Skip to main content
SpringerLink
Log in
Book cover

Endothelin pp 223–268Cite as

Pathophysiological Role of Endothelin and Potential Therapeutic Targets for Receptor Antagonists

  • Chapter

Part of the book series: Contemporary Biomedicine ((CB))

Abstract

In the decade following the discovery of endothelin (ET) by Yanagisawa and his colleagues (1), there has been a prodigious number of studies on endothelin, its receptors, and their potential role in physiological and pathophysiological processes. There is an ever-increasing literature describing the importance of endothelin and the potential use of ET-receptor antagonists in a number of diverse diseases (Table 1). A detailed description of the evidence implicating endothelin in all the diseases listed as well as citing all the relevant papers cannot be conducted within the confines of one chapter. We have, on occasion, therefore, used review articles in place of multiple citations and have concentrated our discussion on four disease areas for which there is the most evidence and provide brief descriptions of some of the other areas for which reports have appeared. As ET-receptor antagonists enter clinical development and different clinical trials are conducted, it is likely that some of these “other diseases” take more prominent positions with regard to intervention with endothelin antagonists.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K., and Masaki, T. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature (Lond) 332: 411–415.

    Article  CAS  Google Scholar 

  2. Vierhapper, H., Wagner, O., Nowotny, P., and Waldhausl, W. (1990) Effect of endothelin-1 in man. Circulation 81: 1415–1418.

    Google Scholar 

  3. Sorensen, S. S., Madsen, J. K., and Pedersen, E. B. (1994) Systemic and renal effect of intravenous infusion of endothelin-1 in healthy human volunteers. Am. J. Physiol 266: F411 — F418.

    PubMed  CAS  Google Scholar 

  4. Rabelink, T. J., Kaasiager, K. A. H., Boer, P., Stroes, E. G., Braam, B., and Koomans, H. A. (1994) Effects of endothelin-1 on renal function in humans: implications for physiology and pathophysiology. Kidney Int. 46: 376–381.

    Article  PubMed  CAS  Google Scholar 

  5. Yokokawa, K., Tahara, H., Kohno, M., Murakawa, K., Yasunari, K., Nakagawa, K., Hamada, T., Otani, S., Yanagisawa, M., and Takeda, T. (1991) Hypertension associated with endothelin-secreting malignant hemangioendothelioma. Ann. Intern. Med. 114:213–215.

    Google Scholar 

  6. Wilkes, F. C., Jr., Alberola, A., Mizelle, H. L., Opgenorth, T. J., and Granger, J. P. (1993) Chronic pathophysiological circulating endothelin levels produce hypertension in conscious dogs. J. Cardiovasc. Pharmacol. 22(Suppl. 8 ): S325 — S327.

    Google Scholar 

  7. Niranjan, V., Telemaque, S., Dewit, D Gerard, R. D., and Yanagisawa, M. (1996) Systemic hypertension induced by hepatic overexpression of human prepro-endothelin-1 in rats. J. Clin. Invest 98:2364–2372

    Google Scholar 

  8. Jorkasky, D. K., Hay, D. W. P. and Freed, M. I. (1995) The role of endothelin in human disease: implications and potential therapeutic intervention, in Endothelin Receptors: From the Gene to the Human (Ruffolo, R. R., Jr., ed.), CRC, Boca Raton, FL, pp. 215–271.

    Google Scholar 

  9. Letizia, C., Cerci, S., De Ciocchis, A., D’Ambrosio, C., Scuro, L., and Scavo, D. (1995) Plasma endothelin-1 levels in normotensive and borderline hypertensive subjects during a standard cold pressor test. J. Hum. Hypertens. 9:903–907.

    Google Scholar 

  10. Ergul, S., Parish, D. C., Puett, D., and Ergul, A. (1996) Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension. Hypertension 28: 652–655.

    Article  PubMed  CAS  Google Scholar 

  11. Ohlstein, E. H., Douglas, S. A., Brooks, D. P., Hay, D. W. P., Feuerstein, G. Z., and Ruffolo, R. R., Jr. (1995) Functions mediated by peripheral endothelin receptors, in Endothelin Receptors: From the Gene to the Human ( Ruffolo, R. R., Jr., ed.), CRC, Boca Raton, FL, pp. 109–185.

    Google Scholar 

  12. Larivière, R., Thibault, G., and Schiffrin, E. (1993) Increase endothelin1 content in blood vessels of deoxycorticosterone acetate-salt hypertension but not in spontaneously hypertensive rats. Hypertension 21: 294–300.

    Article  PubMed  Google Scholar 

  13. Wong, M. and Jeng, A. Y. (1989) Parallel increases in cardiac endothelin and blood pressure of spontaneously hypertensive rats. Pharmacologist 31: 374 P.

    Google Scholar 

  14. Fujita, K., Matsumura, Y., Miyazaki, Y., Hashimoto, N., Takaoka, M., and Morimoto, S. (1996) ETA receptor-mediated role of endothelin in the kidney of DOCA-salt hypertensive rats. Life Sci. 58:PL1—PL7.

    Google Scholar 

  15. Takada, K., Matsumura, Y., Dohmen, S., Mitsutomi, N., Takaoka, M., and Morimoto, S. (1996) Endothelin-1 secretion from cultured vascular endothelial cells of DOCA-salt hypertensive rats. Life Sci. 59:PL111 PL116.

    Google Scholar 

  16. Schiffrin, E. L., Lariviere, R., and Touyz, R. M. (1995) ETA and ETB receptors on vascular smooth muscle cells from mesenteric vessels of spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. 22(Suppl. 1 ), 5193, 5194.

    Google Scholar 

  17. Hocher, B., Rohmeiss, P., Zart, R., Diekmann, F., Vogt, V., Metz, D., Fakhury, M., Gretz, N., Bauer, C., Koppenhagen, K., Neumayer, H. H., and Distler, A. (1996) Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats. Cardiovasc. Res 31: 499–510.

    PubMed  CAS  Google Scholar 

  18. Hiraoka, J., Arai, H., Yoshimasa, T., Takaya, K., Miyamoto, Y., Yamashita, J., Suga, S., Ogawa, Y., Shirakami, G., and Itoh, H. (1995) Augmented expression of the endothelin-A receptor gene in cultured mesangial cells from stroke-prone spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. 22(Suppl. 1):S191—S192.

    Google Scholar 

  19. Gellai, M., DeWolf, R., Pullen, M., and Nambi, P. (1994) Distribution and functional role of renal ET receptor subtypes in normotensive and hypertensive rats. Kidney Int. 46:1287–1294.

    Google Scholar 

  20. Gu, X.-H., Casley, D. J., Cincotta, M., and Nayler, W. G. (1990) 125IEndothelin-1 binding to brain and cardiac membranes from normotensive and spontaneously hypertensive rats. Eur. J. Pharmacol 177: 205–209.

    Google Scholar 

  21. Evangelista, S., Maggi, C.A., and Castellucci, A. (1992) Effect of endothelin (ET)-1, ET-3 and ET-(16–21) on the isolated and perfused rat kidney from normotensive and spontaneously hypertensive rats. Jpn. J. Pharmacol 59: 239–241.

    Article  PubMed  CAS  Google Scholar 

  22. Goligorsky, M. S., Iijima, K., Morgan, M., Yanagisawa, M., Masaki, T., Lin, L., Nasjletti, A., Kaskel, F., Frazer, M., and Badr, K. F. (1991) Role of endothelin in the development of Dahl hypertension. J. Cardiovasc. Pharmacol. 17(Suppl. 7 ): S484 — S491.

    Google Scholar 

  23. Ohno, A., Naruse, M., Kato, S., Hosaka, M., Karuse, K., and Demura, H. (1992) Endothelin-specific antibodies decrease blood pressure and increase glomerular filtration rate and renal plasma flow in spontaneously hypertensive rats. J. Hypertens 10: 781–785.

    Article  PubMed  CAS  Google Scholar 

  24. Kato, T., Kassab, S., Wilkins, F. C., Jr., Kirchner, K. A., Keiser, J., and Granger, J. P. (1995) Endothelin antagonists improve renal function in spontaneously hypertensive rats. Hypertension 25(part 2): 883–887.

    Google Scholar 

  25. McMahon, E. G., Palomo, M. A., and Moore, W. M. (1991) Phosphor-amidon blocks the pressor activity of big endothelin (1–39) and lowers blood pressure in spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 17(Suppl. 7): S29—S33.

    Google Scholar 

  26. Sogabe, K., Nirei, H., Shoubo, M., Nomoto, A., Ao, S., Notsu, Y., and Ono, T. (1992) Pharmacological profile of FR139317, a novel, potent endothelin ETA receptor antagonist. J. Pharmacol. Exp. Ther. 264:1040–1044.

    Google Scholar 

  27. Nishikibe, M., Tsuchida, S., Okada, M., Fukuroda, R., Shimamoto, K., and Yano, M. (1993) Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model. Life Sci. 52: 717–724.

    Article  PubMed  CAS  Google Scholar 

  28. Ohlstein, E. H., Douglas, S. A., Ezekiel, M., and Gellai, M. (1993) Anti-hypertensive effects of the endothelin antagonist BQ-123 in conscious spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 22(Suppl. 8 ): 5321 — S324.

    Google Scholar 

  29. Ohlstein, E. H., Nambi, P., Douglas, S. A., Edwards, R. M., Gellai, M., Lago, A., Leber, J. D., Cousins, R. D., Gao, A., Frazee, J. S., Peishoff, C. E., Bean, J. W., Eggleston, D. S., Elshourbagy, N. A., Kumar, C., Lee, J. A., Brooks, D. P., Ruffolo, R. R., Jr., Feuerstein, G. Z., Weinstock, J., Gleason, J. G., and Elliott, J. D. (1994) SB 209670, rationally designed potent nonpeptide endothelin receptor antagonist. Proc. Natl. Acad. Sci. USA 9: 8052–8056.

    Google Scholar 

  30. Douglas, S. A., Gellai, M., Ezekiel, M., and Ohlstein, E. H. (1994) BQ123, a selective endothelin (ETA) receptor antagonist, lowers blood pressure in different models of hypertension. J. Hypertens 12: 561–567.

    Article  PubMed  CAS  Google Scholar 

  31. Verma, S., Bhanot, S. and McNeill, J. H. (1995) Effect of chronic endothelin blockade in hyperinsulinemic hypertensive rats. Am. J. Physiol 269: H2017 — H2021.

    PubMed  CAS  Google Scholar 

  32. Stasch, J. P., Hirth-Dietrich, C., Frobel, K., and Wegner, M. (1995) Prolonged endothelin blockade reduces hypertension and cardiac hypertrophy in SHR-SP. J. Cardiovasc. Pharmacol. 26(Suppl. 3 ): 5436 — S438.

    Google Scholar 

  33. Schiffrin, E. L., Sventek, P., Li, J.-S., Turgeon, A., and Reudelhuber, T. (1995) Antihypertensive effect of an endothelin receptor antagonist in DOCA-salt spontaneously hypertensive rats. Br. J. Pharmacol. 115:1377–1381.

    Google Scholar 

  34. Bird, J. E., Moreland, S., Waldron, T. L., and Powell, J. R. (1995) Anti-hypertensive effects of a novel endothelin-A receptor antagonist in rats. Hypertension 25: 1191–1195.

