Ann Thorac Surg 2007;84:1522-1527. doi:10.1016/j.athoracsur.2007.05.064
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Role of Endothelin-1 Receptor Antagonists in Vasoconstriction Mediated by Endothelin and Other Vasoconstrictors in Human Internal Mammary Artery
Guo-Wei He, MD, DSca,b,c,d,*,
Ming-Hui Liu, MD,
Qin Yang, MD, PhDa,b,
Anthony Furnary, MDa,b,
Anthony P.C. Yim, MDc
a Providence Heart and Vascular Institute, Albert Starr Academic Center, Portland, Oregon
b Department of Surgery, Oregon Health and Science University, Portland, Oregon
c Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR
d Wuhan Heart Institute, The Central Hospital of Wuhan, Wuhan, China
Accepted for publication May 29, 2007.
* Address correspondence to Prof He, Department of Surgery, Block B, 5A, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. (Email: gwhe{at}cuhk.edu.hk).
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Abstract
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Background: The action of antagonists for endothelin type A (ETA) and type B (ETB) on the vasoconstriction mediated by various vasoconstrictors in the human bypass grafts have not been well-defined. We studied the role of antagonists for both ETA and ETB receptors in vasoconstriction mediated by endothelin-1 and other vasoconstrictors in the human internal mammary artery (IMA).
Methods: Isolated IMA rings (n = 192, taken from 49 patients) were studied in organ bath for the interaction between endothelin-1, angiotensin II, U46619, and potassium chloride and the antagonist for ETA (BQ-123) or ETB (BQ-788).
Results: Significant relaxations were observed by BQ-123 (agonist: endothelin-1, 84.9 ± 7.9%; angiotensin II, 45.5 ± 5.1%; and U46619, 30.7 ± 5.7%) or BQ-788 (agonist: endothelin-1, 66.5 ± 11.3%; angiotensin II, 38.9 ± 4.2%; and U46619, 30.8 ± 4.0%), but not to potassium chloride-induced precontraction. Incubation of IMA with BQ-123 or BQ-123 + BQ-788 significantly shifted the concentration-contraction curve to endothelin-1 rightward (p < 0.05 vs control) with effective concentration causing 50% of maximal response (EC50) (–7.59 ± 0.04 or –7.81 ± 0.05 vs –8.47 ± 0.05 log M in the control, p < 0.001), whereas BQ-788 alone did not affect the contraction curve (p = 1.0 vs control). In contrast, none of the endothelin-1 inhibitors and the combination demonstrated significant depression effects on angiotensin II, U46619, or potassium chloride-induced contraction.
Conclusions: The present study demonstrates the role of ETA and ETB antagonists in the endothelin-1-mediated contraction in the human IMA and indicates the dominant role of ETA receptors. Although these effects are specific to endothelin-1, cross-action between endothelin-1 and angiotensin II exists. These findings provide useful knowledge for the future development of the clinical antispastic protocol in coronary bypass surgery.
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Introduction
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Endothelin (ET), an endothelium-derived peptide with potent vasoconstrictor actions in vitro and in vivo, exists in three isoforms, ET-1, ET-2, and ET-3 [1]. Endothelin-1, the predominant isopeptide, is likely to be physiologically most important in regulating vascular function by its action on two distinct receptor subtypes, ETA and ETB [2]. The ETA receptor has a high affinity for ET-1, is selectively expressed on vascular smooth muscle cells, and is the predominant ET receptor in the myocardium [3]. The ETB receptor has equal affinity for all three ET isoforms and is present on both endothelial and vascular smooth muscle cells [4]. Endothelin-1, by stimulation of ETA receptors on vascular smooth muscle cells, activates phospholipase C, resulting in increase of inositol triphosphate, intracellular Ca++ accumulation, and vasoconstriction [4, 5]. The level of ET-1 is elevated in conditions associated with vascular endothelial dysfunction such as hyperlipidemia, hypertension, smoking, heart failure, and atherosclerosis, suggesting a possible pathophysiological role of this endothelium-derived peptide in these conditions [6–8]. It has been shown that endogenous ET-1 maintains coronary artery tone by activating ETA receptors [9]. Moreover, ET-1 may also contribute toward vasoconstriction and possible graft spasm in patients undergoing coronary artery bypass grafting [10, 11]. In fact, both ETA and ETB are reported to mediate the ET-1-induced contraction in the human internal mammary artery (IMA) [12].
A number of ET receptor antagonists have been developed and extensively investigated in recent years. The ETA receptor antagonism dilates the forearm microcirculation of health volunteers [13] and subjects with atherosclerosis [14], suggesting that ET-1 regulates resting peripheral vascular tone in humans. In addition, ETA receptor antagonist BQ-123 has been shown to dilate coronary arteries and to improve endothelial dysfunction in patients with atherosclerosis [14] and in vitro [15]. However, the role of the ET receptor antagonists on prevention or treatment of vasospasm of the arterial grafts in patients undergoing coronary artery bypass grafting (CABG) is unknown.
We hypothesized that ET-1 activity, by stimulation of ETA or ETB receptors, may contribute to the graft spasm in patients undergoing CABG. Therefore, we designed this study to investigate the role of the antagonists of both ETA and ETB receptors on vasoconstriction mediated by ET-1, and a number of other important vasoconstrictors in isolated human IMA from patients undergoing CABG.
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Material and Methods
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Human IMA segments (n = 192) were collected from 49 patients (age, 67.8 ± 9.5 years; mean ± SD) undergoing CABG. Approval to use the discarded arterial grafts was given by the Institutional Review Board, Providence St. Vincent Hospital. Each patient signed an informed consent form for use of the discarded IMA tissue before the operation. The discarded distal IMA segments were collected and placed in a container with oxygenated physiological solution (Krebs solution) maintained at 4°C and transferred to the laboratory immediately. The arteries were transferred into a glass dish and carefully dissected out from the surrounding connective tissue. The vessel was cut into 3-mm-long rings and suspended on wires in organ baths for isometric recording of tension. The number of rings taken from each patient varied from four to six. Each IMA ring was set up in a 25-mL bath that contained modified Krebs solution of the following composition (mM): Na+ 144, K+ 5.9, Ca2+ 2.5, Mg2+ 1.2, Cl– 128.7, HCO3
– 25, SO4
2– 1.2, H2PO4
– 1.2, and glucose 11. The solution was continuously aerated with 95% oxygen and 5% carbon dioxide at 37°C.
Organ Bath Technique
A technique to normalize the rings to a physiologic pressure comparable with in vivo situations was used in this study. The details of the technique were described previously [16–18] and repeatedly used in our in vitro studies for human vessels. In brief, the rings were stretched up in progressive steps to determine the length-tension curve for each ring. A computer iterative fitting program (Vastand 2.1; Yang-Hui He, Princeton, NJ) was used to determine the exponential line, pressure, and internal diameter. When the transmural pressure on the rings reached 100 mm Hg, as determined from their own length-tension curves, the stretch-up procedure was stopped and the rings were released to 90% of their internal circumference at 100 mm Hg. This degree of passive tension was then maintained throughout the experiment. After the normalization procedure, the artery rings were equilibrated for at least 45 minutes.
In this study the endothelium was intentionally preserved by cautiously dissecting and mounting the arterial rings [18]. To avoid the influence of a vasodilator on the effect of subsequently used vasodilators, each ring was only used to reconstruct one dose-response curve.
Protocol
Relaxation induced by ET receptor antagonists (n = 8 in each group)
After normalization, the IMA rings were equilibrated for at least 60 minutes; the rings were contracted with one of the four vasoconstrictors: ET-1 (10 nM), angiotensin II (AII, 3 nM), thromboxane A2 mimetic U46619, a TP (thromboxane-prostaglandin) receptor agonist (10 nM), and potassium chloride (KCl; 25 mM). When the contraction reached stable plateau, cumulative concentration-relaxation curves to BQ-123 (ETA receptor antagonist, 1 µM) or BQ-788 (ETB receptor antagonist, 1 µM) were established. The concentrations of these vasoconstrictors to induce the precontraction are equal to those causing 50% to 80% of maximum response (EC50 to EC80) for ET-1, AII, U46619, or KCl induced contractions in the human IMA rings from previous studies [16–18] determined from the logistic curve fitting equations. Only one cumulative concentration-relaxation curve was established from each IMA ring to avoid the interaction between the vasodilators. The relaxation was expressed as percent reversal of the agonist-induced precontraction.
