An artery has many masters.

D uring the last 25 years, a large number of stimuli have been reported to alter the tone of the coronary arteries. Arterial caliber is now known to be affected by the distending pressure, by factors external to the artery (e.g., neural stimulation and humoral substances in the blood perfusing the arterial wall), by the substances produced by the arterial endothelium, and by metabolically mediated changes in microvascular tone.1-3 In addition, many stimuli selectively affect one part of the vasculature (e.g., large epicardial vessels) differently from other portions of the arterial tree (e.g., the microvasculature).45 Despite the large body of information accumulated about the potential effects of specific molecules and stimuli on coronary function, a wide breach exists between the knowledge of what a stimulus can do in highly specified experimental conditions and what it actually does in humans. Compounds that exert profound effects on arterial tone when administered in supraphysiologic doses may have minimal effects See p 850 when studied at physiologic concentrations. Neural reflexes present in animal models are not always operative in humans.6 Furthermore, diseases not present in experimental preparations appear to alter the normal response to many stimuli, making difficult the extrapolation of experimental data obtained in normal animals to patients with atherosclerosis or other pathologic abnormalities.7-16 Hence, the coronary artery is capable of responding to many masters but to which masters is it compelled to respond to and under what in vivo conditions can the response be modified? In this issue of Circulation, Nabel et a117 described an important observation in search of a mechanism. They examined the effects of rapid atrial pacing on the caliber of the epicardial coronary arteries and coronary blood flow. In normal arteries, they found the expected: pacing resulted in an increase in coro-The opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. nary blood flow and dilation of the epicardial vessel. Presumably, the initial increase in blood flow was caused by metabolically mediated microvascular dila-tion. Relaxation of the large upstream coronary artery followed as a result of endothelial-dependent large vessel dilation. In nonstenotic atherosclerotic vessels, pacing failed to elicit large vessel dilation, presumably related to loss of endothelially mediated flow-dependent vasodilation. Surprisingly, however, pacing also failed to cause an increase in coronary blood flow. More surprisingly, in severely stenotic vessels, both large vessel caliber and coronary blood flow fell …