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J Thorac Cardiovasc Surg 1996;112:264-272
© 1996 Mosby, Inc.

SURGERY FOR ACQUIRED HEART DISEASE

TISSUE CONCENTRATIONS OF ENDOTHELINS AND FUNCTIONAL EFFECTS OF ENDOTHELIN-RECEPTOR ACTIVATION IN HUMAN ARTERIES AND VEINS

Supported by grants from the Swedish Medical Research Council, the Heart and Lung Foundation, the Wiberg Foundation, the Wallenberg Foundation, the Thuring Foundation, the Swedish Society for Medicine, the Salus Foundation, and funds from the Karolinska Institute.

Received for publication July 20, 1995 Revisions requested Oct. 9, 1995; revisions received Nov. 17, 1995 Accepted for publication Jan. 3, 1996. Address for reprints: Anders Franco-Cereceda, MD, PhD, Department of Thoracic Surgery, Karolinska Hospital, 171 76 Stockholm, Sweden.

Abstract

In the present study, the tissue content and functional effects of endothelin-1 and endothelin-3 were examined in human vessels of importance in coronary bypass operations. Human coronary arteries (i.e., the left anterior descending coronary artery) were obtained from eight cardiac valve donors within 6 hours after death, pulmonary arteries were perioperatively obtained from 15 patients operated on because of lung tumors, and internal thoracic arteries and great saphenous and cephalic veins were obtained at coronary bypass operations from a total of 28 patients. Endothelin-1 and endothelin-3 content was quantified by radioimmunoassay. For functional experiments, the vessels were mounted in organ baths for recordings of isometric contractions in response to endothelin-1, endothelin-3, and the endothelin_A- receptor agonist sarafotoxin 6c. In all vessels investigated, the endothelin-1 content was higher than that of endothelin-3. The highest levels were found in the left anterior descending coronary artery, followed in declining order by the internal thoracic artery, pulmonary artery, saphenous vein, and cephalic vein. Endothelin-1 contracted all vessels in a concentration-dependent fashion. This effect was enhanced in the left anterior descending and internal thoracic arteries by inhibition of nitric oxide and prostaglandin formation. The contractile effect was attenuated in a concentration-dependent fashion in all vessels by incubation with the endothelin_A-receptor blocker BQ-123. Furthermore, contractions evoked by endothelin-1 in the left anterior descending coronary and pulmonary arteries were antagonized by the combined endothelin_A- and endothelin_B-receptor blocker bosentan. Endothelin-3 contracted the left anterior descending coronary and pulmonary arteries and the saphenous vein, but not the internal thoracic artery, in a BQ-123–sensitive fashion. However, after inhibition with nitric oxide or prostaglandin, endothelin-3 also contracted the internal thoracic artery, and the response in the left anterior descending coronary artery was enhanced. Sarafotoxin 6c evoked a BQ-123–sensitive contraction of the left anterior descending coronary artery. It is concluded that endothelin_Areceptors mediate the major portion of the vasoconstriction observed on exposure to endothelin-1, endothelin-3, and sarafotoxin 6c in the left anterior descending coronary, pulmonary, and internal thoracic arteries and the saphenous vein. Furthermore, endothelin_B-receptor activation, with subsequent formation of nitric oxide or prostaglandin (or both), counteracts the vasoconstrictor response to endothelin in the left anterior descending coronary and internal thoracic arteries, but not in the pulmonary artery or saphenous vein. The present findings therefore suggest that endothelin_A-receptor antagonism might prove beneficial in preventing possible endothelin-induced coronary graft spasm. (J THORAC CARDIOVASC SURG 1996;112:264-72)

