(Circulation. 1995;92:3312-3317.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin at Pathophysiological Concentrations Mediates Coronary Vasoconstriction via the Endothelin-A Receptor
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Internal Medicine, Department of Internal Medicine and Physiology, Mayo Clinic/Foundation, Rochester, Minn.
Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St, SW, Rochester, MN 55905.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at low concentrations of exogenous ET-1 designed to mimic pathophysiological states compared with pharmacological concentrations.
Methods and Results ET-1 (group 1, n=5) or sarafotoxin, a specific ET-B receptor agonist (group 3, n=6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 dogs (n=5), the same dose of ET-1 was infused with 4 µg/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n=5), the same dose of sarafotoxin was infused with 50 µg/kg per minute of the specific inhibitor of nitric oxide formation, NG-monomethyl-L-arginine (L-NMMA). No difference in hemodynamics, coronary blood flow (CBF), coronary vascular resistance (CVR), or coronary artery diameter (CAD) was observed at baseline between the groups. In group 1, intracoronary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group that received ET-1 and the ET-A receptor antagonist (group 2) was significantly less than that in the group that received ET-1 alone (group 1) (-12±3% versus -48±6% [P<.001] and -4.6±0.8 versus 1.0±0.3 [P<.05], respectively). The administration of the ET-A receptor antagonist (group 2) abolished the ET-mediated increase in CVR (7±5% versus 105±21%, P<.005). There was no significant effect on CBF, CVR, or CAD in the group receiving sarafotoxin alone (group 3). The administration of L-NMMA and sarafotoxin (group 4) resulted in a significant percentage decrease in CBF compared with the group that received sarafotoxin alone (-28±7% versus -8±2% [P<.05]).
Conclusions The present study demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction mediated predominantly via the ET-A receptor because such vasoconstriction is significantly attenuated by blockade with FR-139317. The ET-B receptor may have a dual vasoconstrictive and vasodilatory effect.
Key Words: endothelin • coronary • receptors
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The endothelium regulates regional vascular tone by the release of vasodilator substances such as EDRF and vasoconstrictor substances such as endothelin.1 Recent studies have established that endothelin produces potent coronary vasoconstriction at pharmacological and pathophysiological concentrations.2 3 Since circulating endothelin-1 is increased in pathophysiological conditions, such as coronary vasospasm4 and acute myocardial infarction,5 as well as in human atherosclerosis,6 endothelin may have a functionally significant role as a local regulator of coronary vascular tone in these pathophysiological states of altered coronary vascular tone and reactivity.
The mechanism of endothelin-mediated vasoconstriction involves binding to specific receptors on vascular smooth muscle7 and direct activation of voltage-operated calcium channels in vascular smooth muscle membrane.8 9 Two distinct complementary DNAs of endothelin receptors have been identified. The endothelin-A receptor is expressed in vascular smooth muscle cells,10 whereas the endothelin-B receptor has been localized to the endothelial and smooth muscle cells.10 Recent studies have demonstrated that coronary vasoconstriction involves the endothelin-A receptor12 as well as the endothelin-B receptor.11 12 13 Controversy persists regarding the predominant endothelin receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that endothelin mediates local coronary vasoconstriction via the endothelin-A receptor at low concentrations of exogenous endothelin designed to mimic pathophysiological states compared with pharmacological concentrations.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Acute experiments were conducted in four groups of mongrel dogs (weight, 15 to 22 kg) after approval by the Mayo Clinic Institutional Animal Care and Use Committee. Each dog was fasted overnight before the day of study but allowed ad libitum access to tap water. Each animal was initially anesthetized with sodium pentobarbital (30 mg/kg IV), and additional anesthesia was given as needed to maintain a constant level of anesthesia. An endotracheal tube was inserted, and the dogs were ventilated with room air and supplemental oxygen at a rate of 4 L/min (Harvard Apparatus). The right external jugular vein was cannulated with a flow-directed thermodilution catheter (American Edwards Laboratories) for the measurement of right atrial pressure, pulmonary capillary wedge pressure, and cardiac output. The right femoral artery was cannulated with a polyethylene catheter for monitoring MAP, and the right femoral vein was cannulated for infusion of intravenous fluids.
