Cardiovascular Research

Cardiovascular Research 2001 49(1):146-151; doi:10.1016/S0008-6363(00)00244-3
© 2001 by European Society of Cardiology

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Verma, S. Articles by Anderson, T. J Search for Related Content PubMed PubMed Citation Articles by Verma, S. Articles by Anderson, T. J Social Bookmarking          What's this?

Copyright © 2000, European Society of Cardiology

Endothelin receptor blockade improves endothelial function in human internal mammary arteries

Subodh Verma^a, Fina Lovren^a, Aaron S Dumont^a, Kieren J Mather^a, Andrew Maitland^a, Teresa M Kieser^a, William Kidd^a, John H McNeill^b, Duncan J Stewart^c, Christopher R Triggle^a and Todd J Anderson^a,*

^aFaculty of Medicine, The University of Calgary, Calgary, Canada
^bFaculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada
^cFaculty of Medicine, The University of Toronto, Toronto, Canada

^* Corresponding author. Division of Cardiology, Foothills Hospital, 1403-29th Avenue NW, Calgary, Alta, Canada T2N 2T9. Tel.: +1-403-670-1020; fax: +1-403-670-1592 todd.anderson{at}crha-health.ab.ca

Received 16 March 2000; accepted 31 July 2000

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 
Objective: Endothelial dysfunction, specifically endothelium-derived contracting factors have been implicated in the development of arterial conduit vasospasm. The potent vasoconstrictor endothelin-1 (ET-1) has received much attention in this regard. The present study was designed to evaluate the role of ET-1 in the development of endothelial dysfunction in human internal mammary arteries (IMA). To this aim, we examined the effects of specific and non-specific ET-receptor antagonists on endothelial function (assessed using acetylcholine (ACh)-induced vasodilation) in segments of IMA obtained during coronary artery bypass graft (CABG) surgery. Methods: Vascular segments of IMA were obtained from 51 patients undergoing elective coronary artery bypass graft (CABG) surgery and in vitro endothelium-dependent and -independent responses to ACh and sodium nitroprusside (SNP) were assessed. Isometric dose response curves (DRC) to ACh and SNP were constructed in pre-contracted rings in the presence and absence of bosentan (ET_A/B receptor antagonist, 3 µM), BQ-123 (ET_A antagonist, 1 µM) and BQ-788 (ET_B antagonist, 1 µM) using the isolated organ bath apparatus. Percent maximum relaxation (%E_max) and sensitivity (pEC₅₀) were compared between interventions. Results: ACh caused dose-dependent endothelium-mediated relaxation in IMA (%E_max 43±4, pEC₅₀ 6.74±0.12). In the presence of bosentan, BQ-123 and BQ-788 ACh-induced relaxation was significantly augmented (%E_max bosentan 60±3, BQ-123 56±4, BQ-788 53±5 vs. control 43±4, P<0.05) without affecting sensitivity. The effects of these antagonists were endothelium-specific since endothelium-independent responses to SNP remained unaltered. Furthermore, the beneficial effects were independently and maximally mediated by ET_A and ET_B receptors (%E_max BQ-123 56±4 vs. BQ-788 53±5 vs. bosentan 60±3, P>0.05). Conclusions: These data uncover, for the first time, beneficial effects of ET receptor blockade on endothelial-dependent vasorelaxation in human IMA.

KEYWORDS Endothelial function; Endothelins; Cardiovascular surgery; Vasoactive agents; Vasoconstriction/dilation

---

This article is referred to in the Editorial by N. Hoogerwerf (pages 15–16) in this issue.

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 
The endothelium plays a vital role in vascular homeostasis through the release of autocrine and paracrine substances [1,2]. In addition to vasodilation, the endothelium exerts anti-atherogenic effects through potent inhibition of platelet aggregation, smooth muscle proliferation and leukocyte adhesion [1,2]. A growing body of evidence implicates abnormalities in endothelial function as an early and integral mediator of a variety of cardiovascular disease states [2]. Disruption of the critical balance between endothelium-derived relaxing and contracting factors is believed to predispose the vascular smooth muscle to increased tone, decreased vasomotion, altered reactivity, changes in structure/geometry, enhanced platelet aggregation and eventual atherosclerosis/graft failure [2]. Elucidating the mechanism(s) of endothelial dysfunction in bypass conduits has implications in terms of vessel spasm, graft patency and the outcome of coronary artery bypass graft (CABG) surgery.

