(Circulation. 1996;94:2077-2082.)
© 1996 American Heart Association, Inc.
Articles |
Comparable Potent Coronary Constrictor Effects of Endothelin-1 and Big Endothelin-1 in Humans
the Department of Cardiology, Karolinska Hospital (J.P.), Department of Clinical Physiology, Huddinge Hospital (L.K., G.A.), and Department of Physiology and Pharmacology, Karolinska Institute (J.M.L), Stockholm, Sweden.
Correspondence to Dr J. Pernow, Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
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Abstract |
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Background Endothelin-1 (ET-1) is a potent vasoconstrictor produced from the precursor big ET-1 in endothelial cells. The coronary effects of these peptides in humans in vivo are unknown. Therefore, the effects of ET-1 and big ET-1 on coronary blood flow in relation to plasma ET-1 and big ET-1 levels were compared in healthy subjects.
Methods and Results The peptides were infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each dose was administered for 20 minutes except the highest dose of ET-1, which was administered for 10 minutes. ET-1 and big ET-1 evoked dose-related increases in mean arterial blood pressure from 93±4 to 107±4 mm Hg and from 89±2 to 122±5 mm Hg, respectively, at the highest dose. ET-1 and big ET-1 reduced coronary sinus blood flow, measured with thermodilution, by a maximum of 25±4% and 28±8% and increased coronary vascular resistance by 50±9% and 107±26%, respectively. Coronary sinus, but not arterial, oxygen saturation was reduced in parallel with the coronary sinus blood flow. The effects of ET-1 and big ET-1 were similar at corresponding time points. During infusion of ET-1, a 19±5% extraction of ET-1 was observed over the coronary vascular bed (P<.05). Administration of big ET-1 elevated arterial plasma ET-1 levels by 2.4-fold, and after correction for the local extraction of ET-1, a myocardial production of ET-1 was observed.
Conclusions ET-1 and big ET-1 induce comparable increases in blood pressure and coronary constriction in humans in vivo. The results also suggest a net local removal of circulating ET-1 and big ET-1 and a local conversion of big ET-1 into ET-1 within the coronary vascular bed.
Key Words: blood flow • endothelin • hemodynamics • oxygen • vasoconstriction
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Introduction |
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Endothelin-1 (ET-1) is a 21–amino acid peptide produced by vascular endothelial cells.1 ET-1 is generated from a 38–amino acid precursor peptide, big ET-1, by an endothelin-converting enzyme (ECE)1 that is considered to be a membrane-bound metalloprotease.2 To date, the two ECEs ECE-1 and ECE-2 have been cloned.3 The produced ET-1 can activate at least two types of receptors. The ETA receptor is located on the vascular smooth muscle and mediates potent and long-lasting vasoconstriction.4 The ETB receptor mediates either vasoconstriction or vasodilatation depending on whether the receptor is located on the vascular smooth muscle or on the endothelium.5 Results of recent experiments with bosentan, a nonpeptide ET receptor antagonist, suggest that intrinsic systemic and pulmonary vascular tones are ET dependent.6 7
Intravenous administration of ET-1 to humans results in a dose-related increase in arterial blood pressure as well as splanchnic and renal vasoconstriction.8 9 10 In forearm skeletal muscle, ET-1 may evoke either vasodilatation or vasoconstriction depending on the route of administration and possibly the local concentration achieved.11 12 ET-1 is also a potent constrictor of human epicardial coronary arteries in vitro.13 Although the precursor form big ET-1 is metabolically more stable than ET-1,14 it normally evokes less potent vasoconstriction than ET-1. This is most probably due to the fact that big ET-1 has to be converted to ET-1 to produce vascular effects.15 The affinity of big ET-1 to ET-1 binding sites in the human heart is 500 times lower than that of ET-1.13 From studies in the human forearm and in isolated human epicardial coronary arteries, it has been reported that big ET-1 is 
10-fold less potent than ET-1 as a vasoconstrictor.16 17 However, during intravenous infusion into humans, big ET-1 is at least as active as ET-1 in increasing mean arterial blood pressure.18 These results indicate that species variations and regional differences may exist in the relative vascular potency of big ET-1 and ET-1.
