© 1997 American Heart Association, Inc.
Articles |
Enhanced Endothelin-B-Receptor–Mediated Vasoconstriction of Small Porcine Coronary Arteries in Diet-Induced Hypercholesterolemia
From the Division of Internal Medicine and Cardiovascular Diseases (D.H., V.M., R.S.S., D.R.H. Jr), and the Departments of Anesthesiology and Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minn (L.A.S., Z.S.K.).
Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, Minn 55905. E-mail: lerman.amir{at}mayo.edu
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Abstract |
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Abstract The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (<481±25 µm in diameter) to cumulative concentrations (10-10 to 10-6 mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86±7% versus 47±7%, P=.001) and hypercholesterolemic (77±6% versus 37±7%, P<.001) pigs. At 10-10 mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23±6% versus 8±3%, P=.02) and S6c (17±5% versus 4±2%, P=.02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR-139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10-10 mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.
Key Words: endothelin • sarafotoxin • receptors • hypercholesterolemia • pigs • endothelium
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Introduction |
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Endothelins are 21 amino acid peptides that act as modulators of coronary vasomotor tone.1,2 The effects of endothelin on vascular tone are mediated by two major types of endothelin receptors, A (ETA) and B (ETB), each encoded by a different gene.3,4 The two receptor subtypes have distinct tissue distribution and affinity to endothelin isoforms: ETA receptors are present on vascular smooth muscle cells, whereas ETB receptors are found on both vascular smooth muscle and endothelial cells.5 The ETA receptor is selective for the endothelin-1 (ET-1) over the endothelin-3 isoform, while the ETB receptor has similar affinities for all endothelin isoforms.4 Endothelin binding to vascular smooth muscle ETA and ETB receptors mediates vasoconstriction, whereas ETB receptors on the vascular endothelium mediate a vasodilator response, presumably through increased production and release of nitric oxide and/or prostacyclin6 and activation of potassium channels.1 Indeed, the inhibition of endogenous endothelium-derived relaxing factor (ie, nitric oxide) production in vivo results in an enhanced coronary microvessel vasoconstrictor response to ETB-receptor stimulation.2
Endothelins mediate vasoconstriction of noncoronary resistance and capacitance arteries through both ETA and ETB receptors.7–10 The relative contribution made by each receptor to endothelin-mediated vasoconstriction is different between the two vessel types.10 Endothelin at pathophysiological concentrations also causes coronary vasoconstriction through stimulation of both types of receptors.2,11–14 It has been suggested that the relative contribution of each receptor to endothelin-mediated vasoconstriction is different in canine conduit and resistance coronary arteries, in similarity with noncoronary arteries.15
In pathophysiological conditions associated with endothelial dysfunction, such as hypercholesterolemia and heart failure, the vasomotor response of vessels to endothelins may be significantly altered. We have previously demonstrated that inhibition of endogenous endothelium-derived relaxing factor in vivo, mimicking pathophysiological states associated with endothelial dysfunction, results in an enhanced coronary microvessel vasoconstrictor response to ETB-receptor stimulation.2 In addition, experimental heart failure, a pathophysiological state associated with coronary microcirculation endothelial dysfunction and increased circulating ET-1 concentrations, is characterized by an altered coronary microcirculation vasoconstrictor response to stimulation of ETA and ETB receptors.16
Experimental hypercholesterolemia is characterized by coronary endothelial dysfunction extending into the microcirculation17 and elevated plasma ET-1 concentrations.18 The functional significance of ETA- and ETB-receptor stimulation of small coronary arteries in the steady-state and in the setting of hypercholesterolemia is unknown. Thus, these in vitro studies were designed to examine the hypothesis that experimental hypercholesterolemia in the pig is characterized by an altered response to ETA- and ETB-receptor stimulation of small coronary arteries.