    Google Scholar 

  35. Li, J.-S. and Schiffrin, E. L. (1995) Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist. Hypertension 25(part 1 ): 495–500.

    Google Scholar 

  36. Clozel, M. and Breu, V. (1996) The role of ET(B) receptors in normotensive and hypertensive rats as revealed by the non-peptide selective ET(B) receptor antagonist Ro 46–8443. FEBS Lett. 383: 42–45.

    Article  PubMed  CAS  Google Scholar 

  37. Donckier, J., Stoleru, L., Hayashida, W., Van Mechelen, H., Selvais, P., Galanti, L., Clozel, J.-P., Ketelslegers, J.-M., and Pouleur, H. (1995) Role of endogenous endothelin-1 in experimental renal hypertension in dogs. Circulation 92: 106–113.

    Google Scholar 

  38. Kiowski, W., Sutsch, G., Hunziker, P., Muller, P., Kim, J., Oechslin, E., Schmitt, R., Jones, R., and Bertel, O. (1995) Evidence for endothelin1-mediated vasoconstriction in severe chronic heart failure. Lancet 346: 732–736.

    Google Scholar 

  39. Haynes, W. G. and Webb, D. J. (1994) Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 344: 852–854.

    Article  PubMed  CAS  Google Scholar 

  40. Haynes, W. G., Ferro, C. J., O’Kane, K. P., Somerville, D., Lomax, C. C., and Webb, D. J. (1996) Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 93:1860–1870.

    Google Scholar 

  41. Freed, M. I., Thompson, K. A., Wilson, D. E., Ohlstein, E. H., Dennis, M., and Jorkasky, D. K. (1996) Effects of SB 217242, a non-selective endothelin (ET-A and ET-B receptor antagonist, in healthy humans. J. Am. Soc. Nephrol. 7, 1561.

    Google Scholar 

  42. Wei, C. M., Lerman, A., Rodeheffer, R J., McGregor, C. G. A., Brandt, R. R., Wright, S., Kao, P. C., Edwards, W. D Burnett, J. C., and Heublein, D. M. (1994) Endothelin in human congestive heart failure. Circulation 89: 1580–1586

    Google Scholar 

  43. Pacher, R., Stanek, B., Hulsmann, M., Koller-Strametz, J., Berger, R., Schuller, M., Hartter, E., Ogris, E., Frey, B., Heinz, G., and Maurer, G. (1996) Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J. Am. Coll. Cardiol 27: 633–641.

    Article  PubMed  CAS  Google Scholar 

  44. Omland, T., Lie, R. T., Aakvaag, A., Aarsland, T., and Dickstein, K. (1994) Plasma endothelin determinations as a prognostic indication of one year mortality after acute myocardial infarction. Circulation 89: 1573–1579.

    Google Scholar 

  45. Krum, H. and Itescu, S. (1994) Spontaneous endothelin production by circulating mononuclear cells from patients with chronic heart failure but not from normal subjects. Clin. Exp. Pharmacol. Physiol 21: 311–313.

    Article  PubMed  CAS  Google Scholar 

  46. Cavero, P. G., Miller, W. L., Heublein, D. M., Margulies, K. B., and Burnett, J. C. (1990) Endothelin in experimental congestive heart failure in the anesthetized dog. Am. J. Physiol. 259:F312—F317.

    Google Scholar 

  47. Yorikane, R., Sakai, S., Miyauchi, T., Sakurai, T., Sugishita, Y., and Goto, K. (1993) Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload. FEBS Lett. 332: 31–34.

    Article  PubMed  CAS  Google Scholar 

  48. Miyauchi, T., Sakai, S., Ihara, M., Kasuya, Y., Yamaguchi, I., Goto, K., and Sugishita, Y. (1995) Increased endothelin-1 binding sites in the cardiac membranes in rats with chronic heart failure. J. Cardiovasc. Pharmacol 26 (Suppl. 3): S448–5451.

    PubMed  CAS  Google Scholar 

  49. Yamazaki, T., Komuro, I., Kudoh, S., Zou, Y., Shiojima, I., Hiroi, Y., Mizuno, T., Maemura, K., Kurihara, H., Aikawa, R., Takano, H., and Yazaki, Y. (1996) Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy. J. Biol. Chem 271: 3221–3228.

    Article  PubMed  CAS  Google Scholar 

  50. Ito, H., Hiroe, M., Hirata, Y., Fujisaki, H., Adachi, S., Akimoto, H., Ohta, Y., and Marumo, F. (1994) Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation 89: 2198–2203.

    Article  PubMed  CAS  Google Scholar 

  51. Teerlink, J. R., Loffler, B.-M., Hess, P., Maire, J.-P., Clozel, M., and Clozel, J.-P. (1994) Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47–0203 (bosentan). Circulation 90: 2510–2518.

    Article  PubMed  CAS  Google Scholar 

  52. Sakai, S., Miyauchi, T., Kobayashi, M., Yamaguchi, I., Goto, K., and Sugishita, Y. (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 384: 353–355.

    Article  PubMed  CAS  Google Scholar 

  53. Shimoyama, H., Sabbah, H. N., Borzak, S., Tanimura, M., Shevlyagin, S., Scicli, G., and Goldstein, S. (1996) Short-term hemodynamic effects of endothelin receptor blockade in dogs with chronic heart failure. Circulation 94: 779–784.

    Article  PubMed  CAS  Google Scholar 

  54. Tohmo, H., Karanko, M., Korpilahti, K., Scheinin, M., Viinamaki, O., and Neuvonen, P. (1994) Enalaprilat in acute intractable heart failure after myocardial infarction: a prospective, consecutive sample, before and after. Crit. Care Med 22: 965–973.

    Article  PubMed  CAS  Google Scholar 

  55. Davidson, N. C., Coutie, W. J., Webb, D. J., and Struthers, A. D. (1996) Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure. Heart 75: 576–581.

    Article  PubMed  CAS  Google Scholar 

  56. Grenier, O., Pousset, F., Isnard, R., Kalotka, H., Carayon, A., Maistre, G., Lechat, P., Guerot, C., Thomas, D., and Komajda, M. (1996) Captopril does not acutely modulate plasma endothelin-1 concentration in human congestive heart failure. Cardiovasc. Drugs Ther 10: 561–565.

    Article  PubMed  CAS  Google Scholar 

  57. Krum, H., Gu, A., Wilshire-Clement, M., Sackner-Bernstein, J., Goldsmith, R., Medina, N., Yushak, M., Miller, M., and Packer, M. (1996) Changes in plasma endothelin-1 levels reflect clinical response to beta-blockade in chronic heart failure. Am. Heart J 131: 337–341.

    Article  PubMed  CAS  Google Scholar 

  58. Martin-Nizard, F., Houssaini, H. S., Lestavel-Delattre, S., Duriez, P., and Fruchart, J.-C. (1991) Modified low density lipoproteins activate human macrophages to secrete immunoreactive endothelin. FEBS Lett. 293: 127–130.

    Article  PubMed  CAS  Google Scholar 

  59. Salomone, O. A., Elliott, P. M., Calvino, R., Holt, D., and Kaski, J. C. (1996) Plasma immunoreactive endothelin concentration correlates with severity of coronary artery disease in patients with stable angina pectoris and normal ventricular function. J. Am. Coll. Cardiol 28: 14–19.

    Article  PubMed  CAS  Google Scholar 

  60. Ihling, C., Gobel, H. R., Lippoldt, A., Wessels, S., Paul, M., Schaefer, H. E., and Zeiher, A. M. (1996) Endothelin-1-like immunoreactivity in human atherosclerotic coronary tissue: a detailed analysis of the cellular distribution of endothelin-1. J. Pathol 179: 303–308.

    Article  PubMed  CAS  Google Scholar 

  61. Mangiafico, R. A., Malatino, L. S., Santonocito, M., Spada, R. S., Polizzi, G., and Tamburino, G. (1996) Raised plasma endothelin-1 concentrations in patients with primary hypercholesterolemia without evidence of atherosclerosis. Int. Angiol 15: 240–244.

    PubMed  CAS  Google Scholar 

  62. Lerman, A., Webster, M. W., Chesebro, J. H., Edwards, W. D., Wei, C. M., Fuster, V., and Burnett, J. C., Jr. (1993) Circulating and tissue endothelin immunoreactivity in hypercholesterolemic pigs. Circulation 88: 2923–2928.

    Article  PubMed  CAS  Google Scholar 

  63. Azuma, H., Hamasaki, H., Niimi, Y., Terada, T., and Matsubara, O. (1994) Role of endothelin-1 in neointima formation after endothelial removal in rabbit carotid arteries. Am. J. Physiol 267: H2259 — H2267.

    PubMed  CAS  Google Scholar 

  64. Wang, X., Douglas, S. A., and Ohlstein, E. H. (1996) The use of quantitative RT-PCR to demonstrate the increased expression of endothelinrelated mRNAs following angioplasty-induced neointima formation in the rat. Circ. Res 78: 322–328.

    Google Scholar 

  65. Lopez, J. A. G., Armstrong, M. L., Piegors, D. J., and Heistad, D. D. (1990) Vascular responses to endothelin-1 in atherosclerotic primates. Artheriosclerosis 10: 11–13.

    Google Scholar 

  66. Prat, L., Carri6, I., Roca, M., Riambau, V., Berné, L., Estorch, M., Ferrer, I., and Garcia, C. (1993) Polyclonal ’ 11In-IgG, 1251-LDL and 1251-endothelin-1 accumulation in experimental arterial wall injury. Eur. J. Nucl. Med 20: 1141–1145.

    PubMed  CAS  Google Scholar 

  67. Dashwood, M., Barker, S. G. E., Muddle, J. R., Yacoub, M. H., and Martin, J. F. (1993) [125I]-Endothelin-1 binding to vasa vasorum and regions of neovascularization in human and porcine blood vessels: a possible role for endothelin in intimai hyperplasia and atherosclerosis. J. Cardiovasc. Pharmacol 22(Suppl 8):S343—S347.

    Google Scholar 

  68. Dashwood, M. R., Allen, S. P., Luu, T. N., and Muddle, J. R. (1994) The effect of the ETA receptor antagonist, FR 139317, on [1251]-ET-1 binding to the atherosclerotic human coronary artery. Br. J. Pharmacol 112: 386–389.

    Article  PubMed  CAS  Google Scholar 

  69. Kurata, C., Callahan, R. J., Molea, N., Wilkinson, R., Fischman, A. J., and Strauss, H. W. (1995) Localization of [125I] endothelin-1 in injured aorta of rabbits. Eur. J. Pharmacol 293: 109–114.

    Article  PubMed  CAS  Google Scholar 

  70. Bacon, C. R., Cary, N. R., and Davenport, A. P. (1995) Distribution of endothelin receptors in atherosclerotic human coronary arteries. J. Cardiovasc. Pharmacol. 26(Suppl. 3 ): S439 — S441.

    Google Scholar 

  71. Douglas, S. A. and Ohlstein, E. H. (1993) Endothelin-1 promotes neointima formation after balloon angioplasty in the rat. J. Cardiovasc. Pharmacol. 22(Suppl. 8 ): S371 — S373.

    Google Scholar 

  72. Trachtenberg, J. D., Sun, S., Choi, E. T., Callow, A. D., and Ryan, U. S. (1993) Effect of endothelin-1 infusion on the development of intimal hyperplasia after balloon catheter injury. J. Cardiovasc. Pharmacol. 22 (Suppl. 8 ): 5355–359.

    Google Scholar 

  73. Douglas, S. A., Vickery-Clark, L. M., Storer, B. L., Hart, T., Louden, C., Elliott, J. D., and Ohlstein, E. H. (1994) A role for endogenous endothelin-1 in neointima formation following rat carotid artery balloon angioplasty: antiproliferative effects of the non-peptide endothelin receptor antagonist SB 209670. Circ. Res 75: 190–197.

    Article  PubMed  CAS  Google Scholar 

  74. Ferrer, P., Valentine, M., Jenkins-West, T., Weber, H., Goller, N. L., Durham, S. K., Molloy, C. J., and Moreland, S. (1995) Orally active endothelin receptor antagonist BMS-182874 suppresses neointimal development in balloon-injured rat carotid arteries. J. Cardiovasc. Pharmacol 26: 908–915.

    Google Scholar 

  75. Kowala, M. C., Rose, P. M., Stein, P. D., Goller, N., Recce, R., Beyer, S., Valentine, M., Barton, D., and Durham, S. K. (1995) Selective blockade of the endothelin subtype A receptor decreases early atherosclerosis in hamsters fed cholesterol. Am. J. Pathol 146: 819–826.

    PubMed  CAS  Google Scholar 

  76. Larkin, S. W., Clarke, J. G., Keogh, B. E., Araujo, L., Rhodes, C., Davies, G. J., Taylor, K. M., and Maseri, A. (1989) Intracoronary endothelin induces myocardial ischemia by small vessel constriction in the dog. Am. J. Cardiol 64: 956–958.

    Google Scholar 

  77. Lee, S.-Y., Lee, C. Y., Chen, Y. M., and Kochva, E. (1986) Coronary vasospasm as the primary cause of death due to the venom of the burrowing asp, Atractaspis engaddensis. Toxicon 24: 285–291.

    Article  PubMed  Google Scholar 

  78. Setsuta, K., Seino, Y., Tomita, Y., Nejima, J., Takano, T., and Hayakawa, H. (1995) Origin and pathophysiological role of increased plasma endothelin-1 in patients with acute myocardial infarction. Angiology 46: 557–565.

    Google Scholar 

  79. Tonnessen, T., Giaid, A., Saleh, D., Naess, P. A., Yanagisawa, M., and Cristensen, G. (1995) Increased in vivo expression and production of endothelin1 by porcine cardiomyocytes subjected to ischemia. Circ. Res 76: 767–772.

    Google Scholar 

  80. Kyriakides, Z. S., Markianos, M., Iliodromitis, E. K., and Kremastinos, D. T. (1995) Vein plasma endothelin-1 and cyclic GMP increase during coronary angioplasty is related to myocardial ischaemia. Eur. Heart J 16: 894–898.

    PubMed  CAS  Google Scholar 

  81. Franco-Cereceda, A., Grip, L. G., Moor, E., Velander, M., Liska, J., and Lundberg, J. M. (1995) Influence of percutaneous transluminal coronary angioplasty on cardiac release of endothelin, neuropeptide Y and noradrenaline. Int. J. Cardiol 48: 231–233.

    Google Scholar 

  82. Nelson, R. A., Burke, S. E., and Opgenorth, T. (1994) Endothelin receptor antagonist fr 139317 reduces infarct size in a rabbit coronary artery occlusion model. FASEB J. 8: A854.

    Google Scholar 

  83. Lee, J. Y., Warner, R. B., Adler, A. L., and Opgenorth, T. J. (1994) The ETA receptor antagonist FR 139317 reduces myocardial infarction induced by coronary artery occlusion and reperfusion in the rat. FASEB J. 8: A854.

    Google Scholar 

  84. Wang, Q. D., Li, X. S., and Pernow, J. (1995) The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischemic rat heart. J. Cardiovasc. Pharmacol 26 (Suppl. 3): S445–S447.

    Article  PubMed  CAS  Google Scholar 

  85. McMurdo, L., Thiemermann, C., and Vane, J. R. (1994) The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischemia and reperfusion. Br. J. Pharmacol 112: 75–80.

    Article  PubMed  CAS  Google Scholar 

  86. Vitola, J. V., Forman, M. B., Holsinger, J. P., Kawana, M., Atkinson, J. B., Quertermous, T., Jackson, E. K., and Murray, J. J. (1996) Role of endothelin in a rabbit model of acute myocardial infarction—effects of receptor antagonists. J. Cardiovasc. Pharmacol 28: 774–783.

    Article  PubMed  CAS  Google Scholar 

  87. Erikson, J. M. and Velasco, C. E. (1996) Endothelin-1 and myocardial preconditioning. Am. Heart J 132: 84–90.

    Article  PubMed  CAS  Google Scholar 

  88. Mertz, T. E., McClanahan, T. B., Flynn, M. A., Juneau, P., Reynolds, E. E., Hallak, H., Bradford, L., and Gallagher, K. P. (1996) EndothelinA receptor antagonism by PD 156707 does not reduce infarct size after coronary artery occlusion/reperfusion in pigs. J. Pharmacol. Exp. Ther 278: 42–49.

    PubMed  CAS  Google Scholar 

  89. Wang, Q. D., Li, X. S., Lundberg, J. M., and Pernow, J. (1995) Protective effects of non-peptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in the pig. Cardiovasc. Res 29: 805–812.

    PubMed  CAS  Google Scholar 

  90. Grover, G. J., Dzwonczyk, S., and Parham, C. S. (1993) The endothelin1 receptor antagonist BQ123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc. Res. 27: 1613–1618.

    Google Scholar 

  91. Kojima, M., Kusumoto, K., Fujiwara, S., Watanabe, T., and Fujino, M. (1995) Role of endogenous endothelin in the extension of myocardial infarct size studies with the endothelin receptor antagonist, TAK-044. J. Cardiovasc. Pharmacol 26 (Suppl. 3), S365–S368.

    PubMed  CAS  Google Scholar 

  92. Watanabe, T., Awane, Y., Ikeda, S., Fujiwara, S., Kubo, K., Kikuchi, T., Kusumoto, K., Wakimasu, M., and Fujino, M. (1995) Pharmacology of a non-selective ETA and ETB receptor antagonist TAK-044, and the inhibition of myocardial infarct size in rats. Br. J. Pharmacol 114: 949–954.

    Article  PubMed  CAS  Google Scholar 

  93. Illing, B., Horn, M., Han, H., Hahn, S., Bureik, P., Ertl, G., and Neubauer, S. (1996) Protective effect of the specific endothelin-1 antagonist BQ610 on mechanical function and energy metabolism during ischemia/ reperfusion injury in isolated perfused rat hearts. J. Cardiovasc. Pharmacol 27: 487–494.

    Google Scholar 

  94. Garjani, A., Wainwright, C.L., Zeitlin, I. J., Wilson, C., and Slee, S.-J. (1995) Effects of endothelin-1 and the ETA-receptor antagonist, BQ123, on ischemia arrhythmias in anesthetized rats. J. Cardiovasc. Pharmacol 25: 634–642.

    Google Scholar 

  95. Omland, T., Bonarjee, V.V., Lie, R.T., and Caidahl, K. (1995) Neurohumoral measurements as indicators of long-term prognosis after acute myocardial infarction. Am. J. Cardiol 76: 230–235.

    Article  PubMed  CAS  Google Scholar 

  96. Asano, T., Ikegaki, I., Suzuki, Y., Satoh, S.-I., and Shibuya, M. (1989) Endothelin and the production of cerebral vasospasm in dogs. Biochem. Biophys. Res. Commun 159: 1345–1351.

    Article  PubMed  CAS  Google Scholar 

  97. Ohlstein, E. H. and Storer, B. L. (1992) Oxyhemoglobin stimulated endothelin production in cultured endothelial cells. J. Neurosurg 77: 274–278.

    Article  PubMed  CAS  Google Scholar 

  98. Masaoka, H., Suzuki, R., Hirata, Y., Emori, T., Marumo, F., and Hirakawa, K. (1989) Raised plasma endothelin in aneurysmal subarachnoid haemorrhage. Lancet 2: 1402.

    Article  PubMed  CAS  Google Scholar 

  99. Wang, X., Zhu, C., Zhang, G., and Lu, Y. (1995) Changes of endothelin during cerebral vasospasm after experimental subarachnoid hemorrhage. Chin. Med. J. Engl 108: 586–590.

    PubMed  CAS  Google Scholar 

  100. Seifert, V., Loffler, B. M., Zimmermann, M., Roux, S., and Stolke, D. (1995) Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage. Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma. J. Neurosurg. 82:55–62.

    Google Scholar 

  101. Papadopoulos, S. M., Gilbert, L. L., Webb, R. C., and D’Amato, C. J. (1990) Characterization of contractile responses to endothelin in human cerebral arteries: implications for cerebral vasospasm. Neurosurgery 26: 810–815.

    Google Scholar 

  102. Zimmerman, M., Seifert, V., Loffler, B. M., Stolke, D., and Stenzel, W. (1996) Prevention of cerebral vasospasm after experimental subarachnoid hemorrhage by RO 47–0203, a newly developed orally active endothelin receptor antagonist. Neurosurgery 38: 115–120.

    Google Scholar 

  103. Itoh, S., Sasaki, T., Asai, A., and Kuchino, Y. (1994) Prevention of delayed vasospasm by an endothelin ETA receptor antagonist BQ123: change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model. J. Neurosurg. 81: 759–764.

    Google Scholar 

  104. Matsumura, Y., Ikegawa, R., Suzuki, Y., Takaoka, M., Uchida, T., Kido, H., Shinyama, H., Hayashi, K., Watanabe, M., and Morimoto, S. (1991) Phosphoramidon prevents cerebral vasospasm following subarachnoid hemorrhage in dogs: the relationship to endothelin-1 levels in the cerebrospinal fluid. Life Sci. 49: 841–848.

    Google Scholar 

  105. Itoh, S., Sasaki, T., Ide, K., Ishikawa, K., Nishikibe, M., and Yano, M. (1993) A novel endothelin ETA receptor antagonist, BQ-485, and its preventive effect on experimental vasospasm in dogs. Biochem. Biophys. Res. Commun 195: 969–975.

    Article  PubMed  CAS  Google Scholar 

  106. Clozel, M. and Watanabe, H. (1994) BQ-123, a peptidic endothelin ETA receptor antagonist, prevents the early cerebral vasospasm following subarachnoid hemorrhage after intracisternal but not intravenous injection. Life Sci. 52: 825–834.

    Article  Google Scholar 

  107. Foley, P. L., Caner, H. H., Kassell, N. F., and Lee, K. S. (1994) Reversal of subarachnoid hemorrhage-induced vasoconstriction with an endothelin receptor antagonist. Neurosurgery 34: 108–113.

    Google Scholar 

  108. Hino, A., Weir, B. K. A., Macdonald, R. L., Thisted, R. A., Kim, C.-J., and Johns, L. M. (1995) Prospective, randomized, double-blind trial of BQ123 and bosentan for prevention of vasospasm following subarachnoid hemorrhage in monkeys. J. Neurosurg 83: 503–509.

    Article  PubMed  CAS  Google Scholar 

  109. Cosentino, F., Mcmahon, E. G., Carter, J. S., and Katusic, Z. S. (1993) Effect of endothelinA receptor antagonist BQ-123 and phosphoramidon on cerebral vasospasm. J. Cardiovasc. Pharmacol. 22(Suppl. 8): S332—S335.

    Google Scholar 

  110. Caner, H. H Kwan, A. L., Arthur, A., Jeng, A. Y., Lappe, R. W., Kassell, N. F., and Lee, K. S. (1996) Systemic administration of an inhibitor of endothelin converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage. J. Neurosurg 85: 917–922

    Google Scholar 

  111. Clozel, M., Breu, V., Gray, G. A., and Löffler, B. M. (1993) In vivo pharmacology of Ro 46–2005, the first synthetic nonpeptide endothelin receptor antagonist: implications for endothelin physiology. J. Cardiovasc. Pharmacol 22(Suppl 8): S377—S379.

    Google Scholar 

  112. Nirei, H., Hamada, K., Shoubo, M., Sogabe, K., Notsu, Y., and Ono, T. (1993) An endothelin ETA receptor antagonist, FR139317, ameliorates cerebral vasospasm in dogs. Life Sci. 52: 1869–1874.

    Google Scholar 

  113. Roux, S., Loftier, B. M., Gray, G. A., Sprecher, U., Clozel, M., and Clozel, J. P. (1995) The role of endothelin in experimental cerebral vasospasm. Neurosurgery 37: 78–86.

    Article  PubMed  CAS  Google Scholar 

  114. Shigeno, T., Clozel, M., Sakai, S., Saito, A., and Goto, K. (1995) The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm. Neurosurgery 37: 87–90.

    Google Scholar 

  115. Zuccarello, M., Soattin, G. B., Lewis, A., Breu, V., Hallak, H., and Rapoport, R. M. (1996) Prevention of subarachnoid hemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists. J. Neurosurg 84: 503–507.

    Google Scholar 

  116. Willette, R. N., Zhang, H., Mitchell, M. P., Sauermelch, C. F., Ohlstein, E. H., and Sulpizio, A. C. (1994) Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm. Stroke 25: 2450–2456.

    Google Scholar 

  117. Willette, R. N., Feuerstein, G. Z., and Barone, F. C. (1995) Endothelin in the central nervous system, in Endothelin Receptors: From the Gene to the Human ( Ruffolo, R. R., Jr., ed.), CRC, Boca Raton, FL, pp. 187–213.

    Google Scholar 

  118. Barone, F C., Willette, R. N., Yue, T.-L., and Feuerstein, G. (1995) Therapeutic effects of endothelin receptor antagonists in stroke. Neurol. Res 17:259–264.

    Google Scholar 

  119. Sharkey, J. and Butcher, S. P. (1995) Characterization of an experimental model of stroke produced by intracerebral microinjection of endothelin1 adjacent to the rat middle cerebral artery. J. Neurosci. Methods 60: 125–131.

    Google Scholar 

  120. Agnati, L. F., Zoli, M., Kurosawa, M., Benfenati, F., Biagini, G., Zini, I., Hallstrom, A., Ungerstedt, U., Toffano, G., and Fuxe, K. (1991) A new model of focal brain ischemia based on the intracerebral injection of endothelin-l. Ital. J. Neurol. Sci. 12(3 Suppl. 11 ): 49–53.

    Google Scholar 

  121. Ziv, I., Fleminger, G., Djaldetti, R., Achiron, A., Melamed, E., and Sokolovsky, M. (1992) Increased plasma endothelin-1 in acute ischemic stroke. Stroke 23: 1014–1016.

    Google Scholar 

  122. Wei, G. Z., Zhang, J., Sheng, S. L., Ai, H. X., Ma, J. C., and Lui, H. B. (1993) Increased plasma endothelin-1 concentration in patients with acute cerebral infarction and actions of endothelin-1 on pial arterioles of rat. Chin. Med. J. Engl 106: 917–921.

    Google Scholar 

  123. Giuffrida, R., Bellomo, M., Polizzi, G., and Malatino, L. S. (1992) Ischemia-induced changes in he immunoreactivity for endothelin and other vasoactive peptides in the brain of the Mongolian gerbil. J. Cardiovasc. Pharmacol 20 (Suppl. 12): S41 - S44.

    Article  PubMed  CAS  Google Scholar 

  124. Willette, R. N., Ohlstein, E. H., Pullen, M., Sauermelch, C. F., Cohen, A., and Nambi, P. (1993) Transient forebrain ischemia alters acutely endothelin receptor density and immunoreactivity in gerbil brain. Life Sci. 52: 35–40.

    Article  PubMed  CAS  Google Scholar 

  125. Viossat, I Duverger, D., Chapelat, M., Pirotzky, E., Chabrier, P. E., and Braquet, P. (1993) Elevated tissue endothelin content during focal cerebral ischemia in the rat. J. Cardiovasc. Pharmacol 22(Suppl 8):S306–S309.

    Google Scholar 

  126. Barone, F. C., Globus, M. Y., Price, W. J., White, R. F., Storer, B. L., Feuerstein, G. Z., Busto, R., and Ohlstein, E. H. (1994) Endothelin levels increase in rat focal and global ischemia. J. Cereb. Blood Flow Metab 14: 337–342.

    Article  PubMed  CAS  Google Scholar 

  127. Yamashita, K., Kataoka, Y., Niwa, M., Shigematsu, K., Himeno, A., Koizumi, S., and Taniyama, K. (1993) Increased production of endothelins in the hippocampus of stroke-prone spontaneously hypertensive rats following transient forebrain ischemia: histochemical evidence. Cell Mol. Neurobiol. 13: 15–23.

    Google Scholar 

  128. Kohzuki, M., Onodera, H., Yasujima, M., Itoyama, Y., Kanazawa, M., Sato, T., and Abe, K. (1995) Endothelin receptors in ischemic rat brain and Alzheimer brain. J. Cardiovasc. Pharmacol. 26(Suppl. 3): S329–S331.

    Google Scholar 

  129. Feuerstein, G. Z., Gu, J.-L., Ohlstein, E. H., Barone, F. C., and Yue, T. L. (1994) Selective endothelin receptor (ETA) antagonist is neuroprotective in gerbil transient forebrain ischemia. Stroke 25: 264.

    Google Scholar 

  130. Barone, F. C., White, R. F., Elliott, J. D., Feuerstein, G. Z., and Ohlstein, E. H. (1995) The endothelin receptor antagonist SB 217242 reduces cerebral focal ischemic brain injury. J. Cardiovasc. Pharmacol. 26(Suppl. 3 ): S404 - S407.

    Google Scholar 

  131. Patel, T. R. and McCulloch, J. (1996) Failure of an endothelin antagonist to modify hypoperfusion after transient global ischaemia in the rat. J. Cereb. Blood Flow Metab 16: 490–499.

    Article  PubMed  CAS  Google Scholar 

  132. Patel, T. R., McAuley, M. A., and McCulloch, J. (1994) Effects on feline pial arterioles in situ of bosentan, a non-peptide, endothelin receptor antagonist. Eur. J. Pharmacol 260: 65–71.

    Article  PubMed  CAS  Google Scholar 

  133. Patel, T. R., Galbraith, S., Graham, D. I., Hallak, H., Doherty, A. M., and McCulloch, J. (1996) Endothelin receptor antagonist increases cerebral perfusion and reduces ischaemic damage in feline focal cerebral ischaemia. J. Cereb. Blood Flow Metab 16: 950–958.

    Article  PubMed  CAS  Google Scholar 

  134. Wilkes, B. M., Susin, M., and Mento, P. F. (1993) Localization of endothelin-1-like immunoreactivity in human placenta. J. Histochem. Cytochem 41: 535–541.

    Article  PubMed  CAS  Google Scholar 

  135. Nova, A., Sibai, B. M., Barton, J. R., Mercer, B. M., and Mitchell, M. D. (1991) Maternal plasma level of endothelin is increased in preeclampsia. Am. J. Obstet. Gynecol 165: 724–727.

    PubMed  CAS  Google Scholar 

  136. Benigni, A., Orisio, S., Gaspari, F., Frusca, T., Amuso, G., and Remuzzi, G. (1992) Evidence against a pathogenetic role for endothelin in pre-eclampsia. Br. J. Obstet. Gynecol 99: 798–802.

    Article  CAS  Google Scholar 

  137. Cervar, M., Kainer, F., Jones, C. J., and Desoye, G. (1996) Altered release of endothelin-1,2 and thromboxane B2 from trophoblastic cells in pre-eclampsia. Eur. J. Clin. Invest 26: 30–37.

    Article  PubMed  CAS  Google Scholar 

  138. McMahon, L. P., Redman, C. W., and Firth, J. D. (1993) Expression of the three endothelin genes and plasma levels of endothelin in pre-eclampsia and normal gestations. Clin. Sci. Colch 85: 417–424.

    PubMed  CAS  Google Scholar 

  139. Schiff, E., Galron, R., Ben-Baruch, G., Mashiach, S., and Sokolovsky, M. (1993) Endothelin-1 receptors on the human placenta and fetal membranes: evidence for different binding properties in pre-eclamptic pregnancies. Gynecol. Endocrinol 7: 67–72.

    Article  PubMed  CAS  Google Scholar 

  140. Cervar, M., Kainer, F., and Desoye, G. (1995) Pre-eclampsia and gestational age differently alter binding of endothelin-1 to placental and trophoblast membrane preparations. Mol. Cell Endocrinol. 110: 65–71.

    Google Scholar 

  141. Vedernikov, Y. P., Belfort, M. A., Saade, G. R., and Moise, K. J., Jr. (1995) Pre-eclampsia does not alter the response to endothelin-1 in human omental artery. J. Cardiovasc. Pharmacol. 26(Suppl. 3): S233—S235.

    Google Scholar 

  142. Morel, D. R., Lacroix, J. S., Hemsen, A., Steinig, D. A., Pittet, J-F., and Lundberg, J. M. (1989) Increased plasma and pulmonary lymph levels of endothelin during endotoxin shock. Eur. J. Pharmacol 167: 427, 428.

    Google Scholar 

  143. Nambi, P., Pullen, M., Slivjak, M. J., Ohlstein, E. H., Storer, B., and Smith, E. F., III (1994) Endotoxin-mediated changes in plasma endothelin concentrations, renal endothelin receptor and renal function. Pharmacology 48: 147–156.

    Article  PubMed  CAS  Google Scholar 

  144. Smits, P., Hofman, H., Rosmalen, F., Wollersheim, H., and Thien, T. (1991) Endothelin-1 in patients with Raynaud’s phenomenon. Lancet 337: 236.

    Article  PubMed  CAS  Google Scholar 

  145. Farkkila, M., Palo, J., Saijonmaa, O., and Fyhrquist, F. (1992) Raised plasma endothelin during acute migraine attack. Cephalalgia 12: 383-384.

    Google Scholar 

  146. Brandli, P., Loffler, B. M., Breu, V., Osterwalder, R., Maire, J. P., and Clozel, M. (1996) Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater. Pain 64:315–322.

    Google Scholar 

  147. Aoki, T., Kojima, T., Ono, A., Unishi, G., Yoshijima, S., Kameda-Hayashi, N., Yamamoto, C., Hirata, Y., and Kobayashi, Y. (1994) Circulating endothelin-1 levels in patients with bronchial asthma. Ann. Allergy 73: 365–369.

    PubMed  CAS  Google Scholar 

  148. Springall, D. R., Howarth, P. H Counihan, H., Djukanovic, R., Holgate, S. T., and Polak, J. M. (1991) Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet 337: 697–701

    Google Scholar 

  149. Vittori, E., Marini, M., Fasoli, A., De Franchis, R., and Mattoli, S. (1992) Increased expression of endothelin in bronchial epithelial cells of asthmatic patients and effect of corticosteroids. Am. Rev. Respir. Dis 146: 1320–1325.

    PubMed  CAS  Google Scholar 

  150. Ackerman, V., Carpi, S., Bellini, A., Vassalli, G., Marini, M., and Mattoli, S. (1995) Constitutive expression of endothelin in bronchial epithelial cells of patients with symptomatic and asymptomatic asthma and modulation by histamine and interleukin-1. J. Allergy Clin. Immunol 96: 618–627.

    Article  PubMed  CAS  Google Scholar 

  151. Knott, P. G., D’Aprile, A. C., Henry, P. J., Hay, D. W., and Goldie, R. G. (1995) Receptors for endothelin-1 in asthmatic human peripheral lung. Br. J. Pharmacol 114: 1–3.

    Article  PubMed  CAS  Google Scholar 

  152. Chanez, P., Vignola, A. M., Albat, B., Springall, D. R., Polak, J. M., Godard, P., and Bousquet, J. (1996) Involvement of endothelin in mononuclear phagocyte inflammation in asthma. J. Allergy Clin. Immunol 98: 412–420.

    Google Scholar 

  153. Riccio, M. M., Reynolds, C. J., Hay, D. W., and Proud, D. (1995) Effects of intranasal administration of endothelin-1 to allergic and nonallergic individuals. Am. J. Respir. Crit. Care Med 152: 1757–1764.

    PubMed  CAS  Google Scholar 

  154. Uchida, Y., Jun, T., Ninomiya, H., Ohse, H., Hasegawa, S., Nomura, A., Sakamoto, T., Sardessai, M. S., and Hirata, F. (1996) Involvement of endothelins in immediate and late asthmatic responses of guinea pigs. J. Pharmacol. Exp. Ther 277: 1622–1629.

    PubMed  CAS  Google Scholar 

  155. Goerre, S., Wenk, M., Bartsch, P., Luscher, T. F., Niroomand, F., Hohenhaus, E., Oelz, O., and Reinhart, W. H. (1995) Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Circulation 90: 359–364.

    Article  Google Scholar 

  156. Mitaka, C., Hirata, Y., Nagura, T., Tsunoda, Y., and Amaha, K. (1993) Circulating endothelin-1 concentrations in acute respiratory failure. Chest 104: 476–480.

    Article  PubMed  CAS  Google Scholar 

  157. Ishikawa, S., Miyauchi, T., Ueno, H., Ushinohama, H., Sagawa, K., Fusazaki, N., Sunagawa, H., Honda, S., Sakai, S., and Yamaguchi, I. (1995) Influence of pulmonary blood pressure and flow on endothelin-1 production in humans. J. Cardiovasc. Pharmacol. 26(Suppl. 3 ): S429 — S433.

    Google Scholar 

  158. Giaid, A., Yanagisawa, M., Langleben, D., Michel, R. P., Levy, R., Shennib, H., Kimura, S., Masaki, T., Duguid, W. P., and Stewart, D. J. (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New Engl. J. Med. 328: 1732–1739.

    Google Scholar 

  159. Stelzner, T. J., O’Brien, R. F., Yanagisawa, M., Sakurai, T., Sato, K., Webb, S., Zamora, M., McMurtry, I. F., and Fisher, J. H. (1992) Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am. J. Physiol 262: L614 – L618.

    PubMed  CAS  Google Scholar 

  160. Sakai, S., Miyauchi, T., Sakurai, T., Yamaguchi, I., Kobayashi, M., Goto, K., and Sugishita, Y. (1996) Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of an endothelin receptor antagonist. J. Am. Coll. Cardiol. 28: 1580–1588.

    Google Scholar 

  161. MacLean, M. R., McCulloch, K. M., and Baird, M. (1995) Effects of pulmonary hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6c and on inherent tone in rat pulmonary arteries. J. Cardiovasc. Pharmacol 26: 822–830.

    Article  PubMed  CAS  Google Scholar 

  162. Stewart, A. G., Grigoriadis, G., and Harris, T. (1994) Mitogenic actions of endothelin-1 and epidermal growth factor in cultured airway smooth muscle. Clin. Exp. Pharmacol. Physiol 21: 277–285.

    Article  PubMed  CAS  Google Scholar 

  163. Panettieri, R. A., Jr., Goldie, R. G., Rigby, P. J., Eszterhas, A. J., and Hay, D. W. (1996) Endothelin-1-induced potentiation of human airway smooth muscle proliferation: an ETA receptor-mediated phenomenon. Br. J. Pharmacol 118: 191–197.

    Article  PubMed  CAS  Google Scholar 

  164. Marini, M., Carpi, S., Bellini, A., Patalano, F., and Mattoli, S. (1996) Endothelin-1 induces increased fibronectin expression in human bronchial epithelial cells. Biochem. Biophys. Res. Commun 220: 896–899.

    Article  PubMed  CAS  Google Scholar 

  165. Mansoor, A. M., Honda, M., Saida, K., Ishinaga, Y., Kuramochi, T., Maeda, A., Takabatake, T., and Mitsui, Y. (1995) Endothelin-induced collagen remodeling in experimental pulmonary hypertension. Biochem. Biophys. Res. Commun 215: 981–986.

    Article  PubMed  CAS  Google Scholar 

  166. Okada, M., Yamashita, C., Okada, M., and Okada, K. (1995) Role of endothelin-1 in beagles with dehydromonocrotaline-induced pulmonary hypertension. Circulation 92: 114–119.

    Article  PubMed  CAS  Google Scholar 

  167. Wagner, O. F., Vierhapper, H., Gasic, S., Nowotny, P., and Waldhausl, W. (1992) Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation. Eur. J. Clin. Invest 22: 277–282.

    Article  PubMed  CAS  Google Scholar 

  168. Kaasjager, K. A. H., Shaw, S., Koomans, H. A., and Rabelink, T. J. (1997) Role of endothelin receptor subtypes in the systemic and renal responses to endothelin-1 in humans. J. Am. Soc. Nephrol 8: 32–39.

    PubMed  CAS  Google Scholar 

  169. Tomita, K., Ujiie, K., Nakanishi, T., Tomura, S., Matsuda, O., Ando, K., Shichiri, M., Hirata, Y., and Marumo, F. (1989) Plasma ET levels in patients with acute renal failure. Eur. J. Med 32: 1127.

    Google Scholar 

  170. Sandok, E. K., Lerman, A., Stingo, A. J., Perrella, M. A., Gloviczki, P., and Burnett, J. C., Jr. (1992) Endothelin in a model of acute ischemic renal dysfunction: modulating action of atrial natriuretic factor. J. Am. Soc. Nephrol 3: 196–202.

    PubMed  CAS  Google Scholar 

  171. Shibouta, Y., Suzuki, N., Shino, A., Matsumoto, H., Terashita, Z.-I., Kondo, K., and Nishikawa, K. (1990) Pathophysiological role of ET in acute renal failure. Life Sci. 46: 1611–1618.

    Article  PubMed  CAS  Google Scholar 

  172. Firth, J. D. and Ratcliffe, P. J. (1992) Organ distribution of the three rat ET messenger RNAs and the effects of ischemia on renal gene expression. J. Clin. Invest 90, 1023–1031.

    Google Scholar 

  173. Clozel, M., Löffler, B. M. and Gloor, H. (1991) Relative preservation of the responsiveness to ET-1 during reperfusion following renal ischemia in the rat. J. Cardiovasc. Pharmacol. 17(Suppl. 7 ): S313–5315.

    Google Scholar 

  174. Nambi, P., Pullen, M., Jugus, M., and Gellai, M. (1993) Rat kidney ET receptors in ischemia-induced acute renal failure. J. Pharmacol. Exp. Ther 264: 345–348.

    PubMed  CAS  Google Scholar 

  175. Wilkes, B. M., Pearl, A. R., Mento, P. F., Maita, M. E., Macica, C. M., and Girardi, E. P. (1991) Glomerular ET receptors during initiation and maintenance of ischemic acute renal failure in rats. Am. J. Physiol 260: F110 — F118.

    PubMed  CAS  Google Scholar 

  176. Vemulapalli, S., Chiu, P. J. S., Chintala, M., and Bernardino, V. (1993) Attenuation of ischemic acute renal failure by phosphoramidon in rats. Pharmacology 47: 188–193.

    Article  PubMed  CAS  Google Scholar 

  177. Kon, V., Yoshioka, T., Fogo, A., and Ichikawa, I (1989) Glomerular actions of ET in vivo. J. Clin. Invest 83:1762–1767.

    Google Scholar 

  178. López-Farré, A., Gómez-Garre, D., Bernabeu, F., and López-Novoa, J. (1991) A role for ET in the maintenance of post-ischaemic renal failure in the rat. J. Physiol 444: 513–522.

    PubMed  Google Scholar 

  179. Mino, N., Kobayashi, M., Nakajima, A., Amano, H., Shimamoto, K., Ishikawa, K., Watanabe, K., Nishikebe, M., Yano, M., and Ikemoto, F. (1992) Protective effect of a selective ET receptor antagonist, BQ123, in ischemic acute renal failure in rats. Eur. J. Pharmacol 221: 77–83.

    Article  PubMed  CAS  Google Scholar 

  180. Chan, L., Chittinandana, A., Shapiro, J. I., Shanley, P. F., and Schrier, R. W. (1994) Effect of an ET-receptor antagonist on ischemic acute renal failure. Am. J. Physiol 266: F135 — F138.

    PubMed  CAS  Google Scholar 

  181. Gellai, M., Jugus, M., Fletcher, T. A., DeWolf, R., and Nambi, P. (1994) Reversal of postischemic acute renal failure with a selective ETA receptor antagonist in the rat. J. Clin. Invest 93: 900–906.

    Article  PubMed  CAS  Google Scholar 

  182. Brooks, D. P., DePalma, P. D., Gellai, M., Nambi, P., Ohlstein, E. H., Elliott, J. D., Gleason, J., and Ruffolo, R. R., Jr. (1994) Non-peptide ET receptor antagonists. III. Effect of SB 209670 and BQ123 on acute renal failure in anesthetized dogs. J. Pharmacol. Exp. Ther 271: 769–775.

    PubMed  CAS  Google Scholar 

  183. Gellai, M., Jugus, M., Fletcher, T., Nambi, P., Ohlstein, E. H., Elliott, J. D., and Brooks, D. P. (1995) Nonpeptide endothelin receptor antagonists. V: prevention and reversal of acute renal failure in the rat by SB 209670. J. Pharmacol. Exp. Ther 275: 200–206.

    PubMed  CAS  Google Scholar 

  184. Clozel, M., Breu, V., Burri, K., Cassal, J.-M., Fischli, W., Gray, G. A., Hirth, G., Löffler, B.-M., Müller, M., Neidhart, W., and Ramuz, H. (1993) Pathophysiological role of ET revealed by the first orally active ET receptor antagonist. Nature 365: 759–761.

    Article  PubMed  CAS  Google Scholar 

  185. Kusumoto, K., Kubo, K., Kandori, H., Kitayoshi, T., Sato, S., Wakimasu, M., Watanabe, T., and Fujino, M. (1994) Effects of a new endothelin antagonist, TAK-044, on post-ischemic acute renal failure in rats. Life Sci. 55: 301–310.

    Article  PubMed  CAS  Google Scholar 

  186. Stingo, A. J., Clavell, A. L., Aarhus, L. L., and Burnett, J. C., Jr. (1993) Biological role for the ET-A receptor in aortic cross-clamping. Hypertension 22: 62–66.

    Article  PubMed  CAS  Google Scholar 

  187. Brooks, D. P., DePalma, P. D., Pullen, M., and Nambi, P. (1994) Characterization of canine renal ET receptor subtypes and their function. J. Pharmacol. Exp. Ther 268: 1091–1097.

    PubMed  CAS  Google Scholar 

  188. Brooks, D. P. (1996) Role of endothelin in renal function and dysfunction. Clin. Exp. Pharmacol. Physiol 23: 345–348.

    Article  PubMed  CAS  Google Scholar 

  189. Nir, A., Clavell, A. L., Heublein, D., Aarhus, L. L., and Burnett, J. C., Jr. (1994) Acute hypoxia and endogenous renal ET. J. Am. Soc. Nephrol 4: 1920–1924.

    PubMed  CAS  Google Scholar 

  190. Roubert, P., Gillard-Roubert, V., Pourmarin, L., Cornet, S., Guilmard, C., Plas, P., Pirotzky, E., Chabrier, P. E., and Braquet, P. (1993) Endothelin receptor subtypes A and B are up-regulated in an experimental model of acute renal failure. Mol. Pharmacol. 45: 182–188.

    Google Scholar 

  191. Karam, H., Bruneval, P., Clozel, J.-P., Loffler, B.-M., Bariety, J., and Clozel, M. (1995) Role of endothelin in acute renal failure due to rhabdomyolysis in rats. J. Pharmacol. Exp. Ther 274: 481–486.

    PubMed  CAS  Google Scholar 

  192. Bunchman, T. E. and Brookshire, C. A. (1991) Cyclosporine-induced synthesis of ET by cultured human endothelial cells. J. Clin. Invest 88: 310–314.

    Article  PubMed  CAS  Google Scholar 

  193. Nakahama, H. (1990) Stimulatory effect of cyclosporine A on ET secretion by a cultured renal epithelial cell line, LLC-PK1 cells. Eur. J. Pharmacol 180: 191, 192.

    Google Scholar 

  194. Moutabarrik, A., Ishibashi, M., Fukunaga, M., Kameoka, H., Takano, Y., Kokado, Y., Takahar, S., Jiang, H., Sonoda, T., and Okuyama, A. (1991) FK506 mechanism of nephrotoxicity: stimulatory effect on ET secretion by cultured kidney cells. Transplant. Proc 23: 3133–3136.

    PubMed  CAS  Google Scholar 

  195. Edwards, B. S., Hunt, S. A., Fowler, M. B., Valentine, H. A., Anderson, L. M., and Lerman, A. (1991) Effect of cyclosporine on plasma ET levels in humans after cardiac transplantation. Am. J. Cardiol 67: 782–784.

    Article  PubMed  CAS  Google Scholar 

  196. Grieff, M., Loertscher, R., Shohaib, S. A., and Stewart, D. J. (1993) Cyclosporine-induced elevation in circulating ET-1 in patients with solid-organ transplants. Transplantation 56: 880–884.

    Article  PubMed  CAS  Google Scholar 

  197. Haug, C., Duell, T., Lenich, A., Kolb, H. J., and Grunert, A. (1995) Elevated plasma endothelin concentrations in cyclosporine-treated patients after bone marrow transplantation. Bone Marrow Transplant. 16: 191–194.

    PubMed  CAS  Google Scholar 

  198. Textor, S. C., Burnett, J. C., Jr., Romero, C., Canzanello, V. J., Taler, S. J., Wiesner, R., Porayko, M., Krom, R., Gores, G., and Hay, E. (1995) Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 47: 1426–1433.

    Article  PubMed  CAS  Google Scholar 

  199. Tanda, K., Seki, T., Kobayashi, S., Kanagawa, K., Chikaraishi, T., Togashi, M., Nonomura, K., and Koyanagi, T. (1994) In vivo effect of a selective endothelin receptor antagonist, BQ123, on renal function in cyclosporin A-treated rats. Int. J. Urol 1: 309–315.

    CAS  Google Scholar 

  200. Benigni, A., Perico, N., Ladny, J. R., Imberti, O., Bellizzi, L., and Remuzzi, G. (1991) Increased urinary excretion of ET-1 and its precursor, big-ET-1, in rats chronically treated with cyclosporine. Transplantation 52: 175–177.

    Article  PubMed  CAS  Google Scholar 

  201. Abassi, Z. A., Pieruzzi, F., Nakhoul, F., and Keiser, H. R. (1996) Effects of cyclosporin A on the synthesis, excretion and metabolism of endothelin the rat. Hypertension 27: 1140–1148.

    Article  PubMed  CAS  Google Scholar 

  202. Brooks, D. P., Ohlstein, E. H., Contino, L. C., Storer, B., Pullen, M., Caltabiano, M., and Nambi, P. (1991) Effect of nifedipine on cyclosporine A-induced nephrotoxicity, urinary ET excretion and renal ET receptor number. Eur. J. Pharmacol 194: 115–117.

    Article  PubMed  CAS  Google Scholar 

  203. Nambi, P., Pullen, M., Contino, L. C., and Brooks, D. P. (1990) Upregulation of renal ET receptors in rats with cyclosporine A-induced nephrotoxicity. Eur. J. Pharmacol 187: 113–116.

    Article  PubMed  CAS  Google Scholar 

  204. Awazu, M., Sugiura, M., Inagami, T., Ichikawa, I., and Kon, V. (1991) Cyclosporine promotes glomerular ET binding in vivo. J. Am. Soc. Nephrol. 1: 1253–1258.

    CAS  Google Scholar 

  205. Takeda, M., Iwasaki, S., Hellings, S. E., Yoshida, H., Homma, T., and Kon, V. (1994) Divergent expression of ETA and ETB receptors in response to cyclosporine in mesangial cells. Am. J. Pathol 144: 473–479.

    PubMed  CAS  Google Scholar 

  206. Nayler, W. G., Gu, X. H., Casley, D. J., Panagiotopoulos, S., Liu, J., and Mottram, P. L. (1989) Cyclosporine increases ET-1 binding site density in cardiac cell membranes. Biochem. Biophys. Res. Commun 163: 1270–1274.

    Article  PubMed  CAS  Google Scholar 

  207. Iwai, J., Kanayama, Y., Negoro, N., Okamura, M., and Takeda, T. (1995) Gene expression of endothelin receptors in aortic cells from cyclosporineinduced hypertensive rats. Clin. Exp. Pharmacol. Physiol. 22: 40 /1 409.

    Google Scholar 

  208. Kon, V., Sugiura, M., Inagami, T., Harvie, B. R., Ichikawa, I., and Hoover, R. L. (1990) Role of ET in cyclosporine-induced glomerular dysfunction. Kidney Int. 37: 1487–1491.

    Article  PubMed  CAS  Google Scholar 

  209. Perico, N., Dadan, J., and Remuzzi, G. (1990) Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat. J. Am. Soc. Nephrol 1: 76–83.

    PubMed  CAS  Google Scholar 

  210. Bloom, I. T. M., Bentley, F. R., and Garrison, R. N. (1993) Acute cyclosporine-induced renal vasoconstriction is mediated by ET-1. Surgery 114: 480–488.

    PubMed  CAS  Google Scholar 

  211. Brooks, D. P. and Contino, L. C. (1995) Prevention of cyclosporine A-induced renal vasoconstriction by the endothelin receptor antagonist SB 209670. Eur. J. Pharmacol 294: 571–576.

    Article  PubMed  CAS  Google Scholar 

  212. Fogo, A., Hellings, S. E., Inagami, T., and Kon, V. (1992) Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity. Kidney Int. 42: 770–774.

    Article  PubMed  CAS  Google Scholar 

  213. Bartholomeusz, B., Hardy, K. J., Nelson, A. S., and Phillips, P. A. (1996) Bosentan ameliorates cyclosporin A-induced hypertension in rats and primates. Hypertension 27: 1341–1345.

    Article  PubMed  CAS  Google Scholar 

  214. Conger, J. D., Kim, G. E., and Robinette, J. B. (1994) Effects of ANG II, ETA and TxA2 receptor antagonists on cyclosporin A renal vasoconstriction. Am. J. Physiol 267: F443 - F449.

    Google Scholar 

  215. Davis, L. S., Haleen, S. J., Doherty, A. M., Cody, W. L., and Keiser, J. A. (1994) Effects of selective endothelin antagonists on the hemodynamic response to cyclosporin A. J. Am. Soc. Nephrol 4: 1448–1454.

    PubMed  CAS  Google Scholar 

  216. Elzinga, L. W., Rosen, S., and Bennett, W. M. (1993) Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J. Am. Soc. Nephrol 42: 214–221.

    Google Scholar 

  217. Hunley, T. E., Fogo, A., Iwasaki, S., and Kon, V. (1995) Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity. J. Am. Soc. Nephrol 5: 1718–1723.

    PubMed  CAS  Google Scholar 

  218. Kon, V., Hunley, T. E., and Fogo, A. (1995) Combined antagonism of endothelin A/B receptors links endothelin to vasoconstriction whereas angiotensin II effects fibrosis. Transplantation 60: 89–95.

    Article  PubMed  CAS  Google Scholar 

  219. Takeda, Y., Miyamori, I., Wu, P., Yoneda, T., Furukawa, K., and Takeda, R. (1995) Effects of an endothelin receptor antagonist in rats with cyclosporine-induced hypertension. Hypertension 26: 932–936.

    Article  PubMed  CAS  Google Scholar 

  220. Binet, I., Wallnofer, A., Jones, R., and Thiel, G. (1996) Renal hemodynamic effects of an endothelin antagonist bosentan, and interaction with cyclosporin A: a placebo controlled double-blind study. J. Am. Soc. Nephrol 7: 1578.

    Google Scholar 

  221. Goodall, T., Kind, C. N., and Hammond, T. G. (1995) FK506-induced endothelin release by cultured rat mesangial cells. J. Cardiovasc. Pharmacol 26 (Suppl. 3): S482 — S485.

    PubMed  CAS  Google Scholar 

  222. Kumano, K., Chen, J., He, M., Endo, T., and Masaki, Y. (1995) Role of endothelin in FK 506-induced renal hypoperfusion in rats. Transplant. Proc 27: 550–553.

    PubMed  CAS  Google Scholar 

  223. Heyman, S. N., Clark, B. A., Kaiser, N., Spokes, K., Rosen, S., Brezis, M., and Epstein, F. H. (1992) Radiocontrast agents induce ET release in vivo and in vitro. J. Am. Soc. Nephrol. 3: 58–65.

    CAS  Google Scholar 

  224. Sung, J.-M., Shu, G. H. F., Tsai, J.-C., and Huang, J.-J. (1995) Radiocontrast media induced endothelin-1 mRNA expression and peptide release in porcine aortic endothelial cells. J. Formos. Med. Assoc 94: 77–86.

    PubMed  CAS  Google Scholar 

  225. Margulies, K. B., Hildebrand, F. L., Heublein, D. M., and Burnett, J. C., Jr. (1991) Radiocontrast increases plasma and urinary ET. J. Am. Soc. Nephrol 2: 1041–1045.

    PubMed  CAS  Google Scholar 

  226. Cantley, L. G., Spokes, K., Clark, B., McMahon, E. G., Carter, J., and Epstein, F. H. (1993) Role of ET and prostaglandins in radiocontrastinduced renal artery constriction. Kidney Int. 44: 1217–1223.

    Article  PubMed  CAS  Google Scholar 

  227. Oldroyd, S., Slee, S.-J., Haylor, J., Morcos, S. K., and Wilson, C. (1994) Role for endothelin in the renal responses to radiocontrast media in the rat. Clin. Sci 87: 427–434.

    PubMed  CAS  Google Scholar 

  228. Brooks, D. P. and DePalma, P. D. (1996) Blockade of radiocontrastinduced nephrotoxicity by the endothelin receptor antagonist, SB 209670. Nephron 72: 629–636.

    Article  PubMed  CAS  Google Scholar 

  229. Bird, J. E., Giancarli, M. R., Megill, J. R., and Durham, S. K. (1996) Effects of endothelin in radiocontrast-induced nephropathy in rats are mediated through endothelin-A receptors. J. Am. Soc. Nephrol 7: 1153–1157.

    PubMed  CAS  Google Scholar 

  230. Pinzani, M., Milani, S., DeFranco, R., Grappone, C., Caligiuri, A., Gentilini, A., Tosti-Guerra, C., Maggi, M., Failli, P., Ruocco, C., and Gentilini, P. (1996) Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 110: 534–548.

    Article  PubMed  CAS  Google Scholar 

  231. Hocher, B., Zart, R., Diekmann, F., Slowinski, T., Thone-Reineke, C., Lutz, J., and Bauer, C. (1995) Role of the paracrine liver endothelin system in the pathogenesis of CC 14-induced liver injury. Eur. J. Pharmacol 293: 361–368.

    Article  PubMed  CAS  Google Scholar 

  232. Rockey, D. C. and Weisiger, R. A. (1996) Endothelin-induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 24: 233–240.

    Article  PubMed  CAS  Google Scholar 

  233. Moller, S., Gulberg, V., Henriksen, J. H., and Gerbes, A. L. (1995) Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics. J. Hepatol 23: 135–144.

    Article  PubMed  CAS  Google Scholar 

  234. Hocher, B., Zart, R., Diekmann, F., Slowinski, T., Thone-Reineke, C., Lutz, J., and Bauer, C. (1996) Protective effects of the mixed endothelin receptor antagonist bosentan in rats with CCL4-induced liver injury. J. Cardiovasc. Pharmacol$126(Suppl. 3): S130, S131.

    Google Scholar 

  235. Soper, C. P. R., Latif, A. B., and Bending, M. R. (1996) Amelioration of hepatorenal syndrome with selective endothelin-A antagonist. Lancet 347: 1842–1843.

    Article  PubMed  CAS  Google Scholar 

  236. King, A. J., Brenner, B. M., and Anderson, S. (1989) Endothelin: a potent renal and systemic vasoconstrictor peptide. Am. J. Physiol 256: F1051 — F1058.

    PubMed  CAS  Google Scholar 

  237. Simonson, M. S., Wann, S., Mené, P., Dubyak, G. R., Kester, M., Nakazato, Y., Sedor, J. R., and Dunn, M. J. (1989) Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression, and mitogenesis in rat mesangial cells. J. Clin. Invest 83: 708–712.

    Article  PubMed  CAS  Google Scholar 

  238. Bakris, G. L. and Re, R. N. (1993) Endothelin modulates angiotensin II-induced mitogenesis of human mesangial cells. Am. J. Physiol 264: F937 — F942.

    PubMed  CAS  Google Scholar 

  239. Ishimura, E., Shouji, S., Nishizawa, Y., Morii, H., and Kashgarian, M. (1991) Regulation of mRNA expression for extracellular matrix (ECM) by cultured rat mesangial cells (MCs). J. Am. Soc. Nephrol 2: 546 (abst.).

    Google Scholar 

  240. Gomez-Gaffe, D., Ruiz-Ortega, M., Ortego, M., Largo, R., Lopez-Armada, M. J., Plaza, J. J., Gonzalez, E., and Egido, J. (1996) Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension 27: 885–892.

    Article  Google Scholar 

  241. Zoja, C., Orisio, S., Perico, N., Benigni, A., Morigi, M., Benatti, L., Rambaldi, A., and Remuzzi, G. (1991) Constitutive expression of ET gene in cultured human mesangial cells and its modulation by transforming growth factor43, thrombin, and a thromboxane A2 analog. Lab. Invest 64: 16–20.

    PubMed  CAS  Google Scholar 

  242. Horie, M., Uchida, C., Yanagisawa, M., Matsushita, Y., Kurokawa, K., and Ogata, E. (1991) Mechanisms of ET-1 mRNA and peptides induction by TGF 3 and TPA in MDCK cells. J. Cardiovasc. Pharmacol 17 (Suppl. 7): S222 — S225.

    Article  PubMed  CAS  Google Scholar 

  243. Schulz, E., Ruschitzka, F., Lueders, S., Heydenbluth, R., Schrader, J., and Muller, G. A. (1995) Effects of endothelin on hemodynamics, Prostaglandins, blood coagulation and renal function. Kidney Int. 47: 795–801.

    Article  PubMed  CAS  Google Scholar 

  244. Brooks, D. P., Contino, L. C., Storer, B., and Ohlstein, E. H. (1991) Increased ET excretion in rats with renal failure induced by partial nephrectomy. Br. J. Pharmacol 104: 987–989.

    Article  PubMed  CAS  Google Scholar 

  245. Benigni, A., Perico, N., Gaspari, F., Zoja, C., Bellizzi, L., Gabanelli, M., and Remuzzi, G. (1991) Increased renal ET production in rats with reduced renal mass. Am. J. Physiol 260: F331 — F339.

    PubMed  CAS  Google Scholar 

  246. Morabito, E., Corsico, N., and Arrigoni-Martelli, E. (1994) Endothelins urinary excretion is increased in spontaneously diabetic rats: BB/BB. Life Sci. 25: PL 13–18.

    Google Scholar 

  247. Orisio, S., Benigni, A., Bruzzi, I., Corna, D., Perico, N., Zoja, C., Benatti, L., and Remuzzi, G. (1993) Renal ET gene expression is increased in remnant kidney and correlates with disease progression. Kidney Int. 43: 354–358.

    Google Scholar 

  248. Fukui, M., Nakamura, T., Ebihara, I., Osada, S., Tomino, Y., Masaki, T., Goto, K., Furuichi, Y., and Koide, H. (1993) Gene expression for ETs and their receptors in glomeruli of diabetic rats. J. Lab. Clin. Med 122: 149–156.

    Google Scholar 

  249. Nakamura, T., Ebihara, I., Fukui, M., Osada, S., Tamino, Y., Masaki, T., Goto, K., Furuichi, Y., and Koide, H. (1995) Modulation of glomerular endothelin and endothelin receptor gene expression in aminonucleosideinduced nephrosis. J. Am. Soc. Nephrol 5: 1585–1590.

    PubMed  CAS  Google Scholar 

  250. Nakamura, T., Ebihara, I., Fukui, M., Osada, S., Tomino, Y., Masaki, T., Goto, K., Furuichi, Y., and Koide, H. (1993) Increased ET and ET receptor mRNA expression in polycystic kidneys of cpk mice. J. Am. Soc. Nephrol 4: 1064–1072.

    PubMed  CAS  Google Scholar 

  251. Hocher, B., Liefeldt, L., Thone-Reineke, C., Orzechowski, H.-D., Distler, A., Bauer, C., and Paul, M. (1996) Characterization of the renal phenotype of transgenic rats expressing the human endothelin-2 gene. Hypertension 28: 196–201.

    Article  PubMed  CAS  Google Scholar 

  252. Benigni, A., Zoja, C., Corna, D., Orisio, S., Longaretti, L., Bertani, T., and Remuzzi, G. (1993) A specific ET subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int. 44: 440–444.

    Article  PubMed  CAS  Google Scholar 

  253. Nakamura, T., Ebihara, I., Tomino, Y., and Koide, H. (1995) Effect of a specific endothelin A receptor antagonist on murine lupus nephritis. Kidney Int. 47: 481–489.

    Article  PubMed  CAS  Google Scholar 

  254. Benigni, A., Zoja, C., Corna, D., Orisio, S., Facchinetti, D., Benatti, L., and Remuzzi, G. (1996) Blocking both type A and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney. Am. J. Kid. Dis 27: 416–423.

    Article  PubMed  CAS  Google Scholar 

  255. Nabokov, A., Amann, K., Wagner, J., Gehlen, F., Munter, K., and Ritz, E. (1996) Influence of specific and non-specific endothelin receptor antagonists on renal morphology in rats with surgical renal ablation. Nephrol. Dial. Transplant 11: 514–520.

    Article  PubMed  CAS  Google Scholar 

  256. Pollock, D. M. and Polakowski, J. S. (1997) ETA receptor blockade prevents hypertension associated with exogenous ET-1 but not renal mass reduction in the rat. J. Am. Soc. Nephrol 8: 1054–1060.

    PubMed  CAS  Google Scholar 

  257. Ohta, K., Hirata, Y., Shichiri, M., Ichioka, M., Kubota, T., and Marumo, F. (1991) Cisplatin-induced urinary ET excretion. JAMA 265: 1391, 1392.

    Google Scholar 

  258. Heyman, S. N., Clark, B. A., Kaiser, N., Epstein, F. H., Spokes, K., Rosen, S., and Brezis, M. (1992) In vivo and in vitro studies on the effect of amphotericin B on ET release. J. Antimicrob. Chemother 29: 69–77.

    Article  CAS  Google Scholar 

  259. Morise, Z., Ueda, M., Aiura, K., Endo, M., and Kitajima, M. (1994) Pathophysiologic role of endothelin-1 in renal function in rats with endotoxin shock. Surgery 115: 199–204.

    PubMed  CAS  Google Scholar 

  260. Kelleher, J. P., Shah, V., Godley, M. L., Wakefield, A. J., Gordon, I., Ransley, P. G., Snell, M. E., and Risdon, R. A. (1992) Urinary endothelin (ET1) in complete ureteric obstruction in the miniature pig. Urol. Res 20: 63–65.

    Article  PubMed  CAS  Google Scholar 

  261. Langenstroer, P., Tang, R., Shapiro, E., Divish, B., Opgenorth, T., and Lepor, H. (1993) Endothelin-1 in the human prostate: tissue levels, source of production and isometric tension studies. J. Urol 149: 495–499.

    Google Scholar 

  262. Rossi, G. P., Albertin, G., Franchin, E., Sacchetto, A., Cesari, M., Palu, G., and Pessina, A. C. (1995) Expression of the endothelin-converting enzyme gene in human tissues. Biochem. Biophys. Res. Commun 211: 249–253.