Increased circulating plasma levels of ET-like immunoreactivity (ET-LI) are observed in various cardiovascular disorders such as myocardial infarction,19 unstable angina,20 atherosclerosis,21 and congestive heart failure.22 At least in myocardial infarction, both ET-1 and big ET-1 plasma levels are raised.19 These findings together with the extremely high potency of ET-1 as a vasoconstrictor may indicate a pathophysiological role for the peptide. Recent observations have in fact demonstrated that the ET receptor antagonist bosentan protects against myocardial ischemia and reperfusion injury in the pig.23
Because there appears to be both species and regional variations in the vascular effects of ET-1 in relation to its precursor big ET-1 and because endogenous ET-1 may be involved in various coronary vascular disorders, it was of interest to evaluate the coronary effects of both big ET-1 and ET-1 in humans under in vivo conditions. The aim of the present study was therefore to investigate the effects of ET-1 and big ET-1 on the coronary circulation and to relate their vascular effects to the obtained plasma levels and the conversion of big ET-1 into ET-1 by determining local coronary sinus plasma concentrations of the peptides.
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Methods |
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Procedures
The study was performed on 15 healthy male subjects (age, 20 to 33 years; weight, 66 to 93 kg). All subjects were given written and oral information about the purpose and the possible risks of the study, which was approved by the local ethics committee. One catheter was inserted percutaneously via a cubital vein into the coronary sinus. This catheter was equipped with a thermistor for measurement of coronary sinus blood flow by thermodilution. Another catheter was inserted into the brachial artery of the nondominant arm for measurement of blood pressure. A third catheter was inserted into a cubital vein of the contralateral arm for administration of ET-1. Heart rate and intra-arterial blood pressure were recorded continuously during the investigation. Coronary sinus blood flow was measured with the use of thermodilution by using a constant rate infusion of physiological saline over 35 seconds with computerized on-line integration of the temperature curve during the last 25 seconds for the calculation of flow.24 To ensure that changes between two situations were not caused by sampling from different sites, the catheter was placed in a position such that small movements did not result in differences in flow recordings. To achieve this, in two subjects, the catheter was positioned in the cordis magna vein. The values given for coronary sinus blood flow are the mean values of two consecutive recordings. With this procedure, the variability in flow measurements was 4%.25
After a resting period of 30 minutes after the catheterization, synthetic ET-1 (n=8) or big ET-1 (n=7) was infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each subject received only one of the substances. Big ET-1 was given for 20 minutes at each dose rate. The two lower doses of ET-1 were given for 20 minutes, whereas the highest dose was given for only 10 minutes because in two preliminary investigations, administration of the high dose of ET-1 produced nausea and borborygmi at infusion times exceeding 10 minutes. Hemodynamic measurements and blood sampling from the coronary sinus and the brachial artery were performed before the start of the infusions, at 10 and 20 minutes of each infusion, and up to 90 minutes after the infusions. The blood samples were collected for determination of oxygen saturation and of plasma ET-1-LI and big ET-1-LI levels.
Analysis
Blood samples for the determination of plasma ET-LI were put into prechilled tubes containing EDTA (10 mmol/L final concentration). The samples were centrifuged at 3000g for 10 minutes at 4°C, and plasma (1 mL for each analysis) was separated and stored at -80°C until analysis. After ethanol extraction, ET-1 and big ET-1 were measured by radioimmunoassay. ET-1 was analyzed with antiserum E-1 according to a previously described and validated method.26 The cross-reactivity of this antiserum, when ET-1 is expressed as 100%, is 27% with ET-2, 8% with ET-3, and 0.03% with big ET-1. The intra-assay and interassay variations are 6% and 14%, respectively. Big ET-1 was analyzed with antiserum B6, which cross-reacts with big ET-1(22-38) by 35% and with ET-1 by <0.01%.14 HPLC characterization of human plasma after infusion of exogenous peptides revealed that E-1 and B6 detect mainly ET-1(1-21) and big ET-1(1-38), respectively.14 Blood oxygen saturation was measured spectrophotometrically, and the oxygen content was calculated from the saturation and the hemoglobin concentration.
Calculations and Statistical Analysis
Coronary sinus blood flow is expressed both in absolute values and in percent change from basal flow. Coronary vascular resistance was calculated as mean arterial blood pressure divided by coronary sinus blood flow and is expressed in percent change from basal value. Local fractional extraction of ET-1 and big ET-1 was calculated as the arteriovenous plasma concentration difference divided by the arterial plasma concentration. Local uptake or production rates of ET-1 and big ET-1 over the coronary vascular bed were calculated as the arteriovenous plasma concentration difference multiplied by coronary sinus plasma flow. Significant effects were calculated using ANOVA followed by Dunnett's comparisons test for repeated measurements or Wilcoxon's signed rank test for paired data. Data are presented as mean±SEM values.