The endothelium is involved in the regulation of local vascular tone through release of both vasodilator and vasoconstrictor substances. ¹ Experiments showing potent vasoconstrictor effects of media obtained from cultured aortic endothelial cells suggested the existence of an endothelium-derived vasoconstrictor substance. ² The endothelium was later shown to synthesize the vasoactive peptide endothelin (ET) through enzymatic cleavage of the propeptide big ET. ³ Studies have revealed a group of ET isopeptides named ET-1, ET-2, and ET-3. ⁴ ET has been shown to evoke a variety of effects in the cardiovascular system, including vasoconstriction, ³ vasodilatation, ^5,6 and positive inotropic and chronotropic actions, ^7,8 as well as negative inotropic effects. ⁹ The variability of the effects of the three isopeptides in different vascular beds indicates the existence of multiple ET receptor subtypes. Thus the vascular effects of ET are mediated through interaction with putative ET_A and ET_B receptors. The ET_A receptor is selective for ET-1 and causes vasoconstriction, whereas the ET_B receptor is nonselective for the ET isopeptides and mediates vasodilatation. ¹⁰ Recent reports in addition suggest the existence of ET_B receptor subtypes: the ET_B1 receptor on the endothelium mediates endothelium- dependent vasodilatation; the ET_B2 receptor on smooth muscle cells causes vasoconstriction. ^11,12 A family of snake venom peptides, the sarafotoxins, show a remarkable structural resemblance to ET and act on the same receptor as ET. ¹³ Among these peptides, sarafotoxin 6c is considered to activate ET_B receptors. ^11,13

A variety of pathophysiologic disorders are associated with increased circulating plasma levels of ET. It was recently demonstrated that the concentration of ET in the coronary sinus is increased during coronary bypass operations, ^14,15 although the mechanism of this release remains unclear. ¹⁵ Furthermore, ET is a potent constrictor of human coronary arteries ¹⁶ and of vessels used in coronary revascularization, ¹⁷ whereas ET causes a tone-dependent vasoconstriction or vasodilatation of pulmonary arteries. ¹⁸ In the present study, therefore, a comparison of the functional effects of ET-1 and ET-3 on human coronary (i.e., left anterior descending [LAD]), pulmonary (PA), and internal thoracic (ITA) arteries and great saphenous vein (SV) in vitro has been made. To further evaluate the influence of ET_B-receptor activation, we studied the effects of sarafotoxin 6c on the LAD and PA. In addition, the tissue content of ET-1 and ET-3 in these vessels and in the cephalic vein (CV) has been determined.

Methods

This study was approved by the Ethics Committee of the Karolinska Hospital.

Functional experiments
Coronary arteries with an inner diameter of 0.8 to 1.2 mm (segments 7 and 8 of the LAD according to the American Heart Association Committee Report, 1975) were obtained within 6 hours after death from eight cardiac valve donors (five men and three women, 33 ± 7 years of age) with total cerebral infarction resulting from intracranial bleeding or trauma (or both). PAs of a similar size were obtained from 15 patients undergoing operations for lung tumors (10 men and five women, 67 ± 3 years of age). Distal ITAs and SVs were obtained from 25 patients undergoing coronary artery bypass operations (16 men and nine women, 66 ± 2 years of age). All vessels (1 to 2 mm in length) were dissected out under a microscope and mounted in 2 ml organ baths on two L-shaped holders (diameter 0.3 mm). A resting tension of 10 mN was then applied by adjusting one of the metal holders. The other holder was connected to a Grass polygraph model 7B (Grass Instrument Co., West Warwick, R.I.) for recordings of isometric tension. The resting tension was chosen on the basis of preliminary experiments in which reproducible contractions were obtained at this resting tension. ¹⁶ The vessels were kept in Tyrode's solution (pH 7.4) of the following composition (in millimoles per liter): NaCl 137, KCl 2.7, CaCl₂ 1.8, MgCl₂ 1.05, NaHCO₃ 11.9, NaH₂PO₄ 0.42, and glucose 5.6. The Tyrode's solution was aerated with 95% oxygen and 5% carbon dioxide at 37º C. After 60 minutes of equilibration during which the resting tension was adjusted to compensate for the spontaneous decline in arterial tension, circular contractions were induced by Tyrode's solution in which the NaCl had been replaced with equimolar amounts of KCl to give a final K⁺ concentration of 127 mmol/L. Only vessels responding with two reproducible contractions to K⁺ exposure were used, giving a total of 31 LADs, 47 PAs, 29 ITAs, and 30 SVs. Each experimental procedure was performed in vessels from at least five patients. ET-1, ET-3, sarafotoxin 6c, or the ET_B-receptor agonist Ala ^1,3,11,15ET-1 ¹⁰ was added to the organ baths either at single concentrations or in a cumulative fashion. The functional effects of these agents were studied under control conditions and after ET_A-receptor blockade using BQ-123 ¹⁹ or combined ET_A and ET_B blockade using bosentan. ¹² In addition, the effects of inhibition of prostaglandin and nitric oxide formation were evaluated by incubating the vessels for 1 hour with the cyclooxygenase inhibitor indomethacin (10^-5 mol/L) and the nitric oxide–synthase inhibitor N^g-monomethyl-L-arginine (L-NMMA; 10^-4 mol/L), which were thereafter present throughout the experiments. ¹⁸ Whereas BQ-123 and bosentan did not influence basal contractile tone per se, pretreatment with indomethacin and L-NMMA evoked a minor, but inconsistent, increase in resting tension.

