent. Increased generation of oxygen free radicals during nitrate therapy may be another important mechanism of tolerance. Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action, thus providing an additional mechanism for causing vasodilation. B. ORGAN SYSTEM EFFECTS Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone (Figure 3). It has practically no direct effect on cardiac or skeletal muscle. 1. Vascular smooth muscle All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin. Veins respond at the lowest concentrations, arteries at slightly higher ones. Arterioles and precapillary sphincters are dilated less than the large arteries and the veins, partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide. The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. Pulmonary vascular pressures and heart size are significantly reduced. In the absence of heart failure, cardiac output is reduced. Because venous capacitance is increased, orthostatic hypotension may be marked and syncope can result. Dilation of some large arteries (including the aorta) may be significant because of their large increase in compliance. Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite. In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output in this condition. The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure; this consistently results in tachycardia and increased cardiac contractility. Retention of salt and water may also be significant, especially with intermediate- and long-acting nitrates. These compensatory responses contribute to the development of tolerance. In normal subjects without coronary disease, nitroglycerin can induce a significant, if transient, increase in total coronary blood flow. In contrast, there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease. However, some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin's therapeutic effect. Nitroglycerin also exerts a weak negative inotropic effect via nitric oxide