Drugs
Human ET-1 and big ET-1 (Peninsula Laboratories) were dissolved in saline, filtrated in a sterile manner through a Millipore filter, and thereafter stored frozen at -20°C. Before infusion, the peptide was diluted in saline to obtain the desired concentrations.
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Results |
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Hemodynamics
There was a dose-related increase in mean arterial blood pressure during both the ET-1 and big ET-1 infusions (Fig 1
). ET-1 increased mean arterial blood pressure from a basal value of 93±4 to 104±5 mm Hg at the end of the highest rate of infusion. Blood pressure then increased further to a maximal value of 107±4 mm Hg observed 2 minutes after the infusion. Big ET-1 increased mean arterial blood pressure from 89±2 to 114±3 mm Hg at the end of the highest rate of infusion and further to 122±5 mm Hg by 20 minutes after the infusion. Blood pressure was still significantly elevated 90 minutes after termination of the big ET-1 infusion, and it remained elevated for 30 minutes after the ET-1 infusion. Both infusions were accompanied by a reduction in heart rate (Fig 1).
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Basal coronary sinus blood flow before the start of the infusion was 114±28 mL/min in the ET-1 group and 87±7 mL/min in the big ET-1 group. The larger variation in the ET-1 group is mainly due to one subject in whom basal coronary sinus blood flow was 239 mL/min. Infusion of both ET-1 and big ET-1 evoked dose-related reductions in coronary sinus blood flow. The maximal reduction evoked by ET-1 was 25±4% at 10 minutes of the highest rate of infusion (8 pmol/kg per minute), whereas big ET-1 reduced coronary sinus blood flow by a maximum of 28±8% at 10 minutes after the end of the infusion (Fig 2). Coronary sinus blood flow had returned to basal values 30 and 60 minutes after the infusion of ET-1 and big ET-1, respectively. Coronary vascular resistance had increased by 49±9% and 42±8% with ET-1 and big ET-1, respectively, at 10 minutes of the highest rate of infusion. The maximal increases in coronary vascular resistance induced by ET-1 and big ET-1 were 50% and 107%, respectively (Fig 2).
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Coronary sinus oxygen saturation fell from a basal value of 34.0±1.6% to a lowest value of 21.8±1.6% observed at 2 minutes after the ET-1 infusion (Fig 3). Big ET-1 reduced coronary sinus oxygen saturation from 34.5±3.1% to 14.9±2.9% at 10 minutes after the highest infusion rate. Neither ET-1 nor big ET-1 significantly affected arterial oxygen saturation. Furthermore, myocardial oxygen uptake remained unchanged during and after the infusions of ET-1 or big ET-1 (Fig 3).
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Because ET-1 and big ET-1 were infused for different lengths of time at the highest dose rate (10 and 20 minutes, respectively), comparisons between the vascular responses were made at 20-minute infusions of the two lower dose rates and at 10-minute infusions of the highest dose rate. There were no significant differences between the changes in mean arterial blood pressure, heart rate, coronary sinus blood flow, or coronary sinus oxygen saturation evoked by ET-1 and big ET-1 at these time points.
Plasma Concentrations of ET-1–LI and Big ET-1–LI
Infusion of ET-1 increased arterial plasma levels of ET-1–LI by 30-fold from a basal value of 7.1±0.6 pmol/L (P<.05; Fig 4). At the highest infusion rate, ET-1–LI in plasma from the coronary sinus was 19±5% lower than that in arterial plasma (Fig 4). After the end of the ET-1 infusion, ET-1–LI in arterial plasma decreased rapidly and was 21.9±3.9 pmol/L at 10 minutes and 10.8±1.8 pmol/L at 90 minutes after the infusion. Administration of big ET-1 elevated plasma big ET-1–LI by 200-fold from a basal value of 8.8±0.9 pmol/L. The concentration of big ET-1–LI at the end of the highest rate of infusion was 10±3% lower in coronary sinus plasma than in arterial plasma (Fig 5). After the end of the big ET-1 infusion, big ET-1–LI disappeared from plasma more slowly than ET-1–LI had done after the ET-1 infusion. Thus, at 10 minutes after the infusion, arterial plasma big ET-1–LI was still elevated 60-fold; at 90 minutes after the infusion, it was 34.5±3.0 pmol/L. There also was a significant rise in arterial plasma ET-1–LI from 4.0±0.7 to 9.6±1.0 pmol/L during administration of big ET-1 (Fig 5). The coronary sinus plasma ET-1–LI level obtained at the highest infusion rate of big ET-1 (9.9±1.1 pmol/L) was not significantly different from the level in arterial plasma. However, when taking into account the fractional extraction of ET-1–LI, which had been observed to be 19% during administration of ET-1, coronary sinus plasma ET-1–LI could be calculated to be 26±9% higher than arterial plasma ET-1–LI during the highest rate of big ET-1 infusion (Fig 5). This corresponds to a myocardial spillover of ET-1–LI of 87±32 fmol/min.
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Discussion |
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Results of the present study demonstrate that both ET-1 and its precursor big ET-1 induce pronounced and long-lasting cardiovascular responses, including elevated blood pressure and reduction in coronary blood flow, in healthy humans. The long-lasting increases in mean arterial blood pressure evoked by both ET-1 and big ET-1 are in good agreement with previous observations in human volunteers.9 18 The maximal cardiovascular responses evoked by big ET-1 were clearly larger than those evoked by ET-1. However, when the hemodynamic effects were compared at similar time points, the magnitudes of the responses to big ET-1 and ET-1 were not different. Thus, it seems that the larger maximal responses evoked by big ET-1 were due to the fact that big ET-1 was infused for 20 minutes at the highest rate of infusion, whereas ET-1 was infused for 10 minutes. The similarity indicates that the precursor was just as potent as ET-1 at inducing vascular effects. This finding is somewhat surprising considering previous results showing that big ET-1 is a less potent vasoconstrictor than ET-1.15 Species differences, however, seem to exist since big ET-1 has been reported to evoke potent pressor effects in the rat in vivo.27 When administered locally into the human forearm, ET-1 is
10-fold more potent than big ET-1 as a vasoconstrictor.16 Furthermore, ET-1 is more potent than big ET-1 as a constrictor of isolated human epicardial coronary arteries.17 Our results from the present study clearly indicate that big ET-1 is as potent as ET-1 in increasing arterial blood pressure and in evoking coronary constriction in humans under in vivo conditions. Administration of ET-1 and big ET-1 induced dose-related reductions in coronary sinus blood flow and increases in coronary vascular resistance. The reduction in coronary sinus blood flow may be due to either direct coronary vasoconstrictor effects or reduced myocardial oxygen demand. The finding that the reduced coronary blood flow was accompanied by a reduction in coronary sinus oxygen saturation but unchanged arterial oxygen saturation indicates that an increased myocardial oxygen extraction compensates for the reduction in blood flow. These findings clearly suggest that the reduction in coronary sinus blood flow was related to direct coronary constrictor effects of ET-1 and big ET-1. The coronary responses evoked by ET-1 and big ET-1 were found to be long lasting and of magnitudes comparable to those observed in the renal and splanchnic vascular beds described previously.9 18 The increase in blood pressure and the coronary constriction induced by big ET-1 continued to increase after the infusion, and these effects were somewhat more long lasting than those evoked by ET-1. This may be related to the conversion from big ET-1 into ET-1 that continues after the end of the infusion. However, the difference in duration of the responses may also be due to the fact that big ET-1 was infused for a longer period of time and thus evoked more marked hemodynamic responses than ET-1.
The cardiovascular responses to big ET-1 were seen despite only a small (approximately twofold) increase in arterial plasma concentration of ET-1–LI. This should be compared with the 30-fold increase in plasma ET-1–LI evoked by infusion of ET-1. The finding may suggest that the main part of this conversion of big ET-1 into ET-1 does not take place in circulating blood but rather close to the vascular smooth muscle cells and the receptors responsible for ET-1–mediated coronary constriction. It seems clear that there is no ECE activity in blood26 and that the enzyme is membrane bound. The present results suggest that the enzyme activity is confined to the abluminal side of the endothelial cells or on the vascular smooth muscle cell membrane as demonstrated previously.28 29 If conversion occurs close to the vascular smooth muscle, ET-1 generated from administered big ET-1 will then activate predominantly vasoconstrictor receptors on the vascular smooth muscle, whereas intravenously administered ET-1 will also reach endothelial vasodilator ETB receptors, which may counteract the vasoconstrictor effect. Therefore, the vasoconstrictor potency of the administered ET-1 would be underestimated in relation to that of big ET-1. In human coronary arteries, however, ETA receptors seem to dominate over ETB receptors.30 Furthermore, the low dose of ET-1 did not produce any vasodilator response, which might have been expected if endothelial ETB receptors were abundant. An alternative explanation for the pronounced cardiovascular response to big ET-1 in relation to the low plasma levels of ET-1–LI is that big ET-1 is vasoactive independent of conversion into ET-1. This seems less likely because no big ET-1 receptors have been characterized and because vasoconstrictions induced by big ET-1 in the rat and in the human forearm are blocked by phosphoramidon.15 16 31 The constrictor response to big ET-1 in isolated human epicardial arteries is also attenuated by phosphoramidon, suggesting local conversion in the vascular wall.17 Furthermore, the ETA and ETB receptor antagonist bosentan antagonizes the blood pressure increase and coronary constriction induced by big ET-1 in the dog.7 Taken together, the present results indicate an efficient conversion of big ET-1 into ET-1 close to the ET-1 receptors, which allows the precursor form big ET-1 to be as potent as ET-1 in elevating systemic blood pressure and causing coronary constriction in humans.