    Article  PubMed  CAS  Google Scholar 

  263. Kondo, S., Morita, T., and Tashima, Y. (1995) Benign prostatic hypertrophy affects the endothelin receptor density in the human urinary bladder and prostate. Urol. Int 54: 198–203.

    Article  PubMed  CAS  Google Scholar 

  264. Kobayashi, S., Tang, R., Wang, B., Opgenorth, T., Langenstoer, P., Shapiro, E., and Lepor, H. (1994) Binding and functional properties of endothelin receptor subtypes in the human prostate. Mol. Pharmacol 45: 306–311.

    PubMed  CAS  Google Scholar 

  265. Le Brun, G., Moldovan, F., Aubin, P., Ropiquet, F., Cussenot, O., and Fiet, J. (1996) Identification of endothelin receptors in normal and hyperplasic human prostate tissues. Prostate 28: 379–384.

    Article  PubMed  CAS  Google Scholar 

  266. Kondo, S., Morita, T., and Tashima, Y. (1994) Endothelin receptor density in human hypertrophic and non-hypertrophic prostate tissue. J. Exp. Med 172: 381–384.

    CAS  Google Scholar 

  267. Moriyama, N., Kurimoto, S., Miyata, N., Yamaura, H., Yamazaki, R., Sudoh, K., Inagaki, O., Takenaka, T., and Kawabe, K. (1996) Decreased contractile effect of endothelin-1 on hyperplastic prostate. Gen. Pharmacol 6: 1061–1065.

    Google Scholar 

  268. Kusuhara, M., Yamaguchi, K., Nagasaki, K., Hayashi, C., Suzaki, A., Hori, S., Handa, S., Nakamura, Y., and Abe, K. (1990) Production of endothelin in human cancer cell lines. Cancer Res. 50: 3257–3261.

    PubMed  CAS  Google Scholar 

  269. Giaid, A., Hamid, Q. A., Springall, D. R., Yanagisawa, M., Shinmi, O., Sawamura, T., Masaki, T., Kimura, S., Corrin, B., and Polak, J. M. (1990) Detection of endothelin immunoreactivity and mRNA in pulmonary tumors. J. Pathol 162: 15–22.

    Article  PubMed  CAS  Google Scholar 

  270. Shichiri, M., Hirata, Y., Nakajima, T., Ando, K., Imai, T., Yanagisawa, M., Masaki, T., and Marumo, F. (1991) Endothelin-1 is an autocrine/ paracrine growth factor for human cancer cell lines. J. Clin. Invest 87: 1867–1871.

    Article  PubMed  CAS  Google Scholar 

  271. Oikawa, T., Kushuhara, M., Ishikawa, S., Hitomi, J., Kono, A., Iwanaga, T., and Yamaguchi, K. (1994) Production of endothelin-1 and thrombomodulin by human pancreatic cancer cells. Br. J. Cancer 69: 1059–1064.

    Article  PubMed  CAS  Google Scholar 

  272. Patel, K. V. and Schrey, M. P. (1995) Human breast cancer cells contain a phosphoramidon-sensitive metalloproteinase which can process exogenous big endothelin-1 to endothelin-1: a proposed mitogen for human breast fibroblasts. Br. J. Cancer 71: 442–447.

    Article  PubMed  CAS  Google Scholar 

  273. Nakamuta, M., Ohashi, M., Tabata, S., Tanabe, Y., Goto, K., Naruse, M., Naruse, K., Hiroshe, K., and Nawata, H. (1993) High plasma concentration of endothelin-like immunoreactivities in patients with hepatocellular carcinoma. Am. J. Gastroenterol 88: 248–252.

    PubMed  CAS  Google Scholar 

  274. Economos, K., MacDonald, P. C., and Casey, M. L. (1992) Endothelin-1 gene expression and biosynthesis in human endometrial HEC-1A cancer cells. Cancer Res. 52: 554–557.

    PubMed  CAS  Google Scholar 

  275. Inagaki, H., Bishop, A. E., Eimoto, T., and Polak, J. M. (1992) Autoradiographic localization of endothelin-1 binding sites in human colonic cancer tissue. J. Pathol 168: 263–267.

    Article  PubMed  CAS  Google Scholar 

  276. Nelson, J. B., Chan-Tack, K., Hedican, S. P., Magnuson, S. R., Opgenorth, T. J., Bova, G. S., and Simons, J. W. (1996) Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res. 56: 663–668.

    PubMed  CAS  Google Scholar 

  277. Takuwa, Y., Masaki, T., and Yamashita, K. (1990) The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae. Biochem. Biophys. Res. Commun 170: 998–1005.

    Article  PubMed  CAS  Google Scholar 

  278. Nelson, J. B., Hedican, S. P., George, D. J., Reddi, A. H., Piantadosi, S., Eisenberger, M. A., and Simons, J. W. (1995) Identification of endothelin1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature 1:944–949.

    Google Scholar 

  279. Oliver, F. J., de la Rubia, G., Feener, E. P., Lee, M. E., Loeken, M. R., Shiba, T., Quertermous, T., and King, G. L. (1991) Stimulation of endothelin-1 gene expression by insulin in endothelial cells. J. Biol. Chem 266: 23251–23256.

    PubMed  CAS  Google Scholar 

  280. Takahashi, K., Ghatei, M. A., Lam, H.-C., O’Halloran, D. J., and Bloom, S. R. (1990) Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 33: 306–310.

    Article  PubMed  CAS  Google Scholar 

  281. Totsune, K., Sone, M., Takahashi, K., Ohneda, M., Itoi, K., Murakami, O., Saito, T., Mouri, T., and Yoshinaga, K. (1991) Immunoreactive endothelin in urine of patients with and without diabetes mellitus. J. Cardiovasc. Pharmacol. 17(Suppl. 7 ): 5423–5424.

    Google Scholar 

  282. Nugent, A. G., McGurk, C., Hayes, J. R., and Johnston, G. D. (1996) Impaired vasoconstriction to endothelin-1 in patients with NIDDM. Diabetes 45: 105–107.

    Article  PubMed  CAS  Google Scholar 

  283. Kawamura, M., Ohgawara, H., Naruse, M., Suzuki, N., Iwasaki, N., Naruse, K., Hori, S., Demura, H., and Omori, Y. (1992) Increased plasma endothelin in NIDDM patients with retinopathy. Diabetes Care 15: 1396, 1397.

    Google Scholar 

  284. Kaiser, H. J., Flammer, J., Wenk, M., and Luscher, T. (1995) Endothelin1 plasma levels in normal-tension glaucoma: abnormal response to postural changes. Graefes. Arch. Clin. Exp. Ophthalmol 233: 484–488.

    Article  PubMed  CAS  Google Scholar 

  285. Kawaguchi, Y., Suzuki, K., Hara, M., Hidaka, T., Ishizuka, T., Kawagoe, M., and Nakamura, H. (1994) Increased endothelin-1 production in fibroblasts derived from patients with systemic sclerosis. Ann. Rheum. Dis 53: 506–510.

    Article  PubMed  CAS  Google Scholar 

  286. Watschinger, B., Vychytil, A., Schuller, M., Hartter, E., and Traindl, O. (1991) The pathophysiologic role of ET in acute vascular rejection after renal transplantation. Transplantation 52: 743–746.

    Article  PubMed  CAS  Google Scholar 

  287. Wallace, J. L., Cirino, G., De Nucci, G., McKnight, W., and MacNaughton, W. K. (1989) Endothelin has potent ulcerogenic and vasoconstrictor actions in the stomach. Am. J. Physiol 256: G661 — G666.

    Google Scholar 

  288. Murch, S. H., Braegger, C. P., Sessa, W. C., and MacDonald, T. T. (1992) High endothelin-1 immunoreactivity in Crohn’s disease and ulcerative colitis. Lancet 339: 381–385.

    Google Scholar 

  289. Rachmilewitz, D., Eliakim, R., Ackerman, Z., and Karmeli, F. (1992) Colonic endothelin-1 immunoreactivity in active ulcerative colitis. Lancet 339: 1062.

    Article  PubMed  CAS  Google Scholar 

  290. Hosoda, K., Hammer, R. E., Richardson, J. A., Greenstein Baynash, A., Cheung, J. C., Giaid, A., and Yanagisawa, M. (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79: 1267–1276.

    Article  PubMed  CAS  Google Scholar 

  291. Baynash, A. G., Hosoda, K., Giaid, A., Richardson, J. A., Emotom, N., Hammer, R. E., and Yanagisawa, M. (1994) Interaction of endothelin-3 with endothelin B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79: 1277–1285.

    Article  PubMed  CAS  Google Scholar 

  292. Hofstra, R. M., Osinga, J., Tan Sindhunata, G., Wu, Y., Kamsteeg, E. J., Stulp, R. P., van Ravenswaaij, A. C., Majoor Krakauer, D., Angrist, M., Chakravarti, A., Meijers, C., and Buys, C. H. (1996) A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat. Genet 12: 445–447.

    Article  PubMed  CAS  Google Scholar 

  293. Edery, P., Attie, T., Amiel, J., Pelet, A., Eng, C., Hofstra, R. M., Martelli, H., Bidaud, C., Munnich, A., and Lyonnet, S. (1996) Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (ShahWaardenburg syndrome). Nat. Genet 12: 442–444.

    Article  PubMed  CAS  Google Scholar 

  294. Tsuboi, R., Sato, C., Shi, C.-M., Nakamura, T., Sakurai, T., and Ogawa, H. (1994) Endothelin-1 acts as an autocrine growth factor for normal human keratinocytes. J. Cell Physiol 159: 213–220.

    Article  PubMed  CAS  Google Scholar 

  295. Bagnato, A., Venuti, A., DiCastro, V., and Marcante, M. L. (1995) Identification of the ETA receptor subtype that mediates endothelin induced autocrine proliferation of normal human keratinocytes. Biochem. Biophys. Res. Commun 209: 80–86.

    Article  PubMed  CAS  Google Scholar 

  296. Zachariae, H., Heickendorff, L., and Bjerring, P. (1996) Plasma endothelin in psoriasis—possible relations to therapy and toxicity. Acta. Dermatol. Venereol 76: 442, 443.

    Google Scholar 

  297. Teraki, E., Tajima, S., Manaka, I., Kawashima, M., Miyagishi, M., and Imokawa, G. (1996) Role of endothelin-1 in hyperpigmentation in seborrheic keratosis. Br. J. Dermatol 96: 918–923.

    Article  Google Scholar 

  298. Kurihara, Y., Kurihara, H., Suzuki, H., Kodama, T., Maemura, K., Nagai, R., Oda, H., Kuwaki, T., Cao, W.-H., Kamada, N., Jishage, K., Ouchi, Y., Azuma, S., Toyoda, Y., Ishikawa, T., Kumada, M., and Yazaki, Y. (1994) Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368: 703–710.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. David P. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diane K. Jorkasky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin I. Freed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eliot H. Ohlstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Robert F. Highsmith

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Brooks, D.P., Jorkasky, D.K., Freed, M.I., Ohlstein, E.H. (1998). Pathophysiological Role of Endothelin and Potential Therapeutic Targets for Receptor Antagonists. In: Highsmith, R.F. (eds) Endothelin. Contemporary Biomedicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4757-2783-8_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-4757-2783-8_8

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-035-9

  • Online ISBN: 978-1-4757-2783-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation