Serotonin release after intracoronary platelet aggregation may be implicated in acute coronary artery disease syndromes (1,2). In patients with complex coronary artery lesions, increased serotonin levels have been observed by sampling blood from the coronary sinus (3). Plasma samples from coronary sinus during ischaemia also are capable of inducing canine coronary artery vasoconstriction in vitro, an action inhibited by serotonin-receptor antagonists (4).
In vitro responses with human epicardial coronary artery rings from explanted hearts have shown that serotonin causes constriction mediated by both 5-hydroxytryptamine (5-HT1 and 5-HT2) receptors (5,6). Serotonin administration in vivo, however, displays divergent effects, acting as a vasodilator on normal coronary arteries, but eliciting vasoconstriction in the presence of coronary artery atherosclerosis (7). Serotonin was postulated to act as a vasodilator via a 5-HT1-like mechanism, whereas vasoconstriction was 5-HT2 mediated. Two more recent studies, however, confirmed an important role for 5-HT2 receptors when vasoconstriction is observed during percutaneous transluminal coronary angioplasty (PTCA; 8,9), suggesting a potential role for agonist or antagonist drugs. The degree of vasoconstriction was related to the quantity of serotonin liberated and was attenuated, at least partly, by ketanserin, a 5-HT2 antagonist (8). However, the effects of ketanserin on the coronary circulation in the absence of platelet aggregation and in patients with stable symptoms has not been reported.
This study was conducted to establish the haemodynamic effects of ketanserin on the systemic and pulmonary circulations and to examine the effects of ketanserin on normal and diseased coronary artery segments in patients with stable angina.
Invasive investigations were performed in 10 patients (seven men, three women; mean age, 57 ± 6 years) being investigated by arteriography for diagnostic purposes with a view to selection of patients for coronary intervention by angioplasty or coronary artery bypass surgery. All vasoactive therapy was discontinued 24 h before the study, with the exception of sublingual glyceryl trinitrate (GTN), which was discontinued 6 h before study entry. Patients with unstable angina, recent (within 3 months) myocardial infarction, cardiac arrhythmias, and hypertension were excluded. Patients with prolonged QT interval or taking regular diuretic therapy also were excluded.
This study was approved by the West Ethics Committee. Each patient was issued an appropriate information sheet, and written informed consent was obtained.
Heart rate was monitored from a continuously monitored ECG, and hard-copy ECGs were recorded throughout the study. Routine left ventricular angiography and selective coronary arteriography were performed by the conventional Judkin technique. After the diagnostic procedure, either the left or right coronary artery system was selected for further study. A 7F balloon-flotation catheter (Swan-Ganz) was positioned in the pulmonary artery and used to measure pulmonary artery systolic and diastolic pressures, right atrial pressure, and occluded wedge pressure. Hard copies of systemic and pulmonary pressure tracings were obtained at 5-min intervals until stable and at a further 5 min after i.v. placebo injection (Table 1).
Ketanserin (10 mg, i.v.) was then administered, and further pressure recordings were made at 5 and 15 min after active drug. Cardiac output was measured by the thermodilution technique, mean value of at least three measurements at each time point. The total systemic (SVR) and pulmonary (PVR) vascular resistance were calculated for each time point from these formulae. (Equation (1)) where A is mean arterial pressure (mm Hg), and RA is mean right atrial pressure (mm Hg). (Equation (2)) where PA is mean pulmonary artery pressure, and PAW is mean pulmonary artery wedge pressure.
As administration of the drugs was on an open basis, hard copies of ECGs and pressure tracings were analysed by a blinded observer.
Quantitative coronary angiography
After baseline measurements, placebo and ketanserin were administered via an intravenous cannula in the right forearm. Quantitative angiography was performed of six right and four left coronary arteries. The chosen artery was determined after visualisation of the coronary artery system in the standard views. A projection was chosen that allowed simultaneous visualisation of the coronary artery system and the diagnostic 6F catheter, which was used for reference calibration. Serial angiograms were obtained with a Siemens angioscope C-arm (Siemens AG Medical Engineering Group, Erlangen, Germany). X-Ray tube-to-patient distance was fixed to maintain identical magnification. Nonionic contrast medium (Ultravist; 4-7 ml, Schering-Plough Pharmaceuticals, Kenilworth, NJ, U.S.A.) was injected by hand into the coronary artery under study. Recordings of the angiograms were stored on digital tape and analysed on a Siemens angiographic workstation (AWOS V4.0) with automatic edge detection. End-diastolic frames from the third or fourth cardiac cycle were stored for analysis, and several corresponding segments were identified along the lengths of the artery. Twelve proximal, eight mid, six distal, and six stenotic sites were identified. Two blinded observers measured coronary artery diameter at these sites by using the automated edge-detection programme. Absolute values were obtained by using the 6F catheter diameter (1.98 mm) as a calibration factor. Stenotic areas in the arteries also were identified, and the stenotic index (percentage) automatically calculated by the computer.
