Divergent Effects of Serotonin on Coronary-Artery Dimensions and Blood Flow in Patients with Coronary Atherosclerosis and Control Patients
List of authors.Abstract
Background.
Studies in animals have shown that serotonin constricts coronary arteries if the endothelium is damaged, but in vitro studies have revealed a vasodilating effect on isolated coronary segments with an intact endothelium. To investigate the effect of serotonin in humans, we studied coronary-artery cross-sectional area and blood flow before and after the infusion of serotonin in seven patients with angiographically normal coronary arteries and in seven with coronary artery disease.
Methods.
We measured the cross-sectional area of the coronary artery by quantitative angiography and coronary blood flow with an intracoronary Doppler catheter. Measurements were obtained at base line and during intracoronary infusions of serotonin (0.1, 1, and 10 μg per kilogram of body weight per minute, for two minutes). We repeated the measurements after an infusion of ketanserin, an antagonist of serotonin receptors that is thought to block the effect of serotonin on receptors in the arterial wall but not in the endothelium.
Results.
In patients with normal coronary arteries, the highest dose of serotonin increased cross-sectional area by 52 percent (P<0.001) and blood flow by 58 percent (P<0.01). The effect was significantly potentiated by administration of ketanserin. In patients with coronary-artery atherosclerosis, serotonin reduced cross-sectional area by 64 percent (P<0.001) and blood flow by 59 percent (P<0.001). Ketanserin prevented this effect.
Conclusions.
Serotonin has a vasodilating effect on normal human coronary arteries; when the endothelium is damaged, as in coronary artery disease, serotonin has a direct, unopposed vasoconstricting effect. When considered with other evidence, these data suggest that platelet-derived factors such as serotonin may have a role in certain acute coronary ischemic syndromes. (N Engl J Med 1991; 324:641–8.)
Methods
Patient Selection
We enrolled 14 patients referred to our institution for cardiac catheterization and coronary angiography, selecting them according to the criteria described below. These patients were divided into two groups on the basis of the presence or absence of coronary atherosclerosis, as documented by the diagnostic angiogram.
One group consisted of patients with angiographically normal coronary arteries. To reduce the possibility of including patients with abnormal coronary vasomotion, we selected only patients referred to the catheterization laboratory for the evaluation of mitral stenosis without concomitant clinical evidence of coronary artery disease. By performing complete catheterization of the right and left portions of the heart and coronary angiography, we identified seven patients (mean [±SEM] age, 46±4; range, 41 to 53) with mild-to-moderate mitral stenosis who had no history of angina pectoris. Each had normal-appearing arteries on coronary arteriography.
The other group consisted of patients with coronary-artery atherosclerosis. Seven patients (mean age, 54±5; range, 48 to 63) with advanced coronary artery disease, as defined by the presence of a stenosis of ≥50 percent of the luminal diameter in at least one coronary artery and a concomitant, less severe stenosis (between 30 and 50 percent) in another coronary artery, were included in this group. Each patient had stable effort angina and a positive standard stress test for myocardial ischemia.
Patients were excluded from the study if they had unstable angina, Prinzmetal's variant angina, diabetes mellitus, a history or electrocardiographic evidence of myocardial infarction, left ventricular hypertrophy (on echocardiography), left ventricular dysfunction (left ventricular ejection fraction <50 percent, or regional wall-motion abnormalities), or valvular heart disease other than mild-to-moderate mitral stenosis.
The study was approved by the institutional review board of the University of Naples, and informed consent was obtained from each patient studied.
Study Design
The patients were brought to the cardiac-catheterization laboratory in a fasting state. All medications were discontinued 48 hours before the study. Heparin (10,000 units) was administered at the beginning of the catheterization procedure. At the completion of the diagnostic catheterization and coronary angiography, an additional 5000 units of heparin was administered, followed by 500 mg of lysine aspirin given intravenously (Aspegic, Lirca, Milan, Italy). Then, a 3-French 20-MHz intracoronary Doppler catheter (NuMed, Hopkinton, N.Y.) was advanced through an 8-French large-lumen coronary guiding catheter (USCI Bard, San Francisco) over a flexible guide wire (Advanced Catheter System, Temecula, Calif.) into a coronary artery (the left anterior descending artery in five patients, the circumflex artery in four, and the right coronary artery in five). In the patients with coronary atherosclerosis, the Doppler catheter was placed in a coronary artery with a stenosis of less than 50 percent of the luminal diameter, with its tip just proximal to the stenosis. Care was taken to position the catheter in a coronary segment with no collateral branch. The position and range gate of the catheter were adjusted to obtain an adequate tracing of phasic coronary blood-flow velocity within the artery. Phasic and mean coronary blood-flow velocity (expressed in centimeters per second), mean arterial pressure (measured through the side port of the arterial sheath), and the electrocardiographic tracing were recorded continuously on a multichannel recorder (Siemens Mingograf 804, Erlangen, Germany).