The plasma concentrations of ET-1 and big ET-1 were significantly higher in arterial plasma than in coronary sinus plasma at the highest infusion rates of the respective substances, indicating extraction by the coronary vascular bed. Extraction of circulating ET-1 in humans has previously been reported to occur in skeletal muscle tissue in the forearm, kidney, lungs, and splanchnic circulation.9 10 11 12 Based on the present results, the coronary circulation also contributes to the elimination of circulating ET-1, albeit to a lesser extent. The extraction of big ET-1–LI most likely reflects conversion to ET-1, which was found to increase in plasma only at the highest infusion rate of big ET-1, when the extraction of big ET-1 was significant. There was no significant arteriocoronary sinus concentration difference of ET-1–LI during administration of big ET-1. This may indicate that the conversion to ET-1 and the extraction of ET-1 were the same. With the assumption that the extraction of ET-1 during big ET-1 infusion is similar to that observed during infusion of ET-1, a significant negative arteriocoronary sinus concentration difference of ET-1–LI during the infusion of big ET-1 is achieved. This would suggest a myocardial production of ET-1 from the infused big ET-1.
The plasma level of big ET-1–LI decreased more slowly than that of ET-1–LI after the respective infusions. This finding is in agreement with the reported longer half-life of circulating big ET-1 (6.6 minutes) than of circulating ET-1 (1.4 minutes) in humans.9 14 The slower elimination of big ET-1 also accounts for the higher plasma levels of big ET-1 compared with ET-1 at corresponding time points.
It has been suggested that evaluation of the pharmacological effects of big ET-1 is a more physiological way of investigating the role of endogenous ET-1 than administration of ET-1, since the endothelial cells may release big ET-1, which is locally converted to ET-1 close to the receptor sites.2 7 If this is the case, the plasma levels of ET-1 obtained during administration of big ET-1 may be more relevant than those obtained during administration of ET-1 when considering plasma levels observed under various physiological and pathophysiological conditions. In the present study, arterial plasma ET-1 levels increased during infusion of big ET-1 to 9.6 pmol/L, which produced marked elevation of systemic blood pressure and coronary constriction. This plasma level is within the range observed during various cardiovascular disorders in humans, including sepsis syndrome,32 myocardial infarction,19 20 and congestive heart failure.22 It is also interesting to note that plasma big ET-1 levels are significantly elevated in patients with myocardial infarction,19 which may be relevant considering the pronounced coronary constrictor effect induced by the administered big ET-1 in the present study.
In conclusion, the results of the present study demonstrate that intravenous administration of ET-1 or big ET-1 to healthy humans evokes long-lasting reductions in coronary blood flow, which seem to be due to direct coronary constriction. The coronary constrictor effect of big ET-1 is not less pronounced than that of ET-1. The results further indicate that there is a net removal of both circulating big ET-1 and ET-1, as well as conversion of big ET-1 into ET-1 over the coronary vascular bed. The clear-cut coronary effects of big ET-1 suggest efficient local conversion into ET-1 and that it is relevant to explore the roles of both of these forms of ET in various cardiovascular pathological situations.
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Acknowledgments |
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This work was supported by grants from the Swedish Medical Research Council (10857, 10374, 6554, 4494), King Gustav and Queen Victoria Foundation, Swedish Heart and Lung Foundation, Bergvall Foundation, Laerdal Foundation, and Karolinska Institute. We are grateful to Anette Hemsen, Carina Nihlen, and Margareta Stensdotter for technical assistance.
Received December 28, 1995; revision received April 24, 1996; accepted May 21, 1996.
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