Tissue determination of ET-1 and ET-3
Vessels were obtained from the above-mentioned patients and, in addition, CV specimens were obtained from another two patients (two women; 71 and 75 years old). The vessels were frozen on Dry Ice and weighed. For extraction of ET-1– and ET-3–like immunoreactivity, the samples were heated at 95º C in water for 10 minutes, homogenized, and centrifuged. With this extraction the recovery of ET in plasma is greater than 80%. ²⁰ The supernatants were lyophilized and the content of ET-like immunoreactivity was determined by radioimmunoassay with two different antisera: ET-1 was determined by an ET-1 antiserum raised against ET-1 in rabbits (the cross-reactivity to ET-3 was <8%); ET-3 was determined with a commercially available antiserum, RAS 6911 (Peninsula, Belmont, Calif.), with less than 0.1% cross-reactivity to ET-1. None of the antisera used showed any cross-reactivity (<0.1%) to a variety of other peptides tested, including neuropeptide Y, angiotensins I, II, and III, neurokinin A, and calcitonin gene-related peptide. Human ET-1 or ET-3 labeled with iodine 125 was used as tracer and synthetic ET-1 or ET-3 as standard. The assay samples were incubated at 4º C in phosphate buffer 0.1 mol/L, pH 7.4, containing 0.1% bovine serum albumin and 0.1% Triton X (Union Carbide Corp., Danbury, Conn.). The detection limit of the assays was 0.40 fmol/tube (for further details of the radioimmunoassays, see Hemsén and associates ²⁰). For comparison, the tissue content of neuropeptide Y and calcitonin gene-related peptide, which are present in perivascular sympathetic and afferent nerve terminals, respectively, was determined. ²¹

Drugs
ET-1, ET-3, BQ-123, Ala ^1,3,11,15ET-1, sarafotoxin 6c, indomethacin, and L-NMMA were obtained from Peninsula Laboratories, Merseyside, England. Indomethacin was dissolved in absolute ethanol and the other compounds were dissolved in saline solution. Bosentan was generously provided by Dr. M. Clozel, F. Hoffman-La Roche, Basel, Switzerland.

Statistical evaluation
Values are given as means ± standard error of the mean and expressed as percentage of contractions induced by a 127 mmol/L concentration of K⁺ in control experiments. For statistical evaluation, the Mann-Whitney U test was used; p < 0.05 was considered significant.

Results

Tissue content of ET-1 and ET-3
When quantified by radioimmunoassay, the content of ET-1 always exceeded that of ET-3 (Table I). The highest levels of both ETs were found in the LAD (1.14 ± 0.13 and 0.27 ± 0.05 pmol/gm for ET-1 and ET-3, respectively), followed in declining order by the ITA, PA, SV, and CV. The concentration of neuropeptide Y was higher than that of the other peptides in all vessels investigated, whereas the distribution of calcitonin gene-related peptide more closely resembled that of ET-1 (Table I).

View larger version (78K): [in this window] [in a new window]   Fig. 1. Contractile effects of ET-1 in human LADs, PAs, ITAs, and SVs in control experiments (open squares) and after incubation with indomethacin 10-5 mol/L and L-NMMA 10-4 mol/L (black squares). Data are presented as means ± standard error of the mean and are expressed as percentage of the maximal contraction induced by a 127 mmol/L concentration of K+. *p < 0.05, **p < 0.01, Mann-Whitney U test, compared with control experiments.

View larger version (87K): [in this window] [in a new window]   Fig. 2. Contractile effects of ET-1 in human LADs, PAs, ITAs, and SVs in control experiments (open squares) and after incubation with BQ-123 at 10-6 mol/L (black circles) or 10-5 mol/L (black triangles). Data are presented as means ± standard error of the mean and are expressed as percentage of the maximal contraction induced by a 127 mmol/L concentration of K+. *p < 0.05, **p < 0.01, Mann-Whitney U test, compared with control experiments.

View larger version (47K): [in this window] [in a new window]   Fig. 3. Contractile effects of ET-1 in human LADs and PAs in control experiments (open squares) and after incubation with bosentan at 10-6 mol/L (black circles) or 10-5 mol/L (black triangles). Data are presented as means ± standard error of the mean and are expressed as percentage of the maximal contraction induced by a 127 mmol/L concentration of K+. *p < 0.05, **p < 0.01, ***p < 0.001, Mann-Whitney U test, compared with control experiments.

View larger version (71K): [in this window] [in a new window]   Fig. 4. Contractile effects of ET-3 in human LADs, PAs, ITAs, and SVs in control experiments (open circles) and after incubation with indomethacin 10-5 mol/L and L-NMMA 10-4 mol/L (black circles). Data are presented as means ± standard error of the mean and are expressed as percentage of the maximal contraction induced by a 127 mmol/L concentration of K+. *p < 0.05, **p < 0.01, Mann-Whitney U test, compared with control experiments.

View larger version (72K): [in this window] [in a new window]   Fig. 5. Contractile effects of ET-3 in human LADs, PAs, ITAs, and SVs in control experiments (open circles) and after incubation with BQ-123 at 10-6 mol/L (black circles) or 10-5 mol/L (black triangles). Data are presented as means ± standard error of the mean and are expressed as percentage of the maximal contraction induced by a 127 mmol/L concentration of K+. *p < 0.05, **p < 0.01, ***p < 0.001, Mann-Whitney U test, compared with control experiments.

View larger version (21K): [in this window] [in a new window]   Fig. 6. Contractile effects of sarafotoxin 6c on LADs in control experiments (open triangles) and after incubation with BQ-123 at 10-6 mol/L (black circles) or 10-5 mol/L (black triangles). Data are presented as means ± standard error of the mean and are expressed as percentage of the maximal contraction induced by a 127 mmol/L concentration of K+. *p < 0.05, **p < 0.01, Mann-Whitney U test, compared with control experiments.

ITAs
In the ITA potassium exposure evoked a contraction of 1.34 ± 0.22 mN. ET-1 caused a concentration-dependent contraction of the ITA, which was increased after indomethacin and L-NMMA incubation (see Fig. 1). Incubation with BQ-123, 10^-6 and 10^-5 mol/L, significantly reduced the response to ET-1 (see Fig. 2). ET-3 did not per se evoke any contractions of the ITA. However, after incubation with indomethacin and L-NMMA, ET-3 evoked a sustained BQ-123–sensitive, concentration-dependent contraction of the ITA (see Figs. 4 and 5).

SVs
Potassium exposure caused a strong contraction of the SV (3.06 ± 0.66 mN). Both ET-1 and ET-3 induced concentration-dependent contractions of the SV, which were not affected by incubation with indomethacin and L-NMMA (see Figs. 1 and 4). After addition of BQ-123, the response to ET-1 was shifted to the right, whereas the response to ET-3 was completely abolished (see Figs. 2 and 5).

Discussion

The important findings of this study are as follows: (1) The content of ET-1 exceeded that of ET-3 in all vessels investigated; (2) ET-induced contractions of the vessels investigated are primarily caused by activation of ET_A receptors; (3) neither prostaglandin nor nitric oxide is produced in the SV or PA in response to ET, whereas production of both is induced in the ITA and LAD.

The coronary and pulmonary levels of ET-1–like immunoreactivity detected in the present study are similar to those previously reported for total ET-like immunoreactivity. ²⁰ The present study implies that the major portion of ET present in the vessels investigated is indeed ET-1. However, the use of an ET-3 antibody with no cross-reactivity to ET-1 clearly demonstrates that ET-3 is also found in human vessels, in agreement with studies on rat cardiopulmonary tissue. ²² However, because the vessels investigated were obtained from different patient groups with variability in age and sex, the relationship of ET content between the vessels should be interpreted with caution.

Our study demonstrates that selective antagonism of ET_A receptors may be used to reveal functional receptor populations within vessels. Evidence for heterogeneity of ET receptor distribution of human coronary arteries has been presented. ²³ It was suggested that the ET receptor population may differ within the same coronary vessel, with ET_A receptors predominantly in distal preresistant coronary arteries, whereas both ET_A and ET_B receptors were present in larger, proximal coronary arteries. According to the criteria used in that study, ²³ all the coronary vessels used in the present study would be classified as preresistant; thus our study, demonstrating only ET_A receptors, does not confirm the earlier findings. However, it may well be that the ET-receptor population and functional effects differ with vascular diameter within certain vascular beds. There are reports of ET_B-mediated vasoconstriction of various vessels including canine and porcine coronary arteries, rabbit pulmonary arteries, and porcine PAs and pulmonary veins. ^10,24 The ET_B receptor agonist sarafotoxin 6c was recently shown to contract the ITA, indicating the presence of contractile ET_B receptors also in human arteries. ²⁵ Interestingly, Davenport and associates ²⁶ could not demonstrate any contractile activity in human coronary or pulmonary arteries of BQ-3020 or Ala ^1,3,11,15ET-1, two compounds with affinity for the ET_B receptors. In contrast, 60% of the arteries responded to sarafotoxin 6c. ²⁷ In accord, we observed a concentration-dependent vasoconstriction of the LAD on exposure to sarafotoxin 6c but not Ala ^1,3,11,15ET-1. Moreover, the response to sarafotoxin 6c was attenuated equally by BQ-123 and bosentan. The magnitude of ET-1 contractions was twofold to fivefold greater than that of ET-3–induced contractions in the presently studied vessels, indicating that the observed vasoconstriction is mediated predominantly by the ET_A-receptor subtype. This is further substantiated by the competitive antagonism by the selective ET_A-receptor blocker BQ-123 on the response to ET-1 and ET-3 in all investigated vessels. Although it has recently been reported that ET_B-mediated vasoconstriction is present in the pulmonary circulation of various species, ^10,24 no effects of sarafotoxin 6c were observed in the PA in the present study. Marked species differences are obviously present, but the receptor population may also differ in different vascular beds in the same species. Thus human kidney cortex contains ET_A and ET_B receptors in a 30:70 ratio, ²⁸ whereas the ratio in the human PA is 93:7. ²⁹ Finally, the selectivity of agonists and antagonists is not absolute but depend on the concentrations used.