Accumulating evidence suggests that endothelium-derived vasoconstrictors (thromboxane, prostanoids and endothelin) may represent important mediators of peri-operative spasm in arterial conduits [3–5]. Commendable studies from Schaff's group [3] have suggested that these vasoconstrictors may be released secondary to hypoxemia. The growing interest in the role of endothelin-1 (ET-1) as a potential arterial spasmogen has been fueled by several distinct lines of evidence. First, bypass conduits react strongly and dose-dependently to ET-1 [6]. Second, ET-1 exaggerates the pressor responses to endogenous constrictors such as norepinephrine [7] and inhibits the actions of endothelium-derived nitric oxide (NO). Third, the plasma levels of ET-1 are elevated in patients undergoing CABG surgery [8] and, fourth, blood vessel ET-1 content is increased in atherosclerotic human internal mammary arteries (IMA) and modulates graft flow in the peri-operative period [9]. Although ET antagonists have been shown to inhibit ET-1 mediated contraction in IMA [10], whether these agents improve endothelial function remains unknown. Given the potent vasoconstrictor, mitogenic and pro-thrombotic actions of ET-1 [11], targeting these defects may uncover novel approaches to the management of acute peri-operative spasm. Additionally, such interventions may serve to impede long-term graft atherosclerosis. We herein describe, for the first time, the endothelial protective effects of ET receptor blockade in IMA from patients undergoing CABG surgery.

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 
2.1 Patient characteristics and risk factors
A total of 51 patients undergoing elective CABG surgery were recruited following written informed consent. The study was approved by the Institutional Review Committee for Scientific and Ethical Standards. The patient characteristics and risk factors are detailed in Table 1.

View this table: [in this window] [in a new window]   Table 1 Demographic characteristicsa

 
2.2 Isolated vascular ring experiments
Distal segments of the IMA not used for bypass grafting were placed in oxygenated physiological salt solution and immediately transferred to the pharmacology laboratory (within 30 min). The vessels were cleaned of adherent tissue and cut into rings (5 mm in length) and suspended in isolated tissue baths (volume 25 ml) containing oxygenated Krebs–Ringer bicarbonate buffer with the following composition (in mmol/l): NaCl (118), KCl (4.7), CaCl₂ (2.5), KH₂PO₄ (1.2), MgSO₄ (1.2), NaHCO₃ (25), dextrose (11.1) and disodium calcium edetate (0.026), maintained at 37°C and bubbled with 95% O₂ and 5% CO₂ as described previously [12]. A progressive resting tension of 2.5 g was applied (determined by preliminary experiments to afford the optimum tension-length relationship). All experiments were performed in the presence of indomethacin (10^–5 mol/l) to prevent the synthesis of vascular prostaglandins. Following equilibration for 90 min, isometric dose response curves (DRC) were recorded using the following protocol: (a) cumulative DRC to phenylephrine (10^–8 to 10^–5), (b) cumulative DRC to acetylcholine (ACh) in rings pre-contracted with the ED₇₅ of phenylephrine, (c) cumulative DRC to ACh in the presence and absence of bosentan (ET_A/B receptor antagonist, 3 µM for 20 min), BQ-123 (ET_A receptor antagonist, 1 µM for 20 min) and BQ-788 (ET_B receptor antagonist, 1 µM for 20 min), and (d) cumulative DRC to sodium nitroprusside (SNP) in the presence and absence of ET antagonists. Since ET antagonists bind strongly and often irreversibly to ET receptors, distinct segments were used to evaluate each antagonist. ACh responses in the absence of ET blockade served as the control group. The tissues were allowed to equilibrate between each DRC for 60–90 min. The presence of the endothelium was confirmed in each ring by relaxation to ACh. Bosentan, BQ-123 and BQ-788 are potent endothelin receptor antagonists at the concentrations used [13–15].

All drugs and chemicals were obtained from Sigma (St. Louis, MO, USA). Bosentan was a gift from Actelion (Switzerland).