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Methods |
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Animals
The study procedures and handling of animals were reviewed and approved by the Mayo Foundation Institutional Animal Care and Use Committee. Female juvenile domestic crossbred pigs were randomly allocated to receive either a normal diet or a 2% cholesterol atherogenic diet including 20% tallow and 1% hog bile extract for 10 to 13 weeks.18 Serum lipid profiles were obtained before sacrifice. In addition, plasma ET-1 levels were determined by the ET-1,2[125 I] assay system from Amersham, as previously described.18,19 All animals were euthanized with an intravenous overdose of pentobarbital sodium (Sleepaway).
In Vitro Studies
After euthanasia, the hearts were harvested for in vitro
analysis of coronary vasomotor tone, using a previously
described arteriograph.20 In brief, the hearts
were placed into cold modified Krebs-Ringer bicarbonate solution of the
following millimolar composition (control solution): 118.3 NaCl, 4.7
KCl, 2.5 CaCl2, 1.2 MgSo4,
1.2 KH2PO4, 25
NaHCO3, 0.026 calcium ethylenediamine-tetraacetic
acid, and 11.1 glucose. Segments 2 to 3 mm long of a secondary
branch of the left circumflex coronary artery were dissected
using a dissection microscope, transferred to an arteriograph filled
with oxygenated (94% O2 and 6%
CO2) modified control solution, and then mounted
onto microcannulas (Living System Instrumentation). Control solution
was circulated from a 250 mL oxygenated reservoir through
the arteriograph chamber at a flow rate of 12 mL/min. Temperature was
continuously monitored (model 7000 H, Jenco Electronics) to maintain
the vessel environment at 37±0.5°C. The arteriograph was placed on
the stage of an inverted microscope (Diaphot-TMD, Nikon) with a video
camera attached to the viewing tube. The signal derived was processed
by an electronic system (Living System Instrumentation) for the
continuous measurement and recording of both vessel wall
(lumen) inner diameter and wall thickness. All vessels were first
contracted with 10-6 mol/L U46619 (Cayman
Chemical), a thromboxane A2 analogue,
and then relaxed with 10-6 mol/L bradykinin
(Sigma).20 When indicated, the
endothelium was removed from vessels by intraluminal
perfusion with 0.5%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) for
30 seconds.20 The removal of
endothelium was confirmed by the absence of complete
relaxation to bradykinin. Responses of the pressurized arteries (ie,
not perfused with flow) were measured at a transmural pressure of
50 mm Hg.
After equilibration, sarafotoxin 6c (S6c; Phoenix Pharmaceuticals), a selective ETB-receptor agonist21 was added in a cumulative fashion (10-10 to 10-6 mol/L). After a 45-minute washout period, allowing for full recovery of vessel dimensions, ET-1 (Phoenix Pharmaceuticals) was added in the same manner. In separate experiments, vessels harvested from normal and hypercholesterolemic pigs were also incubated for 20 minutes with 10-6 mol/L FR-139317 (Abbott Laboratories), a selective endothelin ETA-receptor antagonist,22 prior to exposure to S6c and ET-1. Additional vessels from both normal and hypercholesterolemic pigs were incubated for 20 minutes with 10-6 mol/L BQ-788 (Phoenix Pharmaceuticals), a selective ETB-receptor antagonist,23 before exposure to ET-1. The endothelium was removed in additional vessels from both normal and hypercholesterolemic pigs, and the contractile response to S6c was assessed.
At the conclusion of the experiments, arteries were fully relaxed using high concentrations of papaverine (10-4 mol/L). Pressurized porcine coronary arterioles have been shown to manifest myogenic tone.24-31 In our study, vessels that were not exposed to drugs prior to the addition of cumulative concentrations of ET-1 or S6c also manifested myogenic tone. There was no difference in the myogenic tone between vessels harvested from control and hypercholesterolemic animals (reduction of diameter relative to the maximal diameter after papaverine by 16±6% and 19±5% for control and hypercholesterolemic vessels, respectively—P=NS), before the addition of ET-1 or S6c. To account for the myogenic tone, all subsequent calculations are normalized to the diameter in the passive state (ie, after full relaxation with agents such as sodium nitroprusside or papaverine.24-30 In this study, for each artery, the diameter obtained in response to papaverine was noted as a 100% baseline for the calculation of the contractile response to ET-1 and S6c. The contractile response was calculated by dividing the reduction in diameter caused by the agent by the maximal diameter in response to papaverine. For example, if the vessel diameter after papaverine was 300 µm, and the contractile agent had reduced the diameter by 100 µm, 200 µm, or 300 µm, then these would represent contractile responses of 33%, 67%, and 100%, respectively.
