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. 1988 Nov;82(5):1495–1502. doi: 10.1172/JCI113757

Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation.

V L Brashers 1, M J Peach 1, C E Rose Jr 1
PMCID: PMC442714  PMID: 3263394

Abstract

The role of the endothelium in hypoxic constriction of the intact pulmonary vascular bed has not been clearly elucidated. To test for a possible role for endothelium-derived relaxing factor(s) (EDRF) in the hypoxic pressor response, isolated, whole blood-perfused rat lungs from male Sprague-Dawley rats treated with meclofenamate were prepared. Three protocols were performed, including: (a) normal saline (control); (b) the putative EDRF inhibitors, eicosatetraynoic acid (ETYA, 1 X 10(-4) M) or nordihydroguaiaretic acid (NDGA, 1 X 10(-4) M) versus vehicle DMSO; and (c) the putative EDRF inhibitor hydroquinone (HQ, 1 X 10(-4) M) versus vehicle ethyl alcohol (ETOH). The pulmonary pressor response to angiotensin II (Ang II, 0.25 micrograms) injections alternated with 6-min periods of hypoxic ventilation (3% O2, 5% CO2) was measured before and after the administration of saline, inhibitors, or vehicles. The administration of the EDRF inhibitors ETYA, NDGA, and HQ resulted in a marked accentuation of the hypoxic pressor response that was not seen in the controls (P less than 0.05). In separate experiments, lungs precontracted with norepinephrine (1 X 10(-6) M) were pretreated with edrophonium (1 X 10(-4) M) and then observed for endothelium-dependent vasodilator responses to acetylcholine at increasing doses (1 X 10(-7)-1 X 10(-4) M). Administration of ETYA, NDGA, or HQ abrogated the observed vasodilatation to acetylcholine, which was not seen with vehicles alone (P less than 0.01). These studies suggest an important role for the endothelium in pulmonary vascular responsiveness to alveolar hypoxia through possible release of a relaxing factor(s) that attenuates the degree of pulmonary arterial constriction.