Results are expressed as mean±S.E. Percent maximum relaxation to ACh (%E_max) and agonist sensitivity (pEC₅₀=–logEC₅₀; EC₅₀ is concentration that evokes 50% relaxation. Values were determined using non-linear regression) were compared between interventions. ‘n’ represents the number of patients employed in the study. %E_max values were compared using a paired two-tailed t-test. The DRC were compared using repeated measures analysis of variance followed by a Newman–Keul's test for post-hoc comparisons. A P less than 0.05 was considered to be statistically significant.

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 
3.1 Patient characteristics
Table 1 depicts the characteristics and risk factor profile of the patient population. The distribution of coronary artery disease risk factors in this study population was comparable to other studies employing similar methodologies [16].

3.2 Vascular relaxation
In pre-contracted arteries, ACh caused dose-dependent endothelium-mediated relaxation (%E_max 43±4%, pEC₅₀ 6.74±0.12). This effect was endothelium-specific since it was abolished in vessels denuded of the endothelium (by rolling vessels over a metallic probe, data not shown). The effects of endothelin receptor blockade (with bosentan, BQ-123 and BQ-788) on ACh-mediated relaxation are depicted in Figs. 1–4. In the presence of the mixed ET_A/B receptor blocker (bosentan, 3 µM for 20 min), endothelium-mediated relaxation to ACh was improved significantly (%E_max 60±3 vs. control, P<0.05) without an effect on agonist sensitivity (pEC₅₀ vs. 6.76±0.09 vs. control 6.74±0.12, P>0.05, Fig. 1). Similar endothelial augmenting effects were noted in the presence of the specific ET_A and ET_B receptor antagonists (%E_max BQ-123: 56±4 vs. control, P<0.05, Fig. 2; BQ-788 53±5 vs. control, P<0.05, Fig. 3). Furthermore, ACh-induced relaxation was improved to a similar degree with the three ET antagonists (Fig. 4). The beneficial effects were endothelium-specific since the maximum %E_max to the endothelium-independent vasodilator (SNP, 10^–9 to 10^–5 M), was unchanged following ET receptor blockade (not shown).

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Endothelium-dependent vascular relaxation to ACh in internal mammary arteries in the absence (control) and presence of bosentan (3 µM for 20 min). Data are represented as mean±S.E. Vascular relaxation is expressed as % maximum relaxation in rings pre-contracted with the ED75 of phenylephrine. *P<0.05, different from control. Bosentan augments endothelial function in human internal mammary arteries.

 

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Endothelium-dependent vascular relaxation to ACh in internal mammary arteries in the absence (control) and presence of BQ-123 (1 µM for 20 min). Data are represented as mean±S.E. Vascular relaxation is expressed as % maximum relaxation in rings pre-contracted with the ED75 of phenylephrine. *P<0.05, different from control.

 

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Endothelium-dependent vascular relaxation to ACh in internal mammary arteries in the absence (control) and presence of BQ-788 (1 µM for 20 min). Data are represented as mean±S.E. Vascular relaxation is expressed as % maximum relaxation in rings pre-contracted with the ED75 of phenylephrine. *P<0.05, different from control.

 

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Comparison of percent maximum relaxation (in rings pre-contracted with the ED75 of phenylephrine) in the absence (control) and presence of bosentan, BQ-123 and BQ-788. The observation that BQ-123 and BQ-788 improve endothelium-dependent relaxation to a similar degree suggests that ETA and ETB receptors independently and maximally modulate endothelial dysfunction in internal mammary arteries. There is no apparent additive/synergistic benefit on endothelial function by mixed ETA/ETB blockade. In human IMA, pharmacological characterization has revealed that both ETA and ETB receptors mediate vasoconstriction and that ETB receptor is not functionally coupled to endothelial NO production. *P<0.05, different from control.

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 
4.1 Key observations
The main observations that emanate from this study are (i) endothelin-receptor blockade improves endothelial-mediated vasodilation in human IMA and (ii) the beneficial effects of endothelin antagonism are independently and equally mediated via ET_A and ET_B receptors. To our knowledge, this is the first report describing endothelial protective effects of ET antagonists on ACh-mediated vasorelaxation in IMA. Since endothelial dysfunction may contribute towards the development of peri-operative vasospasm [3–5] and graft atherogenicity [1,2], these results may have both acute and chronic implications for CABG surgery.