It is likely that the vasodilatation and the putative vasoconstriction caused by activation of ET_B receptors are mediated through different receptor subtypes, ET_B1 and ET_B2, present on the vascular endothelium and smooth muscle cells, respectively. ^11,12 Subsequently, formation of prostacyclin or nitric oxide, or both, may counteract the vasoconstrictor effects of ET_B2-receptor activation. The presently observed response to ET-1 in the LAD was markedly enhanced after inhibition of prostaglandin and nitric oxide formation. Furthermore, ET-3 contracted the ITA only after addition of indomethacin and L-NMMA. These findings suggest that formation of prostacyclin or nitric oxide on ET-receptor activation are important determinants of the functional response to ET exposure in the ITA and LAD, but not in the PA or SV, although the investigated vessels respond to exogenous nitric oxide release from drugs such as nitroprusside. ^18,24,25,31 Both prostacyclin formation and nitric oxide release are higher in the ITA than in the SV. It is widely known that the ITA has a higher capacity of endothelium-dependent vasodilatation than does the SV. ^30,31 The lack of influence of nitric oxide and prostaglandin inhibition on the ET effect in the PA is consistent with findings in porcine PAs ¹⁸ and the report that more than 90% of the ET receptors in the human lung belong to the ET_A subgroup. ²⁹

Autologous graft vasospasm may be an important factor in myocardial ischemia and postoperative morbidity after coronary revascularization procedures. ³² The vasoconstrictor peptide ET is known to be released during bypass grafting ^14,15 and may play some role in the development of vasospasm. On the basis of the present study, further investigation should be performed to evaluate whether selective inhibition of ET_A receptors may be clinically beneficial in preventing ET-induced graft spasm after cardiac operations.

Acknowledgments

The technical assistance of M. Utahs, M. Runsiö, M. Stensdotter, and C. Nihlén is gratefully acknowledged.

References

1. Lüscher TF, Vanhoutte PM. Endothelium-dependent responses in human blood vessels. Trends Pharmacol Sci 1988;9:181-4.[Medline]
   
2. Hickey KA, Rubanyi G, Paul RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol 1985;248:C550-6.[Abstract/Free Full Text]
   
3. Yanagisawa M, Kiruhara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-5.[Medline]
   
4. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyashi T, Goto K, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci 1989;86:2863-7.[Abstract/Free Full Text]
   
5. Lippton H, Goff J, Hyman A. Effects of endothelin in the systemic and renal vascular beds in vivo. Eur J Pharmacol 1988;155:197-9.[Medline]
   
6. Wright CE, Fozard JR. Regional vasodilatation is a prominent feature of the haemodynamic response to endothelin in anaesthetized, spontaneously hypertensive rats. Eur J Pharmacol 1988;155:201-3.[Medline]
   
7. Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T. Positive inotropic action of novel vasoconstrictor peptide endothelin on guinea-pig atria. Am J Physiol 1988;255:H970-3.[Abstract/Free Full Text]
   
8. Ishikawa T, Yanagisawa M, Kimura S, Goto K, Masaki T. Positive chronotropic effects of endothelium: a novel endothelium-derived vasoconstrictor peptide. Pflugers Arch 1988;413:108-10.[Medline]
   
9. Franco-Cereceda A, Matran R, Lou Y-P, Lundberg J. Occurrence and effects of endothelin in guinea-pig cardiopulmonary tissue. Acta Physiol Scand 1990;137:539-47.
   
10. Bax WA, Saxena PR. The current endothelin receptor classification: time for reconsideration. Trends Pharmacol Sci 1994;15:379-86.[Medline]
    
11. Warner TD, Allcock GH, Mickley EJ, Vane JR. Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea-pig ileum. Br J Pharmacol 1993;110:783-9.[Medline]
    
12. Clozel M, Breu V, Gray GA, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther 1994;270:228-35.[Abstract/Free Full Text]
    
13. Williams DL, Jones KL, Pettibone DJ, Lis EV, Clineschmidt BV. Sarafotoxin 6c: an agonist which distinguishes between endothelin receptor subtypes. Biochem Biophys Res Commun 1991;175:556-61.[Medline]
    
14. Franco-Cereceda A, Ericsson A, Sellei P, Vaage J, Valen G, Lundberg JM. Endothelin release at reperfusion of the porcine ischaemic heart in relation to noradrenaline and neuropeptide Y. Acta Physiol Scand 1994;151:541-3.[Medline]
    