Statistical Analysis
Data are given as mean±SEM. In all experiments, n
refers to the number of vessels. For statistical analysis, the
unpaired Student's t test or repeated measures ANOVA
followed by Scheffe's test were used. A two-tailed value of
P
.05 was considered significant.
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Mean Maximal Luminal Diameter in Each Protocol
Mean maximal luminal diameters of vessels (after papaverine) in each protocol are depicted in the Table
.
Mean maximal diameters ranged from 296±29 µm to 481±25
µm in the different study protocols. In this range of vessel luminal
diameters, there was no correlation between vessel diameter and the
response to either S6c or ET-1 (data not shown).
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Lipid Profile
Plasma total cholesterol levels were significantly
higher in animals fed a high-cholesterol diet, as compared
with pigs that were given a normal diet (373±20 mg/dL versus
97±4 mg/dL, P<.0001). The increase in total plasma
cholesterol levels could be attributed primarily to
elevated low density lipoprotein levels (287±15 mg/dL versus
43±3 mg/dL, P<.0001), although high density
lipoprotein levels were also higher (77±5 mg/dL versus 47±2
mg/dL, P<.0001).
Endothelin Levels
Plasma endothelin levels obtained prior to sacrifice were
significantly higher in hypercholesterolemic pigs
(12.5±1.1 pg/mL versus 6.1±0.8 pg/mL,
P<.05).
Contractile Response to ET-1 and S6c
To examine the contractile effect of S6c and ET-1, vessels
were exposed to cumulative concentrations of either S6c or ET-1. Both
S6c and ET-1 caused a significant decrease in mean diameter in vessels
harvested from pigs on a normal diet, but the maximal contraction
attained with ET-1 was significantly greater than S6c (86±7% versus
47±7%, P=.001). A similar trend occurred in
hypercholesterolemic pigs (maximal contraction of
77±6% for ET-1 versus 37±7% for S6c, P<.001).
Comparison of Contractile Responses in Normal and
Hypercholesterolemic Animals
The contractile response to 10-6 mol/L
U46619, a thromboxane A2 analogue,
was similar for vessels from normal and
hypercholesterolemic pigs (mean contraction of 56% and
61% for normal and hypercholesterolemic arteries,
P=NS). Vessels harvested from
hypercholesterolemic pigs had a significantly impaired
vasorelaxing response to bradykinin compared with vessels from normal
animals at concentrations <10-6 mol/L
bradykinin (data not shown). However, at 10-6
mol/L bradykinin, there was full relaxation in both groups. In
comparing the contractile response to ET-1 in vessels from normal and
hypercholesterolemic pigs (Fig 1), there was an enhanced response to
ET-1 at low concentrations (10-10 mol/L) in
hypercholesterolemic pigs (23±6% versus 8±3%,
P=.02). Similarly, S6c caused an enhanced contractile
response in hypercholesterolemic pigs at low
concentrations (10-10 mol/L), as compared with
normal pigs (Fig 2; 17±5% versus
4±2%, P=.02). There was no statistically significant
difference between the two groups at higher concentrations of either
ET-1 or S6c.