4.2 IMA, endothelial dysfunction and vasospasm: role of ET-1
The IMA is unequivocally the conduit of choice for coronary revascularization due to its excellent long-term patency [17]. Indeed the resilience of the IMA and its inherent thromboresistance have been attributed, in part, to better endothelial function in these vessels (compared to saphenous veins and other arterial conduits) [18]. However, the small diameter of this arterial conduit predisposes it to acute peri-operative vasospasm which is a critical determinant of postoperative myocardial infarction and death following CABG surgery. Elucidating the mechanism(s) of vasospasm has been an area of intense research and studies by Schaff [3,4] and Lin [5] are widely quoted. Although the definitive mechanisms remain unclear, it appears that endothelial dysfunction, specifically the release of thromboxane A₂ and ET-1 may play a significant role [3,4,19]. In addition to directly causing vascular smooth muscle contraction (via interaction with thromboxane and ET receptors on smooth muscle) these agents can impair endothelial function and vascular reactivity through inhibition of NO production/release [2]. Studies have suggested that the release of endothelium-derived vasoconstrictors may be closely associated with the expression of hypoxemia [3,5], a commonly observed peri-operative complication. Factors such as low cardiac output, intrapulmonary blood shunting, hypoventilation and technical errors may evoke a potent hypoxemic response in the peri-operative period [5] and predispose to arterial spasm via production of thromboxane A₂. Whether such a mechanism underlies the production of ET-1 in IMA is unknown. Another possibility is that cardiopulmonary bypass (with the associated inflammatory and cytokine response) may result in the generation of potent vasoconstrictors and predispose to arterial spasm. We are currently investigating this hypothesis. Whatever the exact mechanism, it is apparent that counteracting the actions of these contracting factors may serve to restore endothelial function and vascular reactivity in IMA.

4.3 Endothelin antagonists and endothelial function in IMA: the present study
In this study we have demonstrated that ET receptor blockade improves endothelial function in human IMA. These data are important since they uncover an improvement in ACh (and hence NO)-mediated vasodilation in response to ET antagonism. Although previous studies have examined the effects of ET receptor blockers on IMA vascular function, they have focussed on the ability of such antagonists to counteract the contraction elicited by graded doses of ET-1 [10]. ACh-mediated vasorelaxation has not been previously assessed in response to acute ET receptor blockade.

A brief discussion of the potential mechanism(s) of endothelial protection by ET blockers deserves mention. As highlighted earlier, endothelial dysfunction can be viewed as the net balance of endothelium-derived vasoconstriction and vasodilation; derangements in either segment (or both) may predispose to increased tone and eventual vasospasm [2]. Therefore, the beneficial effects noted in the present study may be due to (i) antagonism of ET-1 action on vascular smooth muscle ET receptors, (ii) improvement in NO-mediated vasodilation (by release of tonic inhibition of ET-1 on NO production/release) or (iii) a combination of the above mechanisms. Alternatively, it may be hypothesized that decreased endothelium-dependent relaxation in IMA is secondary to diminished NO production and that ET receptor blockade improves endothelial function merely by restoring the balance of NO/ET-1. Although this is an attractive proposition, evidence suggests that the l-arginine NO system is well preserved in human IMA [18–21]. Furthermore, depressed endothelium-dependent relaxation in these vessels is not related to increases in superoxide production, deficiencies in l-arginine, tetrahydrobiopterin or reduced membrane fluidity [16]. These data provide indirect evidence for a primary role of vasoconstrictors in the development of endothelial dysfunction in IMA. Studies documenting increased ET-1 levels in segments of human IMA [9] lend further credence to this concept.

