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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1992;34(Suppl 1):37S–42S. doi: 10.1111/j.1365-2125.1992.tb04147.x

Clinical relevance of endothelium-derived relaxing factor (EDRF)

E Bassenge
PMCID: PMC1381221  PMID: 1633078

Abstract

1 In addition to metabolic and neurohumoral factors endothelium-derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L-arginine by a Ca2+/calmodulin-dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium-dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L-arginine supplementation is effective in a few instances.

Keywords: endothelium-derived relaxing factor, nitric oxide

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Selected References

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  1. Aoki N., Bitterman H., Brezinski M. E., Lefer A. M. Cardioprotective actions of human superoxide dismutase in two reperfusion models of myocardial ischaemia in the rat. Br J Pharmacol. 1988 Nov;95(3):735–740. doi: 10.1111/j.1476-5381.1988.tb11699.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bassenge E., Busse R., Pohl U. Hemmung der Thrombozytenaggregation und -adhäsion durch EDRF und deren pathophysiologische Bedeutung. Z Kardiol. 1989;78 (Suppl 6):54–58. [PubMed] [Google Scholar]
  3. Bassenge E. Endothelium-mediated regulation of coronary tone. Basic Res Cardiol. 1991;86 (Suppl 2):69–76. doi: 10.1007/978-3-642-72461-9_8. [DOI] [PubMed] [Google Scholar]
  4. Bassenge E. Flow-dependent regulation of coronary vasomotor tone. Eur Heart J. 1989 Nov;10 (Suppl F):22–27. doi: 10.1093/eurheartj/10.suppl_f.22. [DOI] [PubMed] [Google Scholar]
  5. Bassenge E., Heusch G. Endothelial and neuro-humoral control of coronary blood flow in health and disease. Rev Physiol Biochem Pharmacol. 1990;116:77–165. doi: 10.1007/3540528806_4. [DOI] [PubMed] [Google Scholar]
  6. Bassenge E., Stewart D. J. Interdependence of pharmacologically-induced and endothelium-mediated coronary vasodilation in antianginal therapy. Cardiovasc Drugs Ther. 1988 May;2(1):27–34. doi: 10.1007/BF00054249. [DOI] [PubMed] [Google Scholar]
  7. Bohn H., Beyerle R., Martorana P. A., Schönafinger K. CAS 936, a novel syndnonimine with direct vasodilating and nitric oxide-donating properties: effects on isolated blood vessels. J Cardiovasc Pharmacol. 1991 Oct;18(4):522–527. doi: 10.1097/00005344-199110000-00007. [DOI] [PubMed] [Google Scholar]
  8. Bredt D. S., Hwang P. M., Glatt C. E., Lowenstein C., Reed R. R., Snyder S. H. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 1991 Jun 27;351(6329):714–718. doi: 10.1038/351714a0. [DOI] [PubMed] [Google Scholar]
  9. Bredt D. S., Hwang P. M., Snyder S. H. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990 Oct 25;347(6295):768–770. doi: 10.1038/347768a0. [DOI] [PubMed] [Google Scholar]
  10. Busse R., Lückhoff A., Bassenge E. Endothelium-derived relaxant factor inhibits platelet activation. Naunyn Schmiedebergs Arch Pharmacol. 1987 Nov;336(5):566–571. doi: 10.1007/BF00169315. [DOI] [PubMed] [Google Scholar]
  11. Busse R., Mülsch A. Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett. 1990 Jun 4;265(1-2):133–136. doi: 10.1016/0014-5793(90)80902-u. [DOI] [PubMed] [Google Scholar]
  12. Busse R., Mülsch A. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett. 1990 Nov 26;275(1-2):87–90. doi: 10.1016/0014-5793(90)81445-t. [DOI] [PubMed] [Google Scholar]
  13. Busse R., Pohl U., Mülsch A., Bassenge E. Modulation of the vasodilator action of SIN-1 by the endothelium. J Cardiovasc Pharmacol. 1989;14 (Suppl 11):S81–S85. doi: 10.1097/00005344-198906152-00015. [DOI] [PubMed] [Google Scholar]
  14. Chesebro J. H., Fuster V., Webster M. W. Endothelial injury and coronary vasomotion. J Am Coll Cardiol. 1989 Nov 1;14(5):1191–1192. doi: 10.1016/0735-1097(89)90415-4. [DOI] [PubMed] [Google Scholar]