Reproducibility of the method of measuring coronary artery dimensions was assessed in 15 additional patients (eight men, seven women) undergoing diagnostic coronary angiography. A total of 54 coronary artery segments was measured, with a mean diameter of 3.18 ± 0.82 mm. The mean inter- and intraobserver variability assessed by this means was 0.13 ± 0.13 mm.
All data are expressed as mean ± SD. The effect of placebo and ketanserin i.v. bolus on central haemodynamics was analysed for each haemodynamic response by using two-way analysis of variance (ANOVA) with Bonferroni multiple comparisons. No significant differences were identified between baseline and postplacebo values. Significant differences between postplacebo values and postketanserin values (p < 0.05) are highlighted by an asterisk.
There were no significant changes in heart rate after placebo or ketanserin injection, nor were there any changes in ECG pattern.
Cardiac output was 5.5 ± 1.1 L/min at baseline and 5.7 ± 1.0 L/min 15 min after ketanserin (p = NS).
Systemic arterial pressure
Systolic arterial pressure (SAP) decreased significantly after ketanserin from a placebo value of 143.2 ± 16.7 to 122.3 ± 15.6 mm Hg (p < 0.05) 5 min after ketanserin. Similarly, diastolic arterial pressure (DAP) decreased significantly from 73.6 ± 10.5 after placebo to 66.4 ± 11.8 mm Hg, 5 min after ketanserin. Mean arterial pressure (MAP) decreased from a postplacebo value of 101.1 ± 11.7 to 89.6 ± 12.1 mm Hg (p < 0.05) 5 min after ketanserin (Fig. 1).
Pulmonary artery pressures
Pulmonary artery systolic pressure (PASP) decreased significantly from a placebo value of 22.3 ± 3.5 to 20.1 ± 4.1 mm Hg (p < 0.05) 15 min after ketanserin. Similarly, mean pulmonary artery pressure (MPAP) decreased from 14.3 ± 2.8 mm Hg after placebo to 11.9 ± 2.4 mm Hg (p < 0.05) 15 min after ketanserin (Fig. 1). Diastolic pulmonary artery pressure (DPAP) decreased by 19% from a placebo value of 8.2 ± 3.3 to 6.7 ± 2.7 mm Hg (p < 0.05).
Pulmonary artery wedge pressure
Pulmonary artery wedge pressure (PAWP) was 7.5 ± 2.3 mm Hg after placebo and 6.8 ± 2.3 mm Hg after ketanserin (p = NS).
Right atrial pressure
Right atrial pressure (RAP) was 4.6 ± 2.2 mm Hg at baseline and 4.8 ± 2.6 mm Hg after ketanserin (p = NS).
Systemic vascular resistance
Systemic vascular resistance (SVR) decreased significantly from a postplacebo value of 1,463 ± 256 to 1,230 ± 198 dyn/s/cm5 (p < 0.05) 5 min after ketanserin (Fig. 2).
Pulmonary vascular resistance
Pulmonary vascular resistance (PVR) decreased significantly from 111 ± 37 dyn/s/cm3 at baseline to 78 ± 48 dyne/s/cm3 (p < 0.05) 5 min after ketanserin (Fig. 2).
Coronary artery dimensions
No significant change in proximal, mid, or distal coronary artery dimensions was observed. Neither was there a change in the stenotic index after ketanserin injection (Table 2).
These results suggest a vasodilator response in the systemic and pulmonary circulation after i.v. injection of 10 mg ketanserin. We assume that these effects are mediated via 5-HT2 or α-adrenergic receptor antagonism, although non-drug-induced changes (e.g., ionic contrast media) cannot be excluded. There is evidence that the antihypertensive effect of ketanserin relies on both of these mechanisms. Ritanserin, a 5-HT2 antagonist with much weaker α-receptor properties, fails to reduce blood pressure when given intravenously to hypertensive patients, whereas ketanserin does (10). On the contrary, however, the pressor response to the α-agonist phenylephrine is not reduced by the i.v. administration of hypotensive doses of ketanserin, although it was markedly reduced by equivalent doses of the potent α-antagonist prazosin (11). Most probably, ketanserin produces an antihypertensive effect because of combined antagonism of both 5-HT2 and α-receptors (12). The observation that ritanserin greatly enhances the antihypertensive effect of small doses of prazosin in the spontaneously hypertensive rat supports this theory (13). A central mechanism of action seems less likely, as the hypotensive effect of ketanserin is not accompanied by reduced noradrenaline levels, unlike those of clonidine and methyldopa (14). The decrease in systemic arterial pressure seen in this study was not associated with a reflex increase in heart rate, a finding consistent with previous reports (15-17). Antagonism at α-adrenoreceptors might explain this.