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Selected References

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  1. Ahern D. G., Downing D. T. Inhibition of prostaglandin biosynthesis by eicosa-5,8,11,14-tetraynoic acid. Biochim Biophys Acta. 1970 Sep 8;210(3):456–461. doi: 10.1016/0005-2760(70)90042-1. [DOI] [PubMed] [Google Scholar]
  2. Bergofsky E. H., Holtzman S. A study of the mechanisms involved in the pulmonary arterial pressor response to hypoxia. Circ Res. 1967 May;20(5):506–519. doi: 10.1161/01.res.20.5.506. [DOI] [PubMed] [Google Scholar]
  3. Chand N., Altura B. M. Acetylcholine and bradykinin relax intrapulmonary arteries by acting on endothelial cells: role in lung vascular diseases. Science. 1981 Sep 18;213(4514):1376–1379. doi: 10.1126/science.7268440. [DOI] [PubMed] [Google Scholar]
  4. Cherry P. D., Gillis C. N. Evidence for the role of endothelium-derived relaxing factor in acetylcholine-induced vasodilatation in the intact lung. J Pharmacol Exp Ther. 1987 May;241(2):516–520. [PubMed] [Google Scholar]
  5. DUFF F., GREENFIELD A. D., SHEPHERD J. T., THOMPSON I. D. A quantitative study of the response to acetylcholine and histamine of the blood vessels of the human hand and forearm. J Physiol. 1953 Apr 28;120(1-2):160–170. doi: 10.1113/jphysiol.1953.sp004883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. De Mey J. G., Vanhoutte P. M. Contribution of the endothelium to the response to anoxia in the canine femoral artery. Arch Int Pharmacodyn Ther. 1981 Oct;253(2):325–326. [PubMed] [Google Scholar]
  7. De Mey J. G., Vanhoutte P. M. Heterogeneous behavior of the canine arterial and venous wall. Importance of the endothelium. Circ Res. 1982 Oct;51(4):439–447. doi: 10.1161/01.res.51.4.439. [DOI] [PubMed] [Google Scholar]
  8. Feddersen C. O., Mathias M. M., McMurtry I. F., Voelkel N. F. Acetylcholine induces vasodilation and prostacyclin synthesis in rat lungs. Prostaglandins. 1986 May;31(5):973–987. doi: 10.1016/0090-6980(86)90027-4. [DOI] [PubMed] [Google Scholar]
  9. Fishman A. P. Hypoxia on the pulmonary circulation. How and where it acts. Circ Res. 1976 Apr;38(4):221–231. doi: 10.1161/01.res.38.4.221. [DOI] [PubMed] [Google Scholar]
  10. Furchgott R. F. The role of endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol. 1984;24:175–197. doi: 10.1146/annurev.pa.24.040184.001135. [DOI] [PubMed] [Google Scholar]
  11. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  12. Förstermann U., Neufang B. The endothelium-dependent relaxation of rabbit aorta: effects of antioxidants and hydroxylated eicosatetraenoic acids. Br J Pharmacol. 1984 Aug;82(4):765–767. doi: 10.1111/j.1476-5381.1984.tb16472.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Förstermann U., Neufang B. The endothelium-dependent vasodilator effect of acetylcholine: characterization of the endothelial relaxing factor with inhibitors of arachidonic acid metabolism. Eur J Pharmacol. 1984 Aug 3;103(1-2):65–70. doi: 10.1016/0014-2999(84)90190-0. [DOI] [PubMed] [Google Scholar]
  14. Garrett R. C., Foster S., Thomas H. M., 3rd Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction. J Appl Physiol (1985) 1987 Jan;62(1):129–133. doi: 10.1152/jappl.1987.62.1.129. [DOI] [PubMed] [Google Scholar]
  15. Griffith T. M., Edwards D. H., Lewis M. J., Newby A. C., Henderson A. H. The nature of endothelium-derived vascular relaxant factor. Nature. 1984 Apr 12;308(5960):645–647. doi: 10.1038/308645a0. [DOI] [PubMed] [Google Scholar]
  16. Gruetter C. A., Ryan E. T., Schoepp D. D. Endothelium enhances tachyphylaxis to angiotensins II and III in rat aorta. Eur J Pharmacol. 1987 Nov 3;143(1):139–142. doi: 10.1016/0014-2999(87)90745-x. [DOI] [PubMed] [Google Scholar]
  17. Hauge A. Role of histamine in hypoxic pulmonary hypertension in the rat. I. Blockade or potentiation of endogenous amines, kinins, and ATP. Circ Res. 1968 Mar;22(3):371–383. doi: 10.1161/01.res.22.3.371. [DOI] [PubMed] [Google Scholar]
  18. Hickey K. A., Rubanyi G., Paul R. J., Highsmith R. F. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985 May;248(5 Pt 1):C550–C556. doi: 10.1152/ajpcell.1985.248.5.C550. [DOI] [PubMed] [Google Scholar]