  15. Creager M. A., Cooke J. P., Mendelsohn M. E., Gallagher S. J., Coleman S. M., Loscalzo J., Dzau V. J. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990 Jul;86(1):228–234. doi: 10.1172/JCI114688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Drexler H., Zeiher A. M., Meinzer K., Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991 Dec 21;338(8782-8783):1546–1550. doi: 10.1016/0140-6736(91)92372-9. [DOI] [PubMed] [Google Scholar]
  17. Feelisch M., Noack E. A. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol. 1987 Jul 2;139(1):19–30. doi: 10.1016/0014-2999(87)90493-6. [DOI] [PubMed] [Google Scholar]
  18. Fischell T. A., Nellessen U., Johnson D. E., Ginsburg R. Endothelium-dependent arterial vasoconstriction after balloon angioplasty. Circulation. 1989 Apr;79(4):899–910. doi: 10.1161/01.cir.79.4.899. [DOI] [PubMed] [Google Scholar]
  19. Förstermann U., Schmidt H. H., Pollock J. S., Sheng H., Mitchell J. A., Warner T. D., Nakane M., Murad F. Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem Pharmacol. 1991 Oct 24;42(10):1849–1857. doi: 10.1016/0006-2952(91)90581-o. [DOI] [PubMed] [Google Scholar]
  20. Garthwaite J., Charles S. L., Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988 Nov 24;336(6197):385–388. doi: 10.1038/336385a0. [DOI] [PubMed] [Google Scholar]
  21. Harrison D. G., Armstrong M. L., Freiman P. C., Heistad D. D. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest. 1987 Dec;80(6):1808–1811. doi: 10.1172/JCI113276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Heistad D. D., Armstrong M. L., Marcus M. L., Piegors D. J., Mark A. L. Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys. Circ Res. 1984 Jun;54(6):711–718. doi: 10.1161/01.res.54.6.711. [DOI] [PubMed] [Google Scholar]
  23. Hongo K., Kassell N. F., Nakagomi T., Sasaki T., Tsukahara T., Ogawa H., Vollmer D. G., Lehman R. M. Subarachnoid hemorrhage inhibition of endothelium-derived relaxing factor in rabbit basilar artery. J Neurosurg. 1988 Aug;69(2):247–253. doi: 10.3171/jns.1988.69.2.0247. [DOI] [PubMed] [Google Scholar]
  24. Katz R. J., Levy W. S., Buff L., Wasserman A. G. Prevention of nitrate tolerance with angiotension converting enzyme inhibitors. Circulation. 1991 Apr;83(4):1271–1277. doi: 10.1161/01.cir.83.4.1271. [DOI] [PubMed] [Google Scholar]
  25. Lamping K. G., Dole W. P. Acute hypertension selectively potentiates constrictor responses of large coronary arteries to serotonin by altering endothelial function in vivo. Circ Res. 1987 Dec;61(6):904–913. doi: 10.1161/01.res.61.6.904. [DOI] [PubMed] [Google Scholar]
  26. Lefer A. M., Lefer D. J. Endothelial dysfunction in myocardial ischemia and reperfusion: role of oxygen-derived free radicals. Basic Res Cardiol. 1991;86 (Suppl 2):109–116. doi: 10.1007/978-3-642-72461-9_12. [DOI] [PubMed] [Google Scholar]
  27. Linder L., Kiowski W., Bühler F. R., Lüscher T. F. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation. 1990 Jun;81(6):1762–1767. doi: 10.1161/01.cir.81.6.1762. [DOI] [PubMed] [Google Scholar]
  28. Lüscher T. F., Raij L., Vanhoutte P. M. Endothelium-dependent vascular responses in normotensive and hypertensive Dahl rats. Hypertension. 1987 Feb;9(2):157–163. doi: 10.1161/01.hyp.9.2.157. [DOI] [PubMed] [Google Scholar]
  29. Lüscher T. F., Vanhoutte P. M., Raij L. Antihypertensive treatment normalizes decreased endothelium-dependent relaxations in rats with salt-induced hypertension. Hypertension. 1987 Jun;9(6 Pt 2):III193–III197. doi: 10.1161/01.hyp.9.6_pt_2.iii193. [DOI] [PubMed] [Google Scholar]
  30. McDonald B. J., Bennett B. M. Cytochrome P-450 mediated biotransformation of organic nitrates. Can J Physiol Pharmacol. 1990 Dec;68(12):1552–1557. doi: 10.1139/y90-236. [DOI] [PubMed] [Google Scholar]
  31. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  32. Nagasawa K., Tomoike H., Hayashi Y., Yamada A., Yamamoto T., Nakamura M. Intramural hemorrhage and endothelial changes in atherosclerotic coronary artery after repetitive episodes of spasm in x-ray-irradiated hypercholesterolemic pigs. Circ Res. 1989 Aug;65(2):272–282. doi: 10.1161/01.res.65.2.272. [DOI] [PubMed] [Google Scholar]
  33. Nakagomi T., Kassell N. F., Sasaki T., Fujiwara S., Lehman R. M., Johshita H., Nazar G. B., Torner J. C. Effect of subarachnoid hemorrhage on endothelium-dependent vasodilation. J Neurosurg. 1987 Jun;66(6):915–923. doi: 10.3171/jns.1987.66.6.0915. [DOI] [PubMed] [Google Scholar]
  34. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  35. Panza J. A., Quyyumi A. A., Brush J. E., Jr, Epstein S. E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990 Jul 5;323(1):22–27. doi: 10.1056/NEJM199007053230105. [DOI] [PubMed] [Google Scholar]
  36. Radomski M. W., Palmer R. M., Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci U S A. 1990 Dec;87(24):10043–10047. doi: 10.1073/pnas.87.24.10043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rafflenbeul W., Bassenge E., Lichtlen P. Konkurrenz zwischen endothelabhängiger und Nitroglygerin-induzierter koronarer Vasodilatation [Competition between endothelium-dependent and nitroglycerin-induced coronary vasodilation]. Z Kardiol. 1989;78 (Suppl 2):45–67. [PubMed] [Google Scholar]
  38. Rees D. D., Palmer R. M., Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989 May;86(9):3375–3378. doi: 10.1073/pnas.86.9.3375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Saenz de Tejada I., Goldstein I., Azadzoi K., Krane R. J., Cohen R. A. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med. 1989 Apr 20;320(16):1025–1030. doi: 10.1056/NEJM198904203201601. [DOI] [PubMed] [Google Scholar]
  40. Servent D., Delaforge M., Ducrocq C., Mansuy D., Lenfant M. Nitric oxide formation during microsomal hepatic denitration of glyceryl trinitrate: involvement of cytochrome P-450. Biochem Biophys Res Commun. 1989 Sep 29;163(3):1210–1216. doi: 10.1016/0006-291x(89)91106-6. [DOI] [PubMed] [Google Scholar]
  41. Shimokawa H., Aarhus L. L., Vanhoutte P. M. Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin. Circ Res. 1987 Aug;61(2):256–270. doi: 10.1161/01.res.61.2.256. [DOI] [PubMed] [Google Scholar]
  42. Shimokawa H., Vanhoutte P. M. Dietary omega 3 fatty acids and endothelium-dependent relaxations in porcine coronary arteries. Am J Physiol. 1989 Apr;256(4 Pt 2):H968–H973. doi: 10.1152/ajpheart.1989.256.4.H968. [DOI] [PubMed] [Google Scholar]
  43. Shimokawa H., Vanhoutte P. M. Impaired endothelium-dependent relaxation to aggregating platelets and related vasoactive substances in porcine coronary arteries in hypercholesterolemia and atherosclerosis. Circ Res. 1989 May;64(5):900–914. doi: 10.1161/01.res.64.5.900. [DOI] [PubMed] [Google Scholar]
  44. Stewart D. J., Elsner D., Sommer O., Holtz J., Bassenge E. Altered spectrum of nitroglycerin action in long-term treatment: nitroglycerin-specific venous tolerance with maintenance of arterial vasodepressor potency. Circulation. 1986 Sep;74(3):573–582. doi: 10.1161/01.cir.74.3.573. [DOI] [PubMed] [Google Scholar]
  45. Stewart D. J., Holtz J., Bassenge E. Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. Circulation. 1987 Apr;75(4):847–856. doi: 10.1161/01.cir.75.4.847. [DOI] [PubMed] [Google Scholar]
  46. Stewart D. J., Pohl U., Bassenge E. Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed. Am J Physiol. 1988 Oct;255(4 Pt 2):H765–H769. doi: 10.1152/ajpheart.1988.255.4.H765. [DOI] [PubMed] [Google Scholar]
  47. Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989 Oct 28;2(8670):997–1000. doi: 10.1016/s0140-6736(89)91013-1. [DOI] [PubMed] [Google Scholar]
  48. Zeiher A. M., Drexler H., Wollschlaeger H., Saurbier B., Just H. Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium. J Am Coll Cardiol. 1989 Nov 1;14(5):1181–1190. doi: 10.1016/0735-1097(89)90414-2. [DOI] [PubMed] [Google Scholar]
  49. Zeiher A. M., Drexler H., Wollschläger H., Just H. Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. Circulation. 1991 Nov;84(5):1984–1992. doi: 10.1161/01.cir.84.5.1984. [DOI] [PubMed] [Google Scholar]
  50. Zeiher A. M., Drexler H., Wollschläger H., Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991 Feb;83(2):391–401. doi: 10.1161/01.cir.83.2.391. [DOI] [PubMed] [Google Scholar]

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