Each animal underwent a left thoracotomy to expose the anterior wall of the left ventricle. One centimeter of the proximal left circumflex coronary artery was carefully dissected free of surrounding tissue. A calibrated electromagnetic flow probe was positioned on the proximal circumflex coronary artery and connected to a flowmeter (model FM 5010, Carolina Medical Electronics) for measurement of CBF. Proximal to the flowmeter, a small needle was carefully positioned in the artery to allow intracoronary infusions. Two piezoelectric crystals (5 MHz, 2.5 mm in diameter) were placed distal to the flow probe on opposite surfaces of the dissected coronary artery segment to allow continuous measurement of its diameter. The correct alignment was verified by on-line sonomicrometry (Sonomicrometer 120, Triton Technology) and oscilloscopic monitoring (2221, Tektronix).14 Cardiac output was averaged from three measurements. Continuous recordings of CBF, coronary diameter, MAP, right atrial pressure, pulmonary arterial pressure, and left ventricular end-diastolic pressure were performed on a model 2200 Gould strip-chart recorder.
After surgical instrumentation, each animal underwent a 60-minute equilibration period to ensure stability of the preparation, during which each animal received an intravenous infusion of normal saline at a rate of 1 mL/min. The equilibration period was followed by a 20-minute baseline period (P1). This was followed by a 15-minute lead-in period, during which saline vehicle in groups 1 (n=5) and 3 (n=6) or an endothelin-A receptor blocker FR-139317 (4 µg/kg per minute, Abbott Laboratories) in group 2 (n=5) and L-NMMA (50 µg/kg per minute, Calbiochem) in group 4 (n=5) were infused directly into the coronary artery. FR-13931715 has been documented in vitro and in vivo16 as an endothelin-A receptor antagonist. L-NMMA inhibits the formation of nitric oxide or EDRF in the endothelial cell from its amino acid precursor, L-arginine.17 After the lead-in period, a 20-minute experimental period (P2) was performed. This was followed by a second 15-minute lead-in period, during which endothelin-1 (2 ng/kg per minute, Peninsula Laboratories) in groups 1 and 2 and sarafotoxin (2 ng/kg per minute, Peninsula Laboratories) in groups 3 and 4 was infused directly into the coronary artery while the intracoronary FR-139317 (group 2), L-NMMA (group 4), or vehicle (groups 1 and 3) infusions continued. The dose of endothelin-1 (2 ng/kg per minute) was the lowest intracoronary dose causing a significant decrease in coronary blood flow in a pilot dog study. Sarafotoxin, a 21–amino acid peptide, is a highly selective endothelin-B receptor agonist18 with approximately the same molecular weight as endothelin-1. After the lead-in period, two 20-minute experimental periods (P3 and P4) were performed. Two additional 20-minute experimental periods (P5 and P6) were performed in group 3 (sarafotoxin) with 10-fold (20 ng/kg per minute) and 100-fold (200 ng/kg per minute) increases in the dose of sarafotoxin infused into the coronary artery to obtain a dose-response curve to sarafotoxin. A total coronary infusion rate of 1 mL/min was maintained throughout the experiment.
During each experimental period, measurements included MAP, cardiac output in triplicate, right atrial pressure, pulmonary capillary wedge pressure, CBF, and coronary artery diameter. At the midpoint of the first three periods, blood was sampled from the ascending aorta for the measurement of plasma endothelin. One dog in group 1 did not have cardiac output measured in the second endothelin period (P4) because of unexpected hemodynamic deterioration secondary to ventricular tachycardia. CBF was averaged for each experimental period from the strip-chart recorder data. Coronary artery diameter was measured at the end of each clearance period. Coronary vascular resistance (CVR) was calculated by the following formula: CVR (mm Hg/mL per minute)=[MAP-RAP]/CBF, and systemic vascular resistance (SVR) was calculated by the following formula: SVR (mm Hg/L per minute)=[MAP-RAP]/cardiac output, where RAP is right atrial pressure.
Blood for endothelin analysis was collected into EDTA tubes, immediately placed on ice, and centrifuged at 2500 rpm at 4°C. Plasma was separated and stored at -20°C until the assay. Plasma endothelin was determined using an endothelin-1 assay system (Amersham) as previously described.19
Statistical Analysis
Data from each period are expressed as
mean±SEM. Within each
group, repeated measurements were analyzed with ANOVA and
Student's paired t test. Comparisons between the groups
were analyzed by ANOVA and Student's unpaired t
test. Significance was achieved with a value of P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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The systemic and coronary effects of intracoronary vehicle and endothelin-1 (group 1), FR-139317 and endothelin-1 (group 2), intracoronary vehicle and sarafotoxin (group 3), and L-NMMA and sarafotoxin (group 4) are illustrated in the Table
. There were no significant
differences in MAP, SVR, heart rate, and cardiac output between groups
at baseline and within groups compared with vehicle and/or FR-139317
groups (P2). In group 4, the administration of L-NMMA alone (P2)
resulted in a significant increase in MAP and systemic vascular
resistance without any change in CBF, coronary vascular
resistance, or coronary artery diameter. There were no
significant changes in cardiac hemodynamics in groups 1
through 3 compared with P2 or between groups during the
intracoronary infusion of endothelin or sarafotoxin (P3 and
P4), with the exception of a decrease in cardiac output in group 3. In
contrast to the other groups, there was a significant increase in MAP
and SVR in association with a decrease in cardiac output in the group
receiving L-NMMA and sarafotoxin (group 4). In groups 1 and 2
(endothelin), no significant changes in plasma endothelin
concentrations were observed.
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In group 1, intracoronary endothelin significantly
decreased CBF and coronary artery diameter in association with
an increase in coronary vascular resistance. The percentage
changes in response to intracoronary endothelin alone
(group 1) for CBF, coronary vascular resistance, and
coronary artery diameter are illustrated in Fig 1. A
proportionately greater change in CBF and
coronary vascular resistance was observed. Two of five dogs in
group 1 had sustained ventricular tachycardia
at the end of the experiment that degenerated into
ventricular fibrillation.
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) in CBF (
), coronary vascular resistance (
), and
coronary artery diameter (
) compared with baseline in the
group that received endothelin-1 alone (group 1). P indicates
experimental period, 20 minutes each.
The percentage decrease in CBF (Fig 2) and
coronary artery diameter in the group that received
endothelin-1 and the endothelin-A receptor antagonist
(group 2) was significantly less than that in the group that received
the endothelin-1 alone (group 1) (-12±3% versus
-48±6%
[P<.001] and -1.0±0.3% versus
-4.6±0.8%
[P<.05], respectively). The administration of the
endothelin-A receptor antagonist (group 2) abolished the
endothelin-mediated increase in coronary vascular
resistance seen in group 1 (7% versus 105%, P<.005) (Fig
3).
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There was no significant effect on CBF or coronary artery
diameter in the group receiving sarafotoxin alone (group 3). Comparison
of the percentage change in CBF and coronary vascular
resistance with groups 1 and 2 is shown in Figs 2
and
3, respectively.
No significant percentage change in coronary vascular
resistance was observed during the infusion of sarafotoxin (group 3)
versus baseline or group 2 (19±10% versus 7±6%,
P=.4).
However, there was a significant change compared with the group that
received endothelin-1 alone (19±10% versus 105±24%,
P<.05) (Fig 3).
In contrast to the group receiving sarafotoxin alone, the infusion of
L-NMMA followed by sarafotoxin (group 4) resulted in a significant
percentage decrease in CBF compared with baseline and with group 3
(28±7% versus 8±2%, P<.05) (Fig 4).
Similarly, there was a significant percentage increase in
coronary vascular resistance compared with baseline that tended
toward significance compared with group 3 (67±24% versus 19±10%,
P=.07). Although the percentage change in CBF in group 4 was
greater than that seen in group 3, it was still less than that seen in
the group receiving endothelin alone (group 1) (28±7% versus
48±7%,
P<.05).
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Increasing the dose of sarafotoxin 10-fold to 20 ng/kg per minute did not result in any significant percentage change in CBF (10±5%), coronary artery diameter (3±0.9%), or coronary vascular resistance (15±6%) compared with baseline. However, on increasing the dose 100-fold to 200 ng/kg per minute, there was a marked decrease in CBF (84±5%) and coronary artery diameter (14±4%) with an increase in coronary vascular resistance (277±55%).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Results of the present study, which used low concentrations of exogenously administrated endothelin-1 to mimic pathophysiological concentrations of intracoronary endothelin-1, demonstrate that endothelin has local coronary vasoconstrictor activity characterized by a decrease in CBF and an increase in coronary vascular resistance. These effects were attenuated in the presence of an endothelin-A–selective receptor antagonist establishing a functionally important role for the endothelin-A receptor in endothelin-1–mediated coronary vasoconstriction. In contrast to the effects observed from endothelin-1, similar concentrations of the highly selective endothelin-B receptor agonist sarafotoxin had no significant effect on the coronary circulation.
Two distinct complementary DNAs of endothelin receptors have been recently identified; one is expressed in vascular smooth muscle cells (endothelin-A receptor) and one is expressed in endothelial cells (endothelin-B receptor).10 Prior in vitro animal studies have demonstrated that both the endothelin-A and endothelin-B receptors may evoke vascular smooth muscle contraction.20 21 22 More recent in vitro studies on human internal mammary vessels showed that both endothelin-A and endothelin-B receptors were present on vascular smooth muscle cells and that both were involved in endothelin-induced vasoconstriction.11 Subsequent in vivo studies of the coronary circulation have resulted in conflicting conclusions. Rigel and Lappe12 demonstrated in anesthetized dogs that conduit and resistance coronary vasoconstriction were mediated by the endothelin-A receptor, with a more specific role for the endothelin-A receptor in mediating resistance vessel constriction. Teerlink and colleagues13 showed evidence of potent vasoconstriction in the coronary circulation in response to large doses of sarafotoxin, with vasodilation occurring at smaller doses. It was suggested that the vasoconstrictor effects of sarafotoxin were mediated by an endothelin-B receptor subtype with high affinity for endothelin-1 but low receptor site density.
In the present study, the pronounced decrease in CBF and the large increase in coronary vascular resistance in response to intracoronary endothelin-1 were associated with a relatively small change in epicardial diameter, suggesting that the resistance vessels and, to a lesser degree, the epicardial coronary arteries are the sites for endothelin-1–induced coronary vasoconstriction. Specifically, low-dose endothelin-1 caused significant decreases in CBF and increases in coronary vascular resistance with minimal changes in coronary artery diameter. The changes that were observed in coronary hemodynamic parameters in the present study were not associated with any alterations in systemic hemodynamics or significant changes in circulating endothelin concentrations, implying that these changes were restricted to the coronary circulation. Thus, the present study confirms repeated investigations establishing the coronary vasoconstrictor action of exogenous endothelin.
The aim of our study was to determine the receptor responsible for coronary vasoconstriction at low concentrations that both mimic pathophysiological conditions in vivo and are free of systemic spillover. Endothelin induced significant coronary vasoconstriction that was attenuated by an endothelin-A receptor antagonist. Although endothelin-1 and sarafotoxin-6c are both 21–amino acid peptides and have similar molecular weights (2491.8 and 2515.8, respectively) and, therefore, almost identical concentrations at the same dose, no significant vasoconstrictor effect was seen from the intracoronary infusion of sarafotoxin. Thus, although pharmacological doses of sarafotoxin may have a coronary vasoconstrictor effect mediated by an endothelin-B receptor with a high affinity for endothelin-1,13 the present study demonstrates that the coronary vasoconstrictor effects of endothelin, as may be seen in pathophysiological states, are predominantly mediated via the endothelin-A receptor.
Endothelin-B receptors are present on both the endothelium and vascular smooth muscle.11 It has been postulated that these may be two different subtypes of endothelin-B receptor—one mediating the release of EDRF, and the other mediating vasoconstriction.23 To assess whether endothelial-dependent relaxation mediated through the endothelin-B receptor may be counteracting the vasoconstricting effect of sarafotoxin, EDRF (or nitric oxide) production was inhibited before the infusion of sarafotoxin. Compared with sarafotoxin alone, the combination of sarafotoxin and L-NMMA resulted in a significant decrease in CBF, suggesting that the stimulation of endothelin-B receptors results in a balance between vasoconstriction and vasodilation with little effect on the coronary circulation. However, when EDRF production is impaired, this balance is interrupted and stimulation of the endothelin-B receptors results in a predominantly vasoconstrictive effect. Although the inhibition of EDRF enhances the vasoconstrictive effect of sarafotoxin, the role of prostacyclins cannot be ruled out by this study.
The decrease in CBF was not completely abolished by the endothelin-A receptor antagonist (group 2). This may have been secondary to time effect, the effect of endothelin-1 on the endothelin-B receptor, or a mechanism other than stimulation of the endothelin-A or endothelin-B receptor. Another consideration is that the inhibition of the endothelin-A receptor by FR-139317 may have been incomplete. However, the endothelin-A receptor antagonist FR-139317 has been shown to be potent, competitive, and selective, both in vitro and in vivo.15 16 FR-139317 has no agonist activity on the endothelin-A receptor, and its affinity is 7300-fold higher for the endothelin-A receptor than for the endothelin-B receptor,15 with no demonstrable inhibitory effect on the endothelin-B receptor.16 Furthermore, Bird and Waldron24 demonstrated endothelin-A receptor inhibition with FR-139317 over a wide dose range, and thus, based on these prior reports, we are confident that there was selective and effective antagonism of the endothelin-A receptor in this study. Nevertheless, this study demonstrates the dominant role of the endothelin-A receptor in mediating local coronary vasoconstriction, although endothelin-1 may have the potential to induce coronary vasoconstriction by other mechanisms. The attenuation of changes in both epicardial diameter and coronary vascular resistance by the endothelin-A receptor antagonist also suggests that the endothelin-A receptors are located on both resistance and epicardial coronary vessels. Prior studies in canine epicardial and resistance vessels have demonstrated a similar distribution of endothelin-A receptors at these two sites in the coronary circulation.12
Two of five dogs receiving intracoronary endothelin-1 alone developed sustained ventricular tachycardia that degenerated into ventricular fibrillation. This was not observed in any dog in the FR-139317 group. Prior in vitro25 and in vivo26 studies have suggested that endothelin exerts a direct arrhythmic action on myocardial cells that cannot be accounted for by ischemia alone. In the present study, underlying myocardial ischemia as a cause for the arrhythmias cannot be ruled out; however, in the absence of hemodynamic changes, one can speculate that endothelin-1 has a direct arrhythmogenic effect that may be mediated through the endothelin-A receptors.
A role for endothelin in the regulation of coronary vascular tone in disease states has been implicated in animals and humans.27 Enhanced regional and systemic endothelin immunoreactivity was associated with myocardial infarction,7 28 congestive heart failure,29 hypertension,30 and atherosclerosis.8 A role for endothelin was also recently suggested in acetylcholine-mediated coronary vasoconstriction associated with hypercholesterolemia.31 Based on the observations of this study, we postulate that endothelin-1 may have potential as a paracrine humoral mediator of coronary vasoconstriction via the endothelin-A receptor and, to a lesser extent, the endothelin-B receptor in cardiovascular disease states. Furthermore, a potential therapeutic role for endothelin receptor antagonism may exist in such cardiovascular disease states.32
In summary, the present study demonstrates that low concentrations of exogenous endothelin-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction, predominantly via the endothelin-A receptor, since such vasoconstriction is significantly attenuated by blockade with FR-139317. The endothelin-B receptor may have a dual vasoconstrictive and vasodilator effect, and, under conditions resulting in impaired EDRF activity, coronary vasoconstriction mediated by the endothelin-B receptors is unmasked. Furthermore, endothelin-1 administered at a low concentration into the coronary circulation is a potent local coronary vasoconstrictor that mediates its actions predominantly at the level of the coronary resistance vasculature. These observations suggest that there may be a therapeutic role for blockade of endothelin receptors in cardiac disease states associated with elevated levels of circulating and tissue coronary endothelin and provide new insight into the role of endothelin-1 as a modulator of coronary vascular tone.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Dr Terry Opgenorth (Abbott Laboratories) for the use and supply of the endothelin-A receptor antagonist FR-139317 and Larry L. Aarhus for his technical expertise.
Received January 23, 1995; revision received June 7, 1995; accepted July 24, 1995.
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