  19. Holden W. E., McCall E. Hypoxia-induced contractions of porcine pulmonary artery strips depend on intact endothelium. Exp Lung Res. 1984;7(2):101–112. doi: 10.3109/01902148409069671. [DOI] [PubMed] [Google Scholar]
  20. Ignarro L. J., Burke T. M., Wood K. S., Wolin M. S., Kadowitz P. J. Association between cyclic GMP accumulation and acetylcholine-elicited relaxation of bovine intrapulmonary artery. J Pharmacol Exp Ther. 1984 Mar;228(3):682–690. [PubMed] [Google Scholar]
  21. McMurtry I. F. BAY K 8644 potentiates and A23187 inhibits hypoxic vasoconstriction in rat lungs. Am J Physiol. 1985 Oct;249(4 Pt 2):H741–H746. doi: 10.1152/ajpheart.1985.249.4.H741. [DOI] [PubMed] [Google Scholar]
  22. McMurtry I. F., Davidson A. B., Reeves J. T., Grover R. F. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res. 1976 Feb;38(2):99–104. doi: 10.1161/01.res.38.2.99. [DOI] [PubMed] [Google Scholar]
  23. Miller M. A., Hales C. A. Role of cytochrome P-450 in alveolar hypoxic pulmonary vasoconstriction in dogs. J Clin Invest. 1979 Aug;64(2):666–673. doi: 10.1172/JCI109507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morganroth M. L., Reeves J. T., Murphy R. C., Voelkel N. F. Leukotriene synthesis and receptor blockers block hypoxic pulmonary vasoconstriction. J Appl Physiol Respir Environ Exerc Physiol. 1984 May;56(5):1340–1346. doi: 10.1152/jappl.1984.56.5.1340. [DOI] [PubMed] [Google Scholar]
  25. Peach M. J., Loeb A. L., Singer H. A., Saye J. Endothelium-derived vascular relaxing factor. Hypertension. 1985 May-Jun;7(3 Pt 2):I94–100. doi: 10.1161/01.hyp.7.3_pt_2.i94. [DOI] [PubMed] [Google Scholar]
  26. Peach M. J., Singer H. A., Loeb A. L. Mechanisms of endothelium-dependent vascular smooth muscle relaxation. Biochem Pharmacol. 1985 Jun 1;34(11):1867–1874. doi: 10.1016/0006-2952(85)90300-4. [DOI] [PubMed] [Google Scholar]
  27. Rounds S., McMurtry I. F. Inhibitors of oxidative ATP production cause transient vasoconstriction and block subsequent pressor responses in rat lungs. Circ Res. 1981 Mar;48(3):393–400. doi: 10.1161/01.res.48.3.393. [DOI] [PubMed] [Google Scholar]
  28. Rubanyi G. M., Vanhoutte P. M. Hypoxia releases a vasoconstrictor substance from the canine vascular endothelium. J Physiol. 1985 Jul;364:45–56. doi: 10.1113/jphysiol.1985.sp015728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Singer H. A., Peach M. J. Endothelium-dependent relaxation of rabbit aorta. I. Relaxation stimulated by arachidonic acid. J Pharmacol Exp Ther. 1983 Sep;226(3):790–795. [PubMed] [Google Scholar]
  30. Singer H. A., Peach M. J. Endothelium-dependent relaxation of rabbit aorta. II. Inhibition of relaxation stimulated by methacholine and A23187 with antagonists of arachidonic acid metabolism. J Pharmacol Exp Ther. 1983 Sep;226(3):796–801. [PubMed] [Google Scholar]
  31. Thompson B., Barer G. R., Shaw J. W. The action of histamine on pulmonary vessels of cats and rats. Clin Exp Pharmacol Physiol. 1976 Sep-Oct;3(5):399–414. doi: 10.1111/j.1440-1681.1976.tb00618.x. [DOI] [PubMed] [Google Scholar]
  32. Vanhoutte P. M. Vascular physiology: the end of the quest? Nature. 1987 Jun 11;327(6122):459–460. doi: 10.1038/327459a0. [DOI] [PubMed] [Google Scholar]
  33. Voelkel N. F., Gerber J. G., McMurtry I. F., Nies A. S., Reeves J. T. Release of vasodilator prostaglandin, PGI2, from isolated rat lung during vasoconstriction. Circ Res. 1981 Feb;48(2):207–213. doi: 10.1161/01.res.48.2.207. [DOI] [PubMed] [Google Scholar]
  34. Voelkel N. F., Morganroth M., Feddersen O. C. Potential role of arachidonic acid metabolites in hypoxic pulmonary vasoconstriction. Chest. 1985 Oct;88(4 Suppl):245S–248S. doi: 10.1378/chest.88.4_supplement.245s. [DOI] [PubMed] [Google Scholar]
  35. Yilmaz G., Aksulu H. E., Demirel E., Ercan Z. S., Zengil H., Türker R. K. Modulation by endothelium of the vascular effects of angiotensin II. Agents Actions. 1987 Jun;21(1-2):184–190. doi: 10.1007/BF01974940. [DOI] [PubMed] [Google Scholar]

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