INTERDEPENDENCE OF PHARMACOLOGICALLY-INDUCED AND ENDOTHELIUM-MEDIATED CORONARY VASODILATION IN ANTIANGINAL THERAPY
SUMMARY. Recent advances in the understanding of vascular physiology have furnished new aspects in the treatment of angina pectoris by various vasodilators. Upon stimulation by various factors (viscous drag from increased flow, pulsatile stretch, ADP/ATP, norepinephrine, serotonin), the coronary endothelium releases a vasodflator called endothelium-derived relaxant factor (EDRF). This factor has recently been shown to probably be nitric oxide (NO), which is identical to the active compound of nitroglycerin. EDRF (NO) dilates both large epicardial arteries and also coronary resistance vessels. It also has a strong platelet antiaggregant effect. The predominant effect of Ca 2+ antagonists is on resistance vessels, increasing myocardial perfusion and viscous drag acting upon the endothelial lining. This, in turn, stimulates EDRF (NO) release in epicardial arteries and dilation. This additional nitrate-like effect augments the direct vasodilator effect of Ca 2+ antagonists. Lack of normal endothelial function results in diminished capacity to dilate, and sometimes even in a shift from dilator to constrictor effects, paralleled by an increased tendency for platelet adhesion, activation, and thrombosis, which is still enhanced when plasma low density lipoprotein (LDL) is augmented. EDRF release, vasodilator capacity, and antiaggregant effects are reduced when LDL is high. Nitrates have a direct, endothelium-independent dilator effect, particularly on large coronary arteries, which seems even more pronounced when the endothelium is absent, but only when the vessel segment is still compliant. Therefore nitrates may particularly be effective in vessels with deficient EDRF release. KEY WORDS. endothelial relaxing factor, nitric oxide, nitrovasodilator action, low density lipoproteins, flow-dependent dilation Vasodilators remain essential pharmacological tools in the treatment of ischemic heart disease. Recent advances in the understanding of vascular physiology have led to new insight into the complex interactions among blood components, elements of the vessel wall, and therapeutic vasodilator agents. The endothelium, by virtue of the potent endothelium-derived relaxing factor (EDRF), plays a critical role in coordinating these interactions and, under physiological conditions, in maintaining an appropriate level of vessel dilation and blood fluidity. However, disturbance of this important endothelial function in disease can initiate a series of negative consequences, which can, in a "vicious cycle" of increased aggregability, lead to vascular occlusion and infarction. The purpose of this