Serotonin selectively aggravates subendocardial ischemia distal to a coronary artery stenosis during exercise

Background. The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischemia. Because serotonin possesses both vasodilator and vasoconstrictor properties, we examined its effect in the coronary circulation distal to an arterial stenosis that resulted in myocardial hypoperfusion during exercise. Methods and Results. Seven chronically instrumented dogs were studied during treadmill exercise in the presence of a stenosis that reduced distal left circumflex coronary artery perfusion pressure to 42±1 mm Hg. Myocardial blood flow was assessed with radioactive microspheres during exercise before and during intracoronary infusion of 0.4 and 2.0 μg/kg^-1·min^-1 serotonin. The stenosis was adjusted to maintain distal coronary pressure constant during control exercise and with the two doses of serotonin. In seven dogs, the effect of serotonin (2.0 μg/kg^-1·min^-1) was also studied during exercise with normal arterial inflow. During control exercise, the stenosis decreased mean myocardial blood flow to 45% of flow in the normally perfused region. This decrease was most pronounced in the subendocardium (endocardial/epicardial ratio 0.36±0.06 versus 1.46±0.14 in the control region; p<0.01). With no change in pressure distal to the stenosis, serotonin decreased subendocardial flow from 0.51±0.09 ml/min^-1·g^-1 to 0.41±0.12 (p<0.05) and then to 0.35±0.08 ml/min^-1·g^-1 (p<0.05) and tended to increase subepicardial flow from 1.47±0.17 to 1.91±0.23 and 1.85±0.21 ml/min^-1·g^-1 (p=0.08) during infusions of 0.5 and 2.0 μg/kg^-1·min^-1, respectively, with no change in total arterial inflow. In contrast, in the absence of a stenosis, serotonin (2.0 μg/kg^-1·min^-1) increased subendocardial flow from 2.43±0.25 to 3.73±0.25 ml/min^-1·g^-1 (p<0.01) and subepicardial flow from 1.88±0.20 to 5.29±0.38 ml/min^-1·g^-1 (p<0.01). Conclusions. During normal arterial inflow, serotonin dilated coronary resistance vessels and increased flow to all myocardial layers. During hypoperfusion, a vasodilator response was still present in the subepicardium, but vasoconstriction was then observed in the subendocardium. Our data suggest that serotonin constricts the intramural penetrating arteries, thereby selectively increasing resistance to subendocardial blood flow.