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FR-139317
To determine the underlying endothelin receptor subtype mediating
the enhanced contraction to endothelins in vessels harvested from
hypercholesterolemic pigs, vessels from normal and
hypercholesterolemic pigs were incubated with FR-139317
(selective ETA-receptor antagonist) prior to exposure to
either ET-1 or S6c. At lower concentrations
(<10-9 mol/L) of ET-1, FR-139317 did not affect
the contractile response of normal (Fig 3) and
hypercholesterolemic pigs (Fig 4). In the presence of FR-139317, the
maximal contractile to ET-1 was lower in
hypercholesterolemic pigs, as compared with normal pigs
(59±10% in normal pigs versus 30±6% for
hypercholesterolemic pigs, P=.03). FR-139317
did not affect the contractile response to S6c (data not shown).
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BQ-788
The effect of a selective ETB-receptor antagonist was
examined in vessels harvested from normal and
hypercholesterolemic pigs. In normal pigs, incubation
with BQ-788 (selective ETB-receptor antagonist) caused an
enhanced contractile response to ET-1 at 10-10
mol/L (Fig 5; 38±11% with BQ-788 versus
8±3% without BQ-788, P=.02). In contrast, in
hypercholesterolemic pigs, BQ-788 attenuated the
contractile response to ET-1 at 10-10 mol/L (Fig 6; 7±3% versus 23±6%,
P=.02). At concentrations >10-9
mol/L, BQ-788 did not affect the contractile response to ET-1 in normal
pigs and attenuated contraction in hypercholesterolemic
pigs only at 10-6 mol/L.
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Contractile Response to S6c in Arteries With Removed
Endothelium
In contrast to the full relaxation to 10-6
mol/L bradykinin in vessels with intact endothelium,
the removal of the endothelium attenuated the
vasorelaxing response for both normal and
hypercholesterolemic animals (data not shown). The
contractile response to 10-6 mol/L U46619 was
not affected by the removal of the endothelium (data
not shown). To evaluate the role of the endothelium in
the enhanced contractile response to ETB-receptor stimulation observed
in hypercholesterolemia, we compared the
contractile response to S6c in endothelium-denuded
vessels from normal and hypercholesterolemic animals.
With the endothelium removed, no difference in the
response to S6c was observed between normal and
hypercholesterolemic pigs (Fig 7).
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Discussion |
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The current in vitro studies demonstrate an enhanced vasoconstrictor response of small coronary arteries to ET-1 and S6c in pigs with experimental hypercholesterolemia. This response is mediated mainly through the ETB receptor. These alterations in the coronary responsiveness occurred in the setting of long-term elevation of circulating ET-1. These studies support a role for both the ETA and ETB receptors in the regulation of coronary tone in the presence and absence of hypercholesterolemia.
Seo and colleagues12 previously demonstrated that the contractile response of porcine epicardial arteries to endothelins is biphasic; the first phase attained at low concentrations is primarily mediated by the endothelin ETB receptor, whereas both endothelin receptors mediate contraction in the latter, more pronounced phase attained at high concentrations. Takase and colleagues32 found similar results in noncoronary resistance vessels. The current studies extend these previous observations and demonstrate that both the ETA and ETB receptors contribute to endothelin-induced vasoconstriction of small coronary arteries. In the present study, the maximal vasoconstrictor response of normal small porcine coronary arteries to ET-1, a nonspecific endothelin receptor agonist, was approximately two-fold greater than the response to S6c, a specific ETB-receptor agonist. While experimental hypercholesterolemia did not change this ratio, vessels from hypercholesterolemic pigs were found to have a significantly greater contractile response to both S6c and ET-1 at low concentrations (10-10 mol/L). The incubation of vessels from hypercholesterolemic pigs with FR-139317, a selective ETA-receptor antagonist, did not attenuate this enhanced contractile response to ET-1 or to S6c. Moreover, preincubation of the vessels with BQ-788, a selective ETB-receptor antagonist, affected the contractile response to ET-1 primarily at low concentrations (10-10 mol/L). Based on these findings, the enhanced contractile response of small coronary arteries to endothelin in diet-induced hypercholesterolemia may be primarily ascribed to an ETB-receptor-modulated mechanism.