15. Franco-Cereceda A, Barr G, Öwall A, Liska J, Lundberg JM. Is endothelin-1 release at reperfusion of the ischaemic human heart due to cold-induced displacement of endothelin from binding sites? Eur J Pharmacol 1995;279:105-7.[Medline]
    
16. Franco-Cereceda A. ET- and NPY-induced vasoconstriction of human coronary arteries in vitro. Br J Pharmacol 1989;97:968-72.[Medline]
    
17. Costello K, Stewart DJ, Baffour R. Endothelin is a potent constrictor of human vessels used in coronary revascularization surgery. Eur J Pharmacol 1990;186:311-4.[Medline]
    
18. Zellers TM, McCormick J, Wu Y. Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins. Am J Physiol 1994;267:H139-47.[Abstract/Free Full Text]
    
19. Ihara M, Nuguchi K, Saeki T, et al. Biological profiles of highly potent novel endothelin antagonists selective for the ET_A receptor. Life Sci 1992;50:247-55.[Medline]
    
20. Hemsén A, Franco-Cereceda A, Matran R, Rudehill A, Lundberg JM. Occurrence, specific binding sites and functional effects of endothelin in human cardiopulmonary tissue. Eur J Pharmacol 1990;191:319-28.[Medline]
    
21. Franco-Cereceda A. Calcitonin gene-related peptide and human epicardial coronary arteries: presence, release and vasodilator effects. Br J Pharmacol 1991;102:506-10.[Medline]
    
22. Matsumoto H, Suzuki N, Onda H, Fujino M. Abundance of endothelin-3 in rat intestine, pituitary gland and brain. Biochem Biophys Res Commun 1989;164:74-80.[Medline]
    
23. Godfraind T. Evidence for heterogeneity of endothelin receptor distribution in human coronary arteries. Br J Pharmacol 1993;110:1201-5.[Medline]
    
24. Davenport AP, Maguire JJ. Is endothelin-induced vasoconstriction mediated only by ET_A receptors in humans? Trends Pharmacol Sci 1994;15:9-11.[Medline]
    
25. Seo B, Oemar BS, Siebenmann R, Segesser L, Lüscher TF. Both ET_A and ET_B receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994;89:1203-8.[Abstract/Free Full Text]
    
26. Davenport AP, O'Reilly G, Molenaar P, Maguire JJ, Kuc RE, Sharkey A, et al. Human endothelin receptors characterized using reverse transcriptase-polymerase chain reaction, in situ hybridization, and subtype-selective ligands BQ-123 and BQ-3020: evidence for expression of ET_B receptors in human vascular smooth muscle. J Cardiovasc Pharmacol 1993;22:S22-5.
    
27. Maguire JJ, Davenport AP. Endothelin-induced vasoconstriction in human isolated vasculature is mediated predominantly via activation of ET_A receptors. Br J Pharmacol 1993;110:47P.
    
28. Nambi P, Pullen M, Wu HL, Aiyar N, Ohlstein EH, Edwards RM. Identification of endothelin-receptor subtypes in human renal cortex and medulla using subtype-selective ligands. Endocrinology 1992;131:1081-6.[Abstract/Free Full Text]
    
29. Fukuroda T, Kobayashi M, Ozaki S, et al. Endothelin receptor subtypes in human versus rabbit pulmonary arteries. J Appl Physiol 1994;76:1976-82.[Abstract/Free Full Text]
    
30. Sala A, Rona P, Pompilio G, et al. Prostacyclin production by different human grafts employed in coronary operations. Ann Thorac Surg 1994;57:1147-50.[Abstract]
    
31. Pearson PJ, Evora PRB, Schaff HV. Bioassay of EDRF from internal mammary arteries: implications for early and late bypass graft patency. Ann Thorac Surg 1992;54:1078-84.[Abstract]
    
32. Sarubu MR, McClung JA, Fuss A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987;44:199-200.[Abstract]
    

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