Serial two-minute intracoronary infusions of vasoactive agents were administered through the lumen of the Doppler catheter in the following sequence: base line 1 (5 percent dextrose in water); graded concentrations of serotonin (0.1, 1, and 10 μg per kilogram of body weight per minute); base line 2 (5 percent dextrose in water, five minutes after the intravenous administration of ketanserin, a selective 5–HT2—receptor antagonist,18 in a dose of 0.25 mg per kilogram); and repeated infusion of serotonin in graded concentrations (0.1, 1, and 10 μg per kilogram per minute). Finally, 200 μg of nitroglycerin was administered into the coronary artery over a period of one minute as an internal control. All the infusions were carried out with a Harvard pump set at a flow rate never exceeding 1 ml per minute. At the end of each infusion, coronary arteriography was performed and the coronary blood-flow velocity, electrocardiographic tracing, and arterial pressure were recorded. A period of at least five minutes was allowed to elapse between infusions.
Quantitative Angiography
Quantitative coronary angiography was performed as previously described by Spears et al.19 Coronary angiograms were recorded on 35-mm cine film (Kodak CFR, Milan) at a rate of 50 frames per second. Four to six milliliters of nonionic contrast medium (iohexol [Omnipaque], Schering, Berlin, Germany) was injected manually into the coronary artery under study. The projection that allowed the best visualization of the coronary artery under study was chosen from among the diagnostic angiograms and was used consistently throughout the study.
The 35-mm film was projected with a Cipro 35 projector (Siemens), and the end-diastolic frame selected for analysis was scanned with a Siemens K 30 video camera. The signal produced by the video camera was digitized and processed by a video digitizer and analyzed with a software system on a MIP D computer (Kontron, Dortmund, Germany) provided with an automatic edge-detection algorithm. To ensure reproducibility of the measurements, 1-cm segments of the coronary artery were selected, starting from the tip of the Doppler catheter. The diameter of the guiding catheter in the field of view was used to convert the imaging data from pixels to millimeters. A series of measurements of the diameter were recorded for each pixel line along the length of the arterial segment, and the data were also displayed as a graph plotting diameter against length. With the use of the graphic display of diameter as a function of length, four 2.5-mm segments were measured and averaged. To distinguish the effects of vasoactive drugs on coronary-artery diameter from those related to increases in coronary blood flow, the same measurements were obtained for a 1-cm coronary segment proximal to the tip of the Doppler catheter — i.e., in a segment not directly exposed to vasoactive drugs.
We had previously determined the intraobserver variability of quantitative coronary angiography in our system in a pilot study analyzing cine films of 11 plexiglass blocks containing precision-drilled models of coronary arteries filled with contrast medium. The mean intraobserver variability (±SD) (determined by repeated analysis of the cineangiograms by one observer) was 2.3±1.8 percent. Finally, all measurements were made by an investigator who was unaware of the patients' group assignments.
Measurements of Coronary Blood-Flow Velocity
The Doppler catheter was connected to a 20-MHz Doppler velocimeter (model MDV 20, Millar Instruments, Houston). This technique for measuring subselective coronary blood-flow velocity has recently been described; it has been found to be safe and reliable in patients with coronary atherosclerotic lesions and those with normal arteries.20 21 22 To obtain an estimate of coronary blood flow in millimeters per minute, the cross-sectional area of the coronary artery (in square centimeters) was multiplied by the mean blood velocity (in centimeters per second) and by 60 seconds.23
Drugs
Ketanserin (Sufrexal; 2-ml vials, 5 mg per milliliter) was obtained from Janssen Pharmaceuticals (Rome). Serotonin (as creatinine sulfate) was purchased from Sigma Products (St. Louis). A solution of serotonin (1 mg per milliliter) was prepared by dissolving the agent in 5 percent dextrose in water. This solution was then filtered through a sterilizing filter (pore size, 0.22 μm) and stored frozen in aliquots at –20°C until the day of the study. The solutions were checked periodically for sterility and the presence of pyrogens.
Statistical Analysis
All data are expressed as means ±SEM. For comparisons of hemodynamic functions and coronary-artery dimensions, a one-way analysis of variance with a design for repeated measures was used. When an F value was found to be significant, a two-tailed Student t-test for paired observations with the Bonferroni correction was used to test differences among the effects of doses.
Results
Systemic Hemodynamic Function
Mean blood pressure averaged 97±6 mm Hg in the group with normal arteries and 94±7 mm Hg in the group with atherosclerotic arteries. Intracoronary infusions of serotonin (up to 10 μg per kilogram per minute) both before and after the administration of ketanserin had no effect on arterial pressure in either group. A small but significant reduction in mean arterial pressure was observed after the administration of ketanserin (to 91±5 mm Hg in the normal group and 87±4 mm Hg in the group with atherosclerosis; P<0.05 for both groups). This decrease in mean blood pressure persisted for the remainder of the study period and was probably due to a slight alpha1-antagonist property of the drug.24 Heart rate did not change significantly in either group throughout the study.
Changes in Coronary-Artery Blood Flow and Dimensions
Patients with Angiographically Normal Coronary Arteries
Figure 1.
Figure 1. Effects of Intracoronary Serotonin on Coronary-Artery Cross-Sectional Area during Diastole in Seven Patients with Angiographically Normal Coronary Arteries. The change in area is expressed as a percentage of the base-line value (±SEM). Serotonin caused a dose-dependent dilation of distal coronary segments — i.e., segments directly exposed to serotonin – from a base-line value of 6.6±0.9 mm2; this dilation was significantly potentiated by the administration of ketanserin, a selective 5-HT2—receptor antagonist. Intracoronary nitroglycerin (200 μg) caused a dilation similar in extent to that observed after the highest dose of serotonin.
Proximal coronary segments — i.e., segments not directly exposed to serotonin — had a significant increase in cross-sectional area during serotonin- and nitroglycerin-mediated increases in coronary blood flow, from a base-line value of 6.7±1.0 mm2. These increases in cross-sectional area were significantly less pronounced, however, than those observed in distal coronary segments.
A single asterisk denotes a significant change from base line (P<0.001), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.05).
Figure 2.
Figure 2. Effect of Serotonin on the Left Anterior Descending Artery of a Patient with Normal Coronary Arteries. The base-line angiogram (right anterior oblique projection) shows the tip of the Doppler catheter, placed in the artery (Panel A, arrow) over a guide wire. During infusion of the highest dose of serotonin (10 μg per kilogram per minute), a significant dilation of the artery was observed (Panel B).
A dose-dependent dilation of coronary-artery segments distal to the site of infusion was observed in response to serotonin in all patients with angiographically normal coronary arteries (Fig. 1). The highest dose of intracoronary serotonin (10 μg per kilogram per minute) caused dilation of these segments, from a mean control value for diastolic cross-sectional area of 6.6±0.9 mm2 to 9.3±0.8 mm2 — an increase of 41 percent (P<0.001) (Fig. 1). To differentiate between possible flow-dependent dilation and the direct effects of serotonin on epicardial coronary cross-sectional area, this variable was measured in coronary segments proximal to the site of infusion that were not directly exposed to serotonin. These segments dilated significantly less than distal coronary segments during administration of the highest dose of serotonin, from a mean base-line value of 6.7± 1.0 mm2 to 7.8±1.0 mm2 — an increase of 16 percent (P<0.01, as compared with corresponding values obtained in distal segments) (Fig. 1) — thus indicating that serotonin exerted a direct vasodilating effect on angiographically normal coronary arteries. Figure 2 shows the vasodilating effect of serotonin in one of the patients in this group.
Figure 3.
Figure 3. Serotonin-Induced Changes in Coronary-Artery Blood Flow in the Patients with Normal Coronary Arteries. The change in flow is expressed as a percentage of the base-line value (±SEM). Flow was significantly increased during intracoronary serotonin infusion, from a base-line value of 75±5 ml per minute. This increase was significantly potentiated by the blockade of 5-HT2 receptors by ketanserin. Intracoronary nitroglycerin caused an increase in flow that was approximately twice that caused by serotonin.
A single asterisk denotes a significant change from base line (P<0.01), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.05).
Estimated coronary blood flow (coronary blood-flow velocity corrected for changes in coronary cross-sectional area) showed a dose-dependent increase in response to serotonin, from a base-line value of 75±5 ml per minute to 116±8 ml per minute during infusion of the highest dose (P<0.01) (Fig. 3).
To identify the type of serotonin receptors responsible for the observed vasodilation, we repeated the measurements of coronary diastolic cross-sectional area and coronary blood flow after the intravenous administration of ketanserin, a selective 5-HT2—receptor antagonist. Ketanserin itself did not have any effect on the cross-sectional area, which was 6.6±0.9 mm2 at base line 1 and 6.5±0.9 mm2 at base line 2 (i.e., after the administration of ketanserin; P not significant). Similarly, resting coronary blood flow remained unchanged after the administration of ketanserin, as compared with values at base line 1. In contrast, ketanserin caused a significant potentiation of the vasodilating effects of serotonin, both on large epicardial coronary vessels and on coronary resistance vessels, as shown by the significant increase in coronary cross-sectional area (Fig. 1) and coronary blood flow (Fig. 3), as compared with the corresponding values obtained before ketanserin administration. Nitroglycerin, an endothelium-independent vasodilator, administered by intracoronary infusion at the end of the study, significantly increased both cross-sectional area (Fig. 1) and blood flow (Fig. 3).
Patients with Coronary-Artery Atherosclerosis
Figure 4.
Figure 4. Effects of Intracoronary Serotonin on Coronary Cross-Sectional Area during Diastole in Seven Patients with Atherosclerotic Coronary Arteries. The change in area is expressed as a percentage of the base-line value (±SEM). Values obtained during infusion of 10 μg of serotonin represent the means in three patients. Serotonin caused a dose-dependent constriction of the distal segments, from a baseline value of 5.1±0.6 mm2. Such vasoconstriction was completely absent after the administration of ketanserin, thus suggesting a 5-HT2—receptor—mediated mechanism. Endothelium-independent dilation was preserved in these patients, since cross-sectional area increased during intracoronary nitroglycerin administration.
No significant changes were observed in the proximal coronary segments during serotonin infusions, both before and after administration of ketanserin and during intracoronary nitroglycerin, thus suggesting an impairment of flow-mediated dilation in these patients.
A single asterisk denotes a significant change from base line (P<0.001), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.001).
Figure 5.
Figure 5. Effect of Serotonin on the Right Coronary Artery of a Patient with Coronary Atherosclerotic Lesions. The Doppler catheter (not visible) was positioned in the midportion of the artery (Panel A, arrow), shown in the right anterior oblique projection on base-line angiography. During infusion of serotonin (10 μg per kilogram per minute), a marked constriction of the coronary arterial segments distal to the infusion site was observed (Panel B, arrow).
The seven patients with coronary artery disease had atherosclerosis that was at least moderately severe (i.e., a stenosis of 50 percent or more of the luminal diameter) in at least one vessel. However, we studied the effects of serotonin on coronary arteries with a stenosis of less than 50 percent of the luminal diameter, as determined during diagnostic angiography. In all seven patients, dose-dependent constriction occurred in the coronary segments distal to the site of serotonin infusion, whereas coronary cross-sectional area remained unchanged in the proximal segments not exposed to serotonin (Fig. 4). Coronary-artery cross-sectional area decreased from a base-line value of 5.1±0.6 mm2 to 1.4±0.4 mm2 during the second infusion of serotonin (1 μg per kilogram per minute) — a decrease of 64 percent (P<0.001) (Fig. 4). Four patients did not receive the highest dose (third infusion) of serotonin because their cross-sectional area decreased severely during the second infusion. Figure 5 shows the effects of the highest dose on coronary dimensions in one of the three patients who received this dose.
Figure 6.
Figure 6. Serotonin-Induced Changes in Coronary Blood Flow in the Patients with Atherosclerotic Coronary Arteries. Values obtained during infusion of 10 μg of serotonin represent the means in three patients.
A marked reduction in coronary blood flow was observed during intracoronary serotonin administration, from a base-line value of 72±5 ml per minute. This reduction in blood flow was completely prevented by the blockade of 5-HT2 receptors by ketanserin. Intracoronary nitroglycerin caused a significant increase in coronary blood flow, to a lesser extent than that observed in the patients with normal coronary arteries.
A single asterisk denotes a significant change from base line (P<0.001), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.001).
Coronary-artery blood flow decreased significantly and in a dose-dependent way during the intracoronary administration of serotonin in this group of patients (Fig. 6). Both coronary blood flow and coronary cross-sectional area measured after the administration of ketanserin (base line 2) did not differ from the corresponding values at base line 1. Ketanserin prevented the vasoconstricting effects of serotonin, since the values for cross-sectional area and blood flow after ketanserin administration were not different from the corresponding base-line values (Fig. 4 and 6). Endothelium-independent dilation of the distal coronary segments was preserved in the patients; the intracoronary infusion of nitroglycerin resulted in a significant dilation of the distal coronary-artery segments in all patients, with a mean increase in cross-sectional area from 5.1±0.6 mm2 to 6.3±0.7 mm2 — a 23 percent increase above the control luminal diameter (P<0.01) (Fig. 4) — and resulted in a significant increase in coronary-artery blood flow (Fig. 6). However, the response to nitroglycerin was reduced in these patients as compared with the patients with angiographically normal coronary arteries (P<0.01).
Discussion
The chief finding of the present study is that serotonin exerts divergent effects on the coronary circulation of patients with coronary atherosclerotic lesions and those with normal coronary arteries. Indeed, several in vitro and in vivo studies have demonstrated that serotonin can both dilate and constrict the coronary vessels of various species, its net effect being related to the presence or absence of a normal endothelium.13 14 15 16 17
Our study demonstrates that the net effect of serotonin in patients with angiographically normal coronary arteries is dilation of both epicardial and coronary resistance vessels. The increase in coronary cross-sectional area was only partially mediated by an increase in coronary blood flow, since coronary segments directly exposed to serotonin dilated significantly more than segments not directly exposed. This suggests that serotonin-induced vasodilation is primarily a direct effect on epicardial coronary arteries. This finding is in agreement with a study in dogs by Chu and Cobb,15 in which the authors found only a slight attenuation of serotonin-induced coronary vasodilation when coronary flow was kept constant.
In contrast, when serotonin was infused into the coronary arteries of patients with atherosclerotic lesions, the net effect of this amine was a paradoxical constriction of coronary-artery segments directly exposed to it and a commensurate decrease in coronary blood flow. Because the vasodilating effects of serotonin are thought to be mediated through the release of labile humoral factors from the endothelium, termed "endothelium-derived relaxing factors" (EDRFs), the marked vasoconstriction observed in patients with coronary atherosclerosis in response to serotonin is consistent with the hypothesis that the endothelium of such patients is unable to synthesize or release adequate amounts of EDRFs,25 thus unmasking the vasoconstricting effects of serotonin.
In patients with angiographically normal coronary arteries, serotonin, significantly increased coronary blood flow, indicating that this agent is also able to relax small coronary resistance vessels. This finding agrees with those of several experimental studies that described a marked coronary arteriolar vasodilation induced by serotonin.14 , 15 , 17 When infused in patients with atherosclerotic lesions, however, serotonin caused a marked reduction in coronary blood flow. This reduction could be due to a direct vasoconstricting effect of serotonin on small resistance vessels (because of a dysfunctional endothelium), to the concomitant decrease in epicardial coronary cross-sectional area, or to both phenomena. However, the observation that coronary blood flow did not increase during serotonin infusions after blockade of 5-HT2, receptors by ketanserin (i.e., in the absence of reductions in coronary cross-sectional area) suggests that the endothelium of coronary arterioles is unable to synthesize or release adequate amounts of EDRFs in patients with coronary atherosclerotic lesions.
Effects of 5–HT2—Receptor Blockade on Serotonin-Induced Responses
To clarify the mechanisms of serotonin-induced vasoactive effects on the human coronary circulation, we measured coronary-artery cross-sectional area and blood flow after the administration of ketanserin, a selective 5-HT2—receptor antagonist. In patients with angiographically normal coronary arteries, ketanserin significantly potentiated the vasodilating effects of serotonin on both epicardial and coronary resistance vessels. This indicates that in humans, serotonin-induced coronary dilating effects are mediated through the activation of non—5-HT2 receptors, probably the 5-HT1 type located on endothelial cells. This finding is in agreement with those of other studies, which demonstrated that the endothelium-dependent dilation induced by serotonin can be prevented by methysergide and metitepine (methiothepin), which are nonselective (5-HT1 or 5-HT2) antagonists, whereas it is not affected by 5-HT2—receptor antagonists, such as ketanserin,15 thus suggesting the activation of non—5-HT2 receptors, probably of the 5-HT1 type.
In patients with coronary atherosclerotic lesions, ketanserin completely prevented serotonin-induced vasoconstriction, thus indicating that the vasoconstriction is mediated by the direct activation of 5-HT2 receptors. However, no vasodilation was observed in epicardial or coronary resistance vessels in response to serotonin after ketanserin administration, thus suggesting that endothelial dysfunction rather than a supersensitivity to vasoconstricting stimuli was the primary defect in these patients.
The doses of serotonin used in the present study were in the physiologic range in which increases in the accumulation of serotonin in the coronary artery have been observed at sites of endothelial injury and stenosis9 and in the coronary sinus of dogs with experimentally induced endothelial injury.26 In fact, we calculated that the doses we used ranged from about 2.4 ×10–7 to 2.4×10–5 mol per liter. In an experimental model of recurrent intracoronary platelet aggregation, Benedict et al. found that the serotonin concentration in the coronary sinus can increase to 2×10–6 mol per liter.26 Furthermore, when serotonin is released by aggregating platelets in numbers equivalent to those present in circulating blood, the concentration may increase to 6×10–4 mol per liter.27
We observed a significant reduction in the vasodilatory response to nitroglycerin in our patients with coronary atherosclerotic lesions. However, it is not clear from our data whether the response to nitroglycerin in these patients was reduced in itself or as a consequence of a reduction in coronary reserve due to the presence of the luminal stenosis.
Clinical Implications
Although it is still uncertain whether serotonin is important in modulating coronary-artery tone in humans, experimental studies clearly indicate its importance in altering tone in isolated coronary arteries28 29 30 31 and in vivo.11 12 13 14 15 Heistad et al. found that in monkeys with experimentally induced hypercholesterolemia or frank atherosclerosis, these conditions were associated with a marked potentiation of the vasoconstricting effects of serotonin.32 On the other hand, De Caterina et al. reported that ketanserin failed to prevent spontaneous attacks of ischemia in patients with Prinzmetal's angina, suggesting that serotonin has no role in mediating coronary-artery spasm in such patients.33
The present study provides evidence that patients with atherosclerotic coronary arteries have a paradoxical coronary vasoconstriction in response to serotonin, probably because the endothelium is unable to synthesize or release adequate amounts of EDRFs, thus leaving unopposed the vasoconstricting effects of serotonin. This study, along with other evidence,1 suggests that selected platelet-derived substances, such as serotonin, may play an important part in certain acute coronary ischemic syndromes. Further studies are needed to clarify whether 5-HT2—receptor antagonists are an effective therapy for these ischemic syndromes.
References (33)
1. Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. . Specific platelet mediators and unstable coronary artery lesions: experimental evidence and potential clinical implications . Circulation 1989; 80:198–205.
2. Hirsh PD, Hillis LD, Campbell WB, Firth BG, Willerson JT. . Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease . N Engl J Med 1981; 304:685–91.
3. van den Berg EK, Schmitz JM, Benedict CR, Malloy CR, Willerson JT, Dehmer GJ. . Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology . Circulation 1989; 79:116–24.
4. Rubanyl GM, Frye RL, Holmes DR Jr, Vanhoutte PM. . Vasoconstrictor activity of coronary sinus plasma from patients with coronary artery disease . J Am Coll Cardiol 1987; 9:1243–9.
5. Bush LR, Campbell WB, Buja LM, Tilton GD, Willerson JT. . Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries . Circulation 1984; 69:1161–70.
6. Ashton JH, Schmitz JM, Campbell WB, et al. . Inhibition of cyclic flow variations in stenosed canine coronary arteries by THROMBOXANE A2/prostaglandin H2 receptor antagonists . Circ Res 1986; 59:568–78.
7. Schmitz JM, Apprill PG, Buja LM, Willerson JT, Campbell WB. . Vascular prostaglandin and thromboxane production in a canine model of myocardial ischemia . Circ Res 1985; 57:223–31.
8. Ashton JH, Ogletree ML, Michel IM, et al. . Cooperative mediation by serotonin S2 and THROMBOXANE A2/prostaglandin H2 receptor activation of cyclic flow variations in dogs with severe coronary artery stenoses . Circulation 1987; 76:952–9.
9. Ashton JH, Benedict CR, Fitzgerald C, et al. . Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries . Circulation 1986; 73:572–8.
10. Golino P, Buja LM, Ashton JH, Kulkarin P, Taylor A, Willerson JT. . Effect of thromboxane and serotonin receptor antagonists on intracoronary platelet deposition in dogs with experimentally stenosed coronary arteries . Circulation 1988; 78:701–11.
11. Golino P, Ashton JH, Buja LM, et al. . Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo: THROMBOXANE A2 and serotonin are possible mediators . Circulation 1988; 79:154–66.
12. Golino P, Buja LM, Yao SK, McNatt J, Willerson JT. . Failure of nitroglycerin and diltiazem to reduce platelet-mediated vasoconstriction in dogs with coronary artery stenosis and endothelial injury: further evidence for THROMBOXANE A2 and serotonin as mediators of coronary artery vasoconstriction in vivo . J Am Coll Cardiol 1990; 15:718–26.
13. Brum JM, Sufan Q, Lane G, Bove AA. . Increased vasoconstrictor activity of proximal coronary arteries with endothelial damage in intact dogs . Circulation 1984; 70:1066–73.
14. Lamping KG, Marcus ML, Dole WP. . Removal of the endothelium potentiates canine large coronary artery constrictor responses to 5-hydroxytryptamine in vivo . Circ Res 1985; 57:46–54.
15. Chu A, Cobb FR. . Vasoactive effects of serotonin on proximal coronary arteries in awake dogs . Circ Res 1987; 61:Suppl II:II–81–II–87.
16. Cocks TM, Angus JA. . Endothelium-dependent relaxation of coronary arteries by nonadrenaline and serotonin . Nature 1983; 305:627–30.
17. Cappelli-Bigazzi M, Lamping KG, Nuno DW, Harrison DG. . Leukocyte and platelet-derived factors augment canine coronary constriction to serotonin . Am J Physiol 1990; 259:H1161–HI170.
18. Awouters F. . The pharmacology of ketanserin, the first selective serotonin S2-antagonist . Drug Dev Res 1985; 6:263–300.
19. Spears JR, Sandor T, Als AV, et al. . Computerized image analysis for quantitative measurement of vessel diameter from cineangiograms . Circulation 1983; 68:453–61.
20. Wilson RF, Laughlin DE, Ackell PH, et al. . Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man . Circulation 1985; 72:82–92.
21. Wilson RF, White CW. . Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans . Circulation 1986; 73:444–51.
22. Sibley DH, Millar HD, Hartley CJ. Whitlow PL. . Subselective measurement of coronary blood flow velocity using a steerable Doppler catheter . J Am Coll Cardiol 1986; 8:1332–40.
23. Nabel EG, Ganz P. Gordon JB, Alexander RW, Selwyn AP. . Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressortest . Circulation 1988: 77:43–52.
24. Cohen ML, Schenck KW, Kurz KD. . 5–HT2-receptor antagonists: alpha1-vs. 5–HT2-receptor blocking properties in blood vessels . J Cardiovasc Pharmacol 1988; 11:Suppl 1:S25–S29.
25. Vanhoutte PM, Shimokawa H. . Endothelium-derived relaxing factor and coronary vasospasm . Circulation 1989; 80:1–9.
26. Benedict CR, Mathew B, Rex KA, Cartwright J Jr, Sordahl LA. . Correlation of plasma serotonin changes with platelet aggregation in an in vivo dog model of spontaneous occlusive coronary thrombus formation . Circ Res 1986; 58:58–67.
27. Cohen RA, Shepherd JT, Vanhoutte PM. . Inhibitory role of the endothelium in the response of isolated coronary arteries to platelets . Science 1983; 221:273–4.
28. Cohen. 5-Hydroxytryptamine can mediate endothelium-dependent relaxation of coronary arteries . Am J Physiol 1983; 245:H1077–H1080.
29. Houston DS, Shepherd JT, Vanhoutte PM. . Adenine nucleotides, serotonin, and endothelium-dependent relaxations to platelets . Am J Physiol 1985; 248:H389–H395.
30. VanNueten JM, Janssen PA, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM. . Vascular effects of ketanserin (R 41 468), a novel antagonist of 5–HT2 serotonergic receptors . J Pharmacol Exp Ther 1981; 218:217–30.
31. Brazenor RM, Angus JA. . Action of serotonin antagonists on dog coronary artery . Eur J Pharmacol 1982; 81:569–76.
32. Heistad DD, Armstrong ML, Marcus ML, Piegors DJ, Mark AL. . Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys . Circ Res 1984; 54:711–8.
33. De Caterina R, Carpeggiani C, L'Abbate A. . A double-blind, placebo controlled study of ketanserin in patients with Prinzmetal's angina: evidence against a role for serotonin in the genesis of coronary vasospasm . Circulation 1984; 69:889–94.
Citing Articles (321)
Letters
Figures/Media
- Figure 1. Effects of Intracoronary Serotonin on Coronary-Artery Cross-Sectional Area during Diastole in Seven Patients with Angiographically Normal Coronary Arteries.
Figure 1. Effects of Intracoronary Serotonin on Coronary-Artery Cross-Sectional Area during Diastole in Seven Patients with Angiographically Normal Coronary Arteries. The change in area is expressed as a percentage of the base-line value (±SEM). Serotonin caused a dose-dependent dilation of distal coronary segments — i.e., segments directly exposed to serotonin – from a base-line value of 6.6±0.9 mm2; this dilation was significantly potentiated by the administration of ketanserin, a selective 5-HT2—receptor antagonist. Intracoronary nitroglycerin (200 μg) caused a dilation similar in extent to that observed after the highest dose of serotonin.
Proximal coronary segments — i.e., segments not directly exposed to serotonin — had a significant increase in cross-sectional area during serotonin- and nitroglycerin-mediated increases in coronary blood flow, from a base-line value of 6.7±1.0 mm2. These increases in cross-sectional area were significantly less pronounced, however, than those observed in distal coronary segments.
A single asterisk denotes a significant change from base line (P<0.001), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.05).
- Figure 2. Effect of Serotonin on the Left Anterior Descending Artery of a Patient with Normal Coronary Arteries.
Figure 2. Effect of Serotonin on the Left Anterior Descending Artery of a Patient with Normal Coronary Arteries. The base-line angiogram (right anterior oblique projection) shows the tip of the Doppler catheter, placed in the artery (Panel A, arrow) over a guide wire. During infusion of the highest dose of serotonin (10 μg per kilogram per minute), a significant dilation of the artery was observed (Panel B).
- Figure 3. Serotonin-Induced Changes in Coronary-Artery Blood Flow in the Patients with Normal Coronary Arteries.
Figure 3. Serotonin-Induced Changes in Coronary-Artery Blood Flow in the Patients with Normal Coronary Arteries. The change in flow is expressed as a percentage of the base-line value (±SEM). Flow was significantly increased during intracoronary serotonin infusion, from a base-line value of 75±5 ml per minute. This increase was significantly potentiated by the blockade of 5-HT2 receptors by ketanserin. Intracoronary nitroglycerin caused an increase in flow that was approximately twice that caused by serotonin.
A single asterisk denotes a significant change from base line (P<0.01), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.05).
- Figure 4. Effects of Intracoronary Serotonin on Coronary Cross-Sectional Area during Diastole in Seven Patients with Atherosclerotic Coronary Arteries.
Figure 4. Effects of Intracoronary Serotonin on Coronary Cross-Sectional Area during Diastole in Seven Patients with Atherosclerotic Coronary Arteries. The change in area is expressed as a percentage of the base-line value (±SEM). Values obtained during infusion of 10 μg of serotonin represent the means in three patients. Serotonin caused a dose-dependent constriction of the distal segments, from a baseline value of 5.1±0.6 mm2. Such vasoconstriction was completely absent after the administration of ketanserin, thus suggesting a 5-HT2—receptor—mediated mechanism. Endothelium-independent dilation was preserved in these patients, since cross-sectional area increased during intracoronary nitroglycerin administration.
No significant changes were observed in the proximal coronary segments during serotonin infusions, both before and after administration of ketanserin and during intracoronary nitroglycerin, thus suggesting an impairment of flow-mediated dilation in these patients.
A single asterisk denotes a significant change from base line (P<0.001), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.001).
- Figure 5. Effect of Serotonin on the Right Coronary Artery of a Patient with Coronary Atherosclerotic Lesions.
Figure 5. Effect of Serotonin on the Right Coronary Artery of a Patient with Coronary Atherosclerotic Lesions. The Doppler catheter (not visible) was positioned in the midportion of the artery (Panel A, arrow), shown in the right anterior oblique projection on base-line angiography. During infusion of serotonin (10 μg per kilogram per minute), a marked constriction of the coronary arterial segments distal to the infusion site was observed (Panel B, arrow).
- Figure 6. Serotonin-Induced Changes in Coronary Blood Flow in the Patients with Atherosclerotic Coronary Arteries.
Figure 6. Serotonin-Induced Changes in Coronary Blood Flow in the Patients with Atherosclerotic Coronary Arteries. Values obtained during infusion of 10 μg of serotonin represent the means in three patients.
A marked reduction in coronary blood flow was observed during intracoronary serotonin administration, from a base-line value of 72±5 ml per minute. This reduction in blood flow was completely prevented by the blockade of 5-HT2 receptors by ketanserin. Intracoronary nitroglycerin caused a significant increase in coronary blood flow, to a lesser extent than that observed in the patients with normal coronary arteries.
A single asterisk denotes a significant change from base line (P<0.001), and a double asterisk a significant change from the corresponding value obtained before ketanserin administration (P<0.001).