Ketanserin has been noted to have pulmonary vasodilatory effects in hypertensive patients undergoing coronary artery bypass surgery. Vandenbroucke et al. (15) observed a significant 5-6% reduction in PAP, 5% reduction in PAWP, and 8% decrease in PVR after successive i.v. bolus doses of ketanserin to a maximum of 30 mg. The magnitude of change in SAP and SVR was approximately twofold greater than that in the pulmonary circulation. Two other studies in similar clinical settings have revealed equipotent vasodilator responses on the pulmonary and systemic circulation. The magnitude of these changes was comparable to that of our findings (16,17).
This study revealed no significant effect of ketanserin on coronary artery dimensions. Both 5-HT1-like and 5-HT2 receptors exist in coronary arteries, although the role of these two receptors in the coronary circulation is complex and not fully understood. In vitro responses with human epicardial coronary artery rings from explanted hearts have shown that serotonin causes contraction (5,6). As ketanserin partially attenuated these responses, it was assumed that 5-HT2 receptors were functionally more important, with a residual contraction (30% of the maximal effect) being 5-HT1-like mediated (6). Kaumann et al. (18), however, reported the predominance of 5-HT1-like over 5-HT2 receptors in mediating serotonin-evoked contraction. In vivo serotonin displays divergent effects on the coronary arteries, acting as a vasodilator in normal arteries and a vasoconstrictor in the presence of coronary atherosclerosis (7). Serotonin-evoked vasoconstriction in diseased coronary arteries is ketanserin sensitive, suggesting that vasoconstriction is a 5-HT2 receptor-mediated phenomenon (7). Two more recent studies confirmed an important role for 5-HT2 receptors when vasoconstriction is observed during percutaneous transluminal coronary angioplasty (PTCA; 8,9). After balloon dilatation, vasoconstriction distal to the angioplasty site is frequently noted. The degree of vasoconstriction is related to the amount of serotonin released into the circulation (8), and in both of these studies, ketanserin attenuated, at least partly, this vasoconstriction.
In theory, therefore, we might have expected a significant change in coronary artery dimensions in our study. For a number of reasons, however, such an effect was not observed. In the absence of platelet aggregation and in a group of patients with stable symptoms, circulating levels of serotonin are likely to be low, and consequently, 5-HT2 receptors may exhibit minimal influence on resting coronary artery tone. Furthermore, patients in this study were taking aspirin, which is likely to have modified platelet function. An identical study in patients with unstable angina (and presumably higher plasma serotonin levels) might have demonstrated a significant vasodilator response to ketanserin. Nonetheless, patients with coronary artery atherosclerosis have locally increased serotonin concentrations, and ketanserin could theoretically have interacted (3). The route of administration or dose of ketanserin used in our study (10 mg, i.v.) may have been insufficient to effect a response. Golino et al. (7,8) used a higher dose of ketanserin (0.25 mg/kg) to inhibit coronary artery vasospasm after PTCA. In the other study investigating the effects of 5-HT2 antagonism during coronary angioplasty, ketanserin was administered by the intracoronary route (9).
The observed nonsignificant reduction in coronary artery dimension is probably a reflection of the decrease in afterload after ketanserin administration. A direct vasoconstrictive action of ketanserin seems very unlikely in view of its known pharmacologic properties and those of 5-HT2 receptors. Attenuation of resting vasodilator tone could explain the minor reduction in coronary artery diameter, but this is not a strong possibility. Serotonin can influence vascular tone indirectly by stimulating release of endothelium-derived relaxant factors (EDRFs). This action, however, appears to be mediated by a 5-HT1-like receptor mechanism as 5-HT2 (ketanserin) and 5-HT3 (ondansetron)-receptor antagonists failed to block these responses, whereas methysergide and methiothepin (nonselective 5-HT antagonists) are potent antagonists (19,20).
In summary, equipotent vasodilator responses were seen in the systemic and pulmonary arterial circulations after an intravenous dose of 10 mg ketanserin. A nonsignificant reduction in coronary artery diameter was observed, which probably reflects the reduction in afterload, but ketanserin had no effect on coronary artery stenotic indices. Further studies assessing the effects of ketanserin and other 5-HT2 antagonists on coronary artery tone at times of platelet aggregation are indicated. Such agents may have therapeutic applications in the treatment of myocardial infarction and unstable angina or during PTCA.
Acknowledgment: We thank sincerely the staff of the Cardiac Catheterisation Suite of the Western Infirmary and Mrs. Jacqueline Clark for preparing and typing the manuscript.
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