The present data raise an important question regarding the involvement of ET_A versus ET_B receptors in mediating endothelial protection. Conventionally, it is believed that the actions of ET-1 are facilitated through ET_A and ET_B receptors, the former mediating the majority of the vasoconstrictor effects (on smooth muscle) and the latter interacting with endothelium-derived NO to induce vasodilation (transient) [11]. In IMA, Pate et al. [22] have demonstrated that ET-1 mediates its effects predominately through ET_A receptors with lesser contribution from ET_B receptors. This would imply that ET receptor blockade with BQ-123 would improve endothelial function to a greater extent than BQ-788 which was not the case in the present study. As correctly pointed out by Pate et al. the results obtained are from patients undergoing CABG surgery with multiple risk factors and damaged vessels to begin with, hence these data may differ from those obtained in healthy vessels. The patient demographics in the study by Pate et al. are not available and hence a direct comparison of the two studies is not feasible. In other studies, pharmacological characterization of receptor subtypes in IMA suggest that both ET_A and ET_B mediate the ET-1-induced contraction [10,21] and that the endothelium of the arteries does not express ET_B receptors linked to NO production [10]. Indeed, the functional significance of these observations is strengthened by the current data demonstrating that both ET_A and ET_B receptors improve endothelial function independently (and to a similar degree) when compared to the mixed ET_A/B blocker bosentan. This is the first report depicting an equal contribution of ET_A and ET_B receptors towards endothelial dysfunction in IMA. The observation that combined ET_A/B receptor blockade (with bosentan) did not result in an additive/synergistic effect may suggest that antagonism of ET_A or ET_B receptors (individually) exerts maximal endothelial protection. In addition, results from the present study were obtained in the presence of indomethacin suggesting that blockade of prostaglandin synthesis may be required to elicit the protective effects noted.

4.4 Limitations
Given the patient demographics, the contribution of individual risk factors towards endothelial dysfunction and the observed effects of ET receptor blockade cannot be assessed. All major risk factors for atherosclerotic vascular disease have been associated with impaired NO activity [23]. Hence it is plausible that the beneficial effects of ET antagonism may extend non-specifically to any process that dampens endothelial function through affecting NO production, release or availability. Unfortunately, the study population undergoing bypass surgery has a clustering of CAD risk factors. Hence to find patients with one isolated risk factor undergoing bypass surgery without other risk factors, such as hypertension, smoking, obesity, hyperlipidemia, family history etc., is extremely difficult. In addition finding patients just on angiotensin converting enzyme inhibitors or beta-blockers without any other risk factors would require us to screen 500–700 patients. Furthermore, it is impossible to discontinue medication usage of these patients prior to CABG surgery. Of the 22 patients on ACEI, 16 were on β-blockers, five on endothelial modifying vitamins, and 12 on nitroglycerin. Therefore, the results depicted in this paper cannot differentiate between the relative roles of medication use towards endothelial dysfunction. However, they do provide an adequate representation of the patient population undergoing bypass surgery and provide evidence that ET receptor blockade improves endothelial function over and above the use of mediations or clustering risks. We believe that this is of direct clinical significance.

	5 Conclusion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 
In conclusion, results from the present study demonstrate, for the first time, that ET receptor blockade improves endothelial function in human IMA. Furthermore, they reveal that the beneficial effects are mediated, independently and maximally via ET_A and ET_B receptors. Understanding and improving endothelial function may promote thromboresistance, decrease peri-operative vasospasm and impede IMA atherosclerosis.

Time for primary review 26 days.

	Acknowledgements

 
This study was supported by the Heart and Stroke Foundation of Canada (T.J.A., C.R.T., J.H.McN.) and the Medical Research Council of Canada (C.R.T., J.H.McN.). Subodh Verma, MD, PhD is a Fellow of the Medical Research Council of Canada, Heart and Stroke Foundation of Canada and Alberta Heritage Foundation for Medical Research (AHFMR). K.M. is an AHFMR Clinical Fellow. A.S.D. is a the recipient of a studentship award from AHFMR. Dr T.J.A. is a Clinical Investigator of the AHFMR. We thank Dr. M. Clozel for constructive criticism of the manuscript and for the generous gift of bosentan (Actelion Ltd, Switzerland). Subodh Verma was the International Society of Heart Research Young Investigator Award finalist for this research (2000).

	References

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusion References

 

1. Moncada S., Higgs A. The l-arginine-NO pathway. N Engl J Med (1993) 329:2002–2012.[Free Full Text]
2. Luscher T.F., Noll G. The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator. Atherosclerosis (1995) 188:S81–90.
3. Lin P.J., Pearson P.J., Schaff H.V. Endothelium-dependent contraction and relaxation of human and canine internal mammary artery: studies on bypass graft vasospasm. Surgery (1991) 110:127–135.[Web of Science][Medline]
4. Cable D.G., Caccitolo J.A., Pearson P.J., O'Brien T., Mullany C.J., Daly R.C., et al. New approaches to prevention and treatment of radial artery graft vasospasm. Circulation (1998) 98:II 15–II 22.[Web of Science][Medline]
5. Lin P.J., Chang C.H., Pearson P.J., Tzen K.Y., Chu J.J., Chang J.P., et al. Thromboxane A₂: an endothelium-derived vasoconstrictor in human internal mammary arteries. Ann Thorac Surg (1993) 56:97–100.[Abstract]
6. Costello K.B., Stewart D.J., Baffour R. Endothelin is a potent constrictor of human vessels used in coronary revascularization surgery. Eur J Pharmacol (1990) 180:311–314.[CrossRef][Web of Science][Medline]
7. Yang Z., Richard V., von Segesser L., Bauer E., Stulz P., Turina M., et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries: a new mechanism of vasospasm? Circulation (1990) 82:188–195.[Abstract/Free Full Text]
8. Van Zwienen J.C.W., van der Linden C.J., Cimbrere J.S.F., Lacquet L.K., Booij L.H.D.J., Hendriks T. Endothelin release during coronary artery bypass grafting. Chest (1993) 103:176S.
9. Gobel H., Ihling C., Dentz J., Schaefer H.E., Zeiher A.M., Fraedrich G. Increased tissue endothelin-1 like immunoreactivity in the internal mammary artery of patients with diabetes or hypercholesterolemia modulates the graft flow in the perioperative period. Eur J Cardiothorac Surg (1998) 14:367–372.[CrossRef][Web of Science][Medline]
10. Seo B., Oemar B.S., Siebenmann R., von Segesser L., Luscher T.F. Both ET_A and ET_B receptors mediate contraction to endothelin-1 in human blood vessels. Circulation (1994) 89:1203–1208.[Abstract/Free Full Text]
11. Miyauchi T., Masaki T. Pathophysiology of endothelin in the cardiovascular system. Ann Rev Physiol (1999) 61:391–415.[CrossRef][Web of Science][Medline]
12. Verma S., Bhanot S., Yao L.F., McNeill J.H. Defective endothelium-dependent relaxation in fructose-hypertensive rats. Am J Hypertens (1996) 9:370–376.[CrossRef][Web of Science][Medline]
13. Clozel M., Breu V., Gray A., Kalina B., Loffler B.M., Burri K., et al. Pharmacological characterization of bosentan, a new orally active non-peptide endothelin receptor antagonist. J Pharmacol Exp Ther (1994) 270:228–235.[Abstract/Free Full Text]
14. Ihara M., Noguchi K., Saeki T., Fukmuroda T., Tsuchida S., Kimura S. Biological profiles of highly potent endothelin antagonists selective for the ET_A receptor. Life Sci (1992) 50:247–255.[CrossRef][Web of Science][Medline]
15. Ishikawa K., Ihara M., Noguchi K., Mase T., Mino N., Saeki T. Biochemical and pharmacological profile of a potent and selective endothelin-B receptor antagonist, BQ-788. Proc Natl Acad Sci USA (1994) 91:4892–4896.[Abstract/Free Full Text]
16. Huraux C., Makita T., Kurz S., Yamaguchi K., Szlam F., Tarpey M.M., et al. Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries. Circulation (1999) 99:53–59.[Abstract/Free Full Text]
17. Loop F.D., Lytle B.W., Cosgrove D.M., Stewart R.W., Goormastic M., Williams G.W., et al. Influence of the internal mammary artery graft on 10-year survival and other cardiac events. N Engl J Med (1986) 314:1–6.[Abstract]
18. Luscher T.F., Diederich D., Siebenmann R., Lehmann K., Stulz P., von Seggesser L., et al. Differences between endothelium-dependent relaxation in arterial and venous coronary bypass grafts. N Engl J Med (1988) 319:462–467.[Abstract]
19. Rosenfeldt F.L., He G.W., Buxton B.F., Angus J.A. Pharmacology of coronary artery bypass grafts. Ann Thorac Surg (1999) 67:878–888.[Abstract/Free Full Text]
20. Luscher T.F., Yang Z., Tschudi M., von Seggesser L., Stulz P., Boulanger C., et al. Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins. Circ Res (1990) 66:1088–1094.[Abstract/Free Full Text]
21. Liu J.J., Chen J.R., Buxton B.F. Unique responses of human arteries to endothelin B receptor agonist and antagonist. Clin Sci (1996) 90:91–96.[Web of Science][Medline]
22. Pate M.D., Chester A.H., Crabbe D.S.T., Amrani M., Brown T.J., Roach A.G., et al. Characterization of constrictor endothelin receptors in the human internal thoracic artery and saphenous vein. J Cardiovasc Pharmacol (1999) 33:567–572.[CrossRef][Web of Science][Medline]
23. Cosentino F., Luscher T.F. Tetrahydrobiopterin and endothelial function. Eur Heart J (1998) 19(Suppl_G):G3–G8.[Web of Science][Medline]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				G.-W. He, M.-H. Liu, Q. Yang, A. Furnary, and A. P.C. Yim Role of Endothelin-1 Receptor Antagonists in Vasoconstriction Mediated by Endothelin and Other Vasoconstrictors in Human Internal Mammary Artery Ann. Thorac. Surg., November 1, 2007; 84(5): 1522 - 1527. [Abstract] [Full Text] [PDF]