Due to the unsustained contraction by ET-1 in the human IMA observed in the previous study [16] as well as in the preliminary studies for the present investigation, a time control to ET-1 contraction was set as the time control in the experiments testing the relaxation in ET-1 precontraction (n = 8). The relaxation in this group was normalized by the time control at each dose of the ETA or ETB induced relaxation [16].
Depression of contraction by pretreatment with ET receptor antagonists (n = 8 in each group)
After normalization and equilibration for at least 60 minutes, 100 mM KCl was added into the organ bath and the contraction force was recorded. This was used as the control value for the contraction induced by other vasoconstrictors. The rings were repeatedly washed with Krebs solution until the baseline vascular tone restored. Four rings from one patient were allocated in four groups for incubation with the following: (1) BQ-123 (1 µM); (2) BQ-788 (1 µM); (3) BQ-123 (1 µM) + BQ-788 (1 µM); or (4) vehicle as control (n = 8 in each group). The cumulative concentration-contraction curves to various vasoconstrictors were then established. Those vasoconstrictors were ET-1 (–10 to –7.5 log M), angiotensin II (AII, –10 to –6.5 log M), thromboxane A2 mimetic U46619 (–10 to –6.5 log M), and KCl (5 to 120 mM). These vasoconstrictors were selected due to their vasoconstrictive effect in the human IMA [11]. The contraction was expressed as percentage of the contraction force induced by 100 mM KCl in the same IMA ring, as mentioned above.
Statistical Analysis
The sensitivity of ET receptor antagonists and vasoconstrictors was expressed as EC50, the effective concentration causing 50% of maximal relaxation or contraction (Emax). The EC50 was determined from each individual concentration-relaxation curve by a sigmoid logistic curve-fitting equation: E = MAp/(Ap + Kp), where E is relaxant response, M is Emax, A is concentration, K is EC50 concentration, and p is the slope parameter. A computerized program was used for the curve fitting and EC50 values were determined and expressed as log10 M.
Statistical analysis was performed with SPSS software (SPSS, Inc, Chicago, IL). All values were expressed as mean ± standard error of the men. Statistical comparisons of the percentage relaxation under different treatments were performed by two-way analysis of variance (ANOVA) (general linear model) with repeated measures, followed by a post hoc Bonferroni test to detect the individual differences. The Emax and EC50 were compared by one-way ANOVA followed by a post hoc Bonferroni test. A p value less than 0.05 was considered statistically significant.
Materials
The ET-1, BQ-123, and BQ-788 were purchased from American Peptide Company (Sunnyvale, CA). The U46619 was purchased from Cayman Chemical (Ann Arbor, K). Other chemicals were purchased from Sigma Chemical Company (St. Louis, MO). Stock solutions of ET-1 and U46619 were held frozen until required. All solutions were freshly prepared before daily use and protected from light when needed.
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Results
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The internal diameter of 192 isolated human IMA rings at an equivalent transmural pressure of 100 mm Hg (D100) was 2.3 ± 0.03 mm as determined from the normalization procedure. When the IMA rings were set at a resting diameter of 90% x D100 (P90), the equivalent transmural pressure was 78.4 ± 0.6 mm Hg, and the resting force was 4.0 ± 0.08 g. The U46619-induced precontraction force was 4.9 ± 0.2 g.
Relaxation Induced by ET Receptor Antagonists
The relaxation curve was established for both BQ-123 and BQ-788 in the precontraction induced by four vasoconstrictors as mentioned above. The precontraction force by these vasoconstrictors is listed in Table 1. The ET-1 induced higher, and AII induced lower, precontraction than that by KCL (p < 0.05). The BQ-123 caused significant relaxations in the human IMA rings precontracted by ET-1 (84.9 ± 7.9%), AII (45.5 ± 5.1%), and U46619 (30.7 ± 5.7%). Similarly, BQ-788 also induced a certain amount of relaxation in the IMA contracted by ET-1 (66.5 ± 11.3%), AII (38.9 ± 4.2%), and U46619 (30.8 ± 4.0%). However, neither BQ-123 nor BQ-788 showed any significant relaxant effect on the IMA rings precontracted by KCl (p < 0.05 vs other groups, two-way ANOVA) (Fig. 1).
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Fig 1. Mean concentration (–log M)-relaxation curves (n = 8 from eight patients in each group) for BQ-123 (A) or BQ-788 (B) in isolated human internal mammary artery rings precontracted by ET-1 (closed triangle; 10 nM), angiotensin II (open triangle; 3 nM), thromboxane A2 mimetic U46619 (closed circle; 10 nM), and potassium chloride (open circle; 25 mM). The relaxation is expressed as percent reversal of the vasoconstrictor-induced contraction. Values are expressed as mean ± standard error of the mean. (*p  0.05 vs other groups, one-way analysis of variance.)
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Depression of Contraction by Pretreatment With ET Receptor Antagonists
Incubation of IMA rings with BQ-123 or BQ-123 + BQ-788 significantly shifted the cumulative concentration-contraction curve to ET-1 to the right (p 0.003 vs control group, two-way ANOVA), whereas BQ-788 alone did not significantly affect the contraction curve (p = 1.0 vs control group). The sensitivity of ET-1-induced contraction in IMA rings incubated with BQ-123 or BQ-123 + BQ-788 was significantly decreased as shown in increased EC50 values in comparison with the control group (EC50: –7.59 ± 0.04 or –7.81 ± 0.05 vs –8.47 ± 0.05 log M in the control group, p < 0.001) (Fig 2A). The inhibitory effect is specific to ET-1. This is shown by the contraction induced by the other three vasoconstrictors. In contrast to the ET-1 contraction, none of the ET-1 inhibitors BQ-123 or BQ-788 and the combination demonstrated significant depression effects on AII, U46619, or KCl-induced contraction with no change of EC50 values in comparison with the control rings (Figs 2B to 2D).
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Fig 2. Mean concentration (–log M)-contraction curves (n = 8 from eight patients in each group) to ET-1 (A), AII (B), U46619 (C), and potassium chloride (KCl) (D) in isolated human internal mammary artery incubated with BQ-123 (open triangle; 1 µm), BQ-788 (closed circle; 1 µm), BQ-123 (1 µm) + BQ-788 (1 µm) (open circle), or vehicle as control (closed triangle). The contraction is expressed as the percentage of the contraction force induced by KCl (100 mM) (see "Method"). Values are expressed as mean ± standard error of the mean. (*p 0.01 vs control group, two-way analysis of variance.)
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Comment
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The major findings from the present study are the following: (1) ETA and ETB receptor antagonists relax the ET-1 induced contraction in the human IMA; (2) only ETA receptor antagonists present significant prevention effect of the ET-1-induced contraction; and (3) these effects are specific on ET-1-related action but may have cross-action with AII.
Methodology
For any relaxation studies, a stable precontraction is required. In this study, we paid particular attention to the accuracy of the relaxation induced by ET-1 receptor antagonists due to the fact that ET-1-induced contraction in the human IMA is usually not stable; according to our observations in the previous study [16] as well as in the present study. Therefore, the relaxation was normalized by the time control and the unsustained portion of the precontraction was deducted from the relaxing effect. This provides reliable results for relaxation.
ET-1 and ETA
In the present study, both ETA and ETB antagonist BQ-123 and BQ-788 induced significant relaxation in the ET-1-precontracted human IMA, suggesting that these two subtypes of ET-1 receptors mediate relaxation in this human artery. This is in accordance with a previous investigation [12]. On the other hand, the ETA antagonist BQ-123 induced a higher relaxation than the BQ-788 did (84.9% vs 66.5%) in the ET-1-precontracted IMA. Although the difference did not reach statistical significance, this may suggest that ETA induces a stronger contraction in the ET-1-mediated response in the human IMA. This is different from the previous observation that the beneficial effects of endothelin antagonism are independently and equally mediated by ETA and ETB receptors [12, 15]. The more significant role of the ETA receptors in the contraction of the human IMA is shown in Fig. 2A, which gives evidence that only the ETA antagonist BQ-123 inhibited the ET-1-induced contraction. The BQ-788 had little effect either used alone or in combination with BQ-123.
ET and AII
In the present study it was found that the AII-induced contraction was relaxed to a significant degree by both ETA and ETB antagonists, BQ-123 and BQ-788 (Fig 1). It has become increasingly clear that angiotensin II (AII) is not the sole contributor of the renin-angiotensin system to cardiovascular regulation. Angiotensin IV (AngIV), the hexapeptide derived from AII can bind to the AII receptors AT1 and AT2 with low affinity. The interaction between AngIV and ET-1 has been observed. Pretreatment of endothelium-intact arteries with the endothelin ETA/ETB receptor inhibitors PD142893 blocked the AngIV-induced contraction. It was suggested that endothelium was mandatory to unmask the effect of AngIV as a source of endogenous ET-1 release [19].
Taken together our findings in accordance with the previous observations suggest that there is a cross-talk in the endothelial-smooth muscle cell between the AII receptors and the ET receptors. This explains why the AII-induced contraction can be partially reversed by ET-1 receptor antagonists and such effect is not seen in the KCl-induced contraction and only seen in U46619-induced contraction in a weak manner (Fig 1). The interaction between ET-1 and AII is certainly worth investigating in the future.
Possible Role of ET-1 Receptor Antagonists in CABG
Endothelin-1 is a strong mediator for vasoconstriction in the human CABGs due to its vasoconstriction effect in these conduit arteries [16, 20] and due to the fact that during cardiopulmonary bypass the plasma concentration of ET-1 increases [21]. The present study demonstrates the effectiveness of ET-1 receptor antagonists in the prevention and treatment of the vasospasm mediated by ET-1. Interestingly, the ETA receptor antagonist BQ-123 has both prevention and treatment effects. In contrast, the ETB antagonist BQ-788 only had the effect of relaxation in ET-1-induced contraction but had little effect on the prevention of the contraction to ET-1 when added before contraction. These results show that in order to antagonize the ET-1-mediated contraction in the human IMA it is probably important to mainly target the ETA receptor. This has clinical significance in the development of drug therapy agonist graft spasm in CABG in the future. In particular, we have previously found that although clinically frequently used vasodilators such as nitroglycerin and nitroprusside may relax the ET-1-mediated contraction in the human IMA [17] and the radial artery [22], incubation with these drugs at the plasma concentrations do not present significant inhibition to the ET-1-induced contraction [16]. The present study therefore provides a new insight in the development of new clinical protocol regarding the use of ET-1 antagonists in the prevention or reverse of vasospasm in the human arteries used as CABG grafts. These ET-1 antagonists are currently at the preclinical stages and intravenous injection in dogs for BQ-123 [23] and in pigs for BQ-788 [24] have been reported. Therefore, these antagonists may be developed as intravenous drugs or for topical use on the grafts in clinical trials as the next step.
In the present study, we only studied the effect of ET-1 antagonists in one CABG graft, the human IMA. The effect of these drugs on other grafts such as the radial artery awaits further investigations.
In conclusion, the present study demonstrates the role of both ETA and ETB antagonists in the ET-1-mediated contraction in the human IMA and indicates the dominant role of the ETA receptor. Although these effects are specific to ET-1, cross-action between ET-1 and AII exists. These findings provide useful knowledge for the future development of the clinical antispastic protocol in CABG surgery.
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Acknowledgments
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This work was fully supported by grants from Providence St. Vincent Medical Foundation, Portland, Oregon, and Research Grants Council of the Hong Kong Special Administrative Region (Project No. CUHK4383/03M) and CUHK Direct Grant 2041164, 440171, & 4450169, China. The technical assistance of the cardiac surgeons and nurses in Cardiovascular Operating Room (Kay Metsger, Victor Bayley, Wendy Buckham, Verna Hilburger, Donna DiModica, and Kate Donaldson), St. Vincent Hospital is gratefully acknowledged.
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Abstract
Introduction