Coronary vasoconstriction in response to endothelins is modulated by ETB receptors,11 found on both endothelial and vascular smooth muscle cells.5 Increased ETB-mediated contraction may therefore reflect an altered endothelium- or vascular smooth muscle-dependent mechanism, or a combination of the two. Expression of the ETA receptor on vascular smooth muscle cells has been shown to be reduced or unchanged in atherosclerosis,5,33 as compared with upregulation of the endothelin ETB receptor.34 Moreover, Elshourbagy and colleagues33 showed that mRNA for the ET-B receptor is diffusely upregulated in marmosets subjected to a high-cholesterol diet for 3 months. However, the functional significance of this upregulation has been challenged.34 The results of our study do not allow any conclusion regarding the localization or activity of ETB receptors on endothelial or smooth muscle cells. However, in our study, the contractile response to S6c was similar in endothelium-denuded vessels from normal and hypercholesterolemic pigs, suggesting that vascular smooth muscle ETB-receptor stimulation results in a similar contractile response in the steady state and in pathophyiological states. Moreover, these findings suggest that the enhanced vasoconstrictor response to ET-1 and S6c via the ETB receptor involve an endothelium-dependent process.
The mechanisms underlying the enhanced coronary contractile response of small coronary arteries to ET-1 and S6c in experimental hypercholesterolemia prompt speculation. The endothelium regulates the vasoconstrictor response to endothelins by secreting both relaxing and contracting factors.6,35–39 Enhanced endothelium-dependent contraction in response to ET-1 and S6c may be caused by increased release of endothelium-derived vasoconstrictors or attenuated release of endothelium-derived vasorelaxing factors. Endothelins cause the release of endothelium-derived contractile factors, such as thromboxane A2, prostaglandin H2 and superoxide anions.35–39 Conversely, stimulation of endothelial ETB receptors by endothelins causes a vasodilator effect through release of endothelium-derived relaxing factor and vasodilator prostaglandins.6 As a result, the net contractile response attained with endothelins is affected by the balance in secretion between relaxing and contracting factors.
In pathophysiological states associated with endothelial dysfunction, such as hypercholesterolemia, the properties of the endothelium are altered and may involve a suppressed endothelium-derived relaxing factor pathway.40 Hence, one could speculate that, in hypercholesterolemia, the dysfunctional endothelium secretes an excess of contractile factors in lieu of relaxing factors in response to stimulation of ETB receptors. Indeed, Lerman and colleagues41 previously showed that the contractile response to ET-1 in vivo is enhanced when production of endogenous endothelium-derived relaxing factor is inhibited, mimicking pathophysiological states. Moreover, intracoronary infusion of S6c at pathophysiological concentrations in normal animals has minimal effects on coronary blood flow, diameter or resistance.2 However, when production of endogenous endothelium-derived relaxing factor is inhibited, S6c decreases coronary blood flow and increases coronary vascular resistance without a significant change in coronary artery diameter, implying that when the endothelium-derived relaxing factor pathway is suppressed, S6c is a potent coronary vasoconstrictor at the microcirculation level.
Our experiments with the selective ETB-receptor antagonist, BQ-788, lend credence to our hypothesis. In vessels harvested from normal pigs, BQ-788 caused an enhanced contractile response to ET-1. Prior studies have also reported that BQ-788 causes enhanced vasoconstriction, presumably by affecting endothelial ETB-receptors to a greater extent than smooth muscle ETB receptors.42–44 In contrast, in vessels from hypercholesterolemic pigs, BQ-788 attenuated the contractile response to ET-1. As mentioned above, stimulation of endothelial ETB receptors in states of endothelial dysfunction may cause the secretion of vasoconstrictor agents. Thus, the inhibition of endothelial ETB receptors by BQ-788, in addition to the inhibition of smooth muscle cell ETB receptors, would be expected to attenuate the contractile response to ET-1 in hypercholesterolemia.
Increased ETB-receptor-mediated coronary vasoconstriction has been demonstrated in other pathophysiological states. Cannan and colleagues16 recently reported that canine coronary microvessels have an enhanced vasoconstrictor response to S6c in an experimental model of heart failure. It is of interest that both experimental hypercholesterolemia and heart failure are characterized by elevated plasma endothelin levels and endothelial dysfunction, supporting a role for the dysfunctional endothelium in modulating the enhanced contractile response to ETB-receptor stimulation.
Moreover, our findings are consistent with prior reports of ETA-receptor downregulation in states associated with atherosclerosis.5 Incubation of vessels with FR-139317 (a selective ETA-receptor antagonist) prior to exposure to ET-1 resulted in an attenuated contractile response to ET-1 in both normal and hypercholesterolemic pigs. However, the inhibitory effect of FR-139317 was significantly more pronounced in hypercholesterolemic pigs. The increased efficacy of FR-139317 in hypercholesterolemic pigs may be explained by downregulation of ETA receptors, and hence a greater ratio of antagonist to receptor.
Several studies have shown that distal, small-caliber segments of coronary arteries are more sensitive to endothelins as compared with proximal, large-caliber segments.45-49 Moreover, endothelin-mediated contraction is presumed to be mediated primarily by nonETA receptors in distal, small vessels.45 Indeed, Dashwood and colleagues50 have suggested that the ETB receptor is the primary mediator of endothelin in coronary microvessels. Bacon et al51 recently showed that there was intense staining for ET-1 in the endothelium of microvessels associated with atherosclerosis. Moreover, the ETB receptor was detected in these vessels by autoradiography.51 It is thus understandable why changes in the response of small coronary arteries to endothelins in hypercholesterolemia were manifested through the ETB receptor in our study.
The contractile response to endothelins is examined in vitro across a wide range of concentrations. It is difficult to determine which range of concentrations reflects the levels of endothelins at pathophysiological states in vivo, since serum levels of ET-1 do not reflect tissue levels;35 Luscher and colleagues35 and Seo and colleagues12 have suggested that it is the endothelin-mediated contraction occurring at lower concentrations that is of pathophysiological importance. The contraction achieved at high concentrations most probably reflects the pharmacological properties of the specific endothelin peptide. It is therefore of interest that the major changes we observed between normal and hypercholesterolemic pigs occurred at the lowest concentrations of endothelins.
Defining the relative contribution of each endothelin subtype to endothelin-mediated vasoconstriction has important clinical implications. Specific endothelin receptor antagonists are currently under investigation for treatment of different pathophysiological states.52 Our results clearly show that both in the steady-state and in pathophysiological conditions, stimulation of either the ETA or ETB receptor may result in coronary vasoconstriction. However, in pathophysiological states associated with elevated circulating endothelin levels, such as atherosclerosis,18,19 changes in ETB-receptor-mediated vasoconstriction may account for the increased sensitivity to endothelins.53 Therefore, inhibition of the ETB receptor may be necessary for the treatment of the vasomotor manifestations elicited by endothelin in these conditions. Further studies are warranted to assess the physiological and the therapeutic significance of the enhanced contractile response to endothelins observed in vitro in experimental hypercholesterolemia
In conclusion, the present studies demonstrate an alteration in small coronary artery responsiveness to ET-1 and S6c in the presence and in the absence of experimental hypercholesterolemia and chronically elevated circulating ET-1 levels. The enhanced coronary vasoconstriction is mediated via the ETB receptor. These studies underscore the importance of both the ETA and ETB receptors in the control of coronary tone in physiological and pathophysiological states.
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Acknowledgments |
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This study was supported by grants from the National Institute of Health (HL-0318001 to A.L. and HL-53542 to Z.S.K.), Miami Heart Research Institute, and Mayo Foundation. Dr. Hasdai is a recipient of a fellowship from the American Physicians Fellowship for Medicine in Israel. The authors would like to thank Dr Terry Opgenorth (Abbott Laboratories) for the supply of FR-139317.
Received April 11, 1997; accepted September 4, 1997.
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