				F. Bohm and J. Pernow The importance of endothelin-1 for vascular dysfunction in cardiovascular disease Cardiovasc Res, October 1, 2007; 76(1): 8 - 18. [Abstract] [Full Text] [PDF]

				M. Clozel, P. Hess, M. Rey, M. Iglarz, C. Binkert, and C. Qiu Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 967 - 973. [Abstract] [Full Text] [PDF]

				A. J. Sutherland, M. I. Nataatmadja, P. J. Walker, L. Cuttle, R. B. Garlick, and M. J. West Vascular Remodeling in the Internal Mammary Artery Graft and Association With In Situ Endothelin-1 and Receptor Expression Circulation, March 7, 2006; 113(9): 1180 - 1188. [Abstract] [Full Text] [PDF]

				S. Verma, P. W. M. Fedak, L. Ko, R. J. Cusimano, N. A. Walton, J. D. Parker, and T. M. Yau Evaluation of a novel sutureless anastomotic connector: From endothelial function to mid-term clinical and angiographic follow-up J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1555 - 1560. [Abstract] [Full Text] [PDF]

				G. Polvani, M. R. Marino, M. Roberto, L. Dainese, A. Parolari, G. Pompilio, S. D. Matteo, A. Fumero, A. Cannata, F. Barili, et al. Acute effects of 17{beta}-estradiol on left internal mammary graft after coronary artery bypass grafting Ann. Thorac. Surg., September 1, 2002; 74(3): 695 - 699. [Abstract] [Full Text] [PDF]

				P. W.M. Fedak, R. D. Weisel, S. Verma, and V. Rao Invited commentary Ann. Thorac. Surg., May 1, 2002; 73(5): 1614 - 1615. [Full Text] [PDF]

				C. Cardillo, U. Campia, C. M. Kilcoyne, M. B. Bryant, and J. A. Panza Improved Endothelium-Dependent Vasodilation After Blockade of Endothelin Receptors in Patients With Essential Hypertension Circulation, January 29, 2002; 105(4): 452 - 456. [Abstract] [Full Text] [PDF]

				M. Barton and B. Glodny Endothelin receptor blockade and nitric oxide bioactivity: [Cardiovascular Research 2001;49:146-151] Cardiovasc Res, October 1, 2001; 52(1): 161 - 163. [Full Text] [PDF]

				N. Hoogerwerf A role for endothelin receptor blockade in improving the endothelial function of coronary artery grafts? Cardiovasc Res, January 1, 2001; 49(1): 15 - 16. [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Verma, S. Articles by Anderson, T. J Search for Related Content PubMed PubMed Citation Articles by Verma, S. Articles by Anderson, T. J Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics