Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1979 Aug;64(2):666–673. doi: 10.1172/JCI109507

Role of Cytochrome P-450 in Alveolar Hypoxic Pulmonary Vasoconstriction in Dogs

Matthew A Miller 1,2, Charles A Hales 1,2
PMCID: PMC372164  PMID: 457876

Abstract

Alveolar hypoxia induces pulmonary vasoconstriction by an unknown mechanism. Cytochrome P-450 (C-P450) is found in the lung and may modify pulmonary vascular tone via its sensitivity to changes in oxygen tension or by affecting metabolism of a chemical mediator. Metyrapone and carbon monoxide are both inhibitors of C-P450. We tested alveolar hypoxic pulmonary vasoconstriction (AHPV) in 20 dogs before, during, and after separate administration of each inhibitor. Anesthetized dogs were ventilated through a double lumen endotracheal tube allowing ventilation of one lung with N2 or CO as a hypoxic challenge and ventilation of the other lung with O2 to maintain adequate systemic oxygenation. Distribution of lung perfusion was determined with intravenous 133Xenon and external chest detectors. Before infusion of metyrapone, mean perfusion to the test lung decreased 30% with alveolar hypoxic challenge, but decreased only 10% during metyrapone infusion and returned to a base-line mean decrease of 31% after completion of metyrapone infusion. Prostaglandin F2 α and angiotensin II infusions produced equivalent increases in pulmonary vascular resistance before and during metyrapone infusion. Before CO, mean test lung perfusion decreased 31% with alveolar hypoxia but was reduced only 10% from control when unilateral end-tidal CO% was >75%. Washout of alveolar CO with unilateral N2 ventilation restored AHPV, with perfusion decreasing 29% from control. Thus, both metyrapone and carbon monoxide can reversibly inhibit AHPV. C-P450 may, therefore, be involved in the transduction process of the vasoconstrictor response to alveolar hypoxia.

Full text

PDF
666

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BALL E. G., STRITTMATTER C. F., COOPER O. The reaction of cytochrome oxidase with carbon monoxide. J Biol Chem. 1951 Dec;193(2):635–647. [PubMed] [Google Scholar]
  2. Bergofsky E. H. Mechanisms underlying vasomotor regulation of regional pulmonary blood flow in normal and disease states. Am J Med. 1974 Sep;57(3):378–394. doi: 10.1016/0002-9343(74)90133-8. [DOI] [PubMed] [Google Scholar]
  3. CHART J. J., SHEPPARD H., ALLEN M. J., BENCZE W. L., GAUNT R. New amphenone analogs as adrenocortical inhibitors. Experientia. 1958 Apr 15;14(4):151–152. doi: 10.1007/BF02157133. [DOI] [PubMed] [Google Scholar]
  4. Coburn R. F. Oxygen tension sensors in vascular smooth muscle. Adv Exp Med Biol. 1977;78:101–115. doi: 10.1007/978-1-4615-9035-4_7. [DOI] [PubMed] [Google Scholar]
  5. DOMINGUEZ O. V., SAMUELS L. T. MECHANISM OF INHIBITION OF ADRENAL STEROID 11BETA-HYDROXYLASE BY METHOPYRAPONE (METOPIRONE). Endocrinology. 1963 Sep;73:304–309. doi: 10.1210/endo-73-3-304. [DOI] [PubMed] [Google Scholar]
  6. DUKE H. N., KILLICK E. M. Pulmonary vasomotor responses of isolated perfused cat lungs to anoxia. J Physiol. 1952 Jul;117(3):303–316. doi: 10.1113/jphysiol.1952.sp004750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. FISHMAN A. P. Respiratory gases in the regulation of the pulmonary circulation. Physiol Rev. 1961 Jan;41:214–280. doi: 10.1152/physrev.1961.41.1.214. [DOI] [PubMed] [Google Scholar]
  8. Fisher A. B., Furia L., Chance B. Evaluation of redox state of isolated perfused rat lung. Am J Physiol. 1976 May;230(5):1198–1204. doi: 10.1152/ajplegacy.1976.230.5.1198. [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. Hales C. A., Kazemi H. Hypoxic vascular response of the lung: effect of aminophylline and epinephrine. Am Rev Respir Dis. 1974 Aug;110(2):126–132. doi: 10.1164/arrd.1974.110.2.126. [DOI] [PubMed] [Google Scholar]
  11. Hales C. A., Kazemi H. Role of histamine in the hypoxic vascular response of the lung. Respir Physiol. 1975 Jun;24(1):81–88. doi: 10.1016/0034-5687(75)90123-1. [DOI] [PubMed] [Google Scholar]
  12. Hales C. A., Rouse E. T., Kazemi H. Failure of saralasin acetate, a competitive inhibitor of angiotensin II, to diminish alveolar hypoxic vasoconstriction in the dog. Cardiovasc Res. 1977 Nov;11(6):541–546. doi: 10.1093/cvr/11.6.541. [DOI] [PubMed] [Google Scholar]
  13. Hales C. A., Rouse E., Buchwald I. A., Kazemi H. Role of prostaglandins in alveolar hypoxic vasoconstriction. Respir Physiol. 1977 Apr;29(2):151–162. doi: 10.1016/0034-5687(77)90088-3. [DOI] [PubMed] [Google Scholar]
  14. Hauge A., Staub N. C. Prevention of hypoxic vasoconstriction in cat lung by histamine-releasing agent 48/80. J Appl Physiol. 1969 Jun;26(6):693–699. doi: 10.1152/jappl.1969.26.6.693. [DOI] [PubMed] [Google Scholar]
  15. Hook G. E., Bend J. R., Hoel D., Fouts J. R., Gram T. E. Preparation of lung microsomes and a comparison of the distribution of enzymes between subcellular fractions of rabbit lung and liver. J Pharmacol Exp Ther. 1972 Sep;182(3):474–490. [PubMed] [Google Scholar]
  16. Itakura N., Fisher A. B., Thurman R. G. Cytochrome P450-linked p-nitroanisole O-demethylation in the perfused lung. J Appl Physiol Respir Environ Exerc Physiol. 1977 Aug;43(2):238–245. doi: 10.1152/jappl.1977.43.2.238. [DOI] [PubMed] [Google Scholar]
  17. Jobsis F. F. What is a molecular oxygen sensor? What is a transduction process? Adv Exp Med Biol. 1977;78:3–18. doi: 10.1007/978-1-4615-9035-4_1. [DOI] [PubMed] [Google Scholar]
  18. KAMPFFMEYER H., KIESE M. THE HYDROXYLATION OF ANILINE AND N-ETHYLANILINE BY MICROSOMAL ENZYMES AT LOW OXYGEN PRESSURES. Biochem Z. 1964 May 22;339:454–459. [PubMed] [Google Scholar]
  19. Kadowitz P. J., Chapnick B. M., Joiner P. D., Hyman A. L. Influence of inhibitors of prostaglandin synthesis on the canine pulmonary vascular bed. Am J Physiol. 1975 Oct;229(4):941–946. doi: 10.1152/ajplegacy.1975.229.4.941. [DOI] [PubMed] [Google Scholar]
  20. Kay J. M., Waymire J. C., Grover R. F. Lung mast cell hyperplasia and pulmonary histamine-forming capacity in hypoxic rats. Am J Physiol. 1974 Jan;226(1):178–184. doi: 10.1152/ajplegacy.1974.226.1.178. [DOI] [PubMed] [Google Scholar]
  21. Kazemi H., Bruecke P. E., Parsons E. F. Role of the autonomic nervous system in the hypoxic response of the pulmonary vascular bed. Respir Physiol. 1972 Jun;15(2):245–254. doi: 10.1016/0034-5687(72)90101-6. [DOI] [PubMed] [Google Scholar]
  22. LEFER A. M., NADZAM G. R. CARDIOVASCULAR EFFECTS OF SU-4885 (MEPYRAPONE), AN INHIBITOR OF CORTICOSTEROID BIOSYNTHESIS. Proc Soc Exp Biol Med. 1964 Feb;115:356–359. doi: 10.3181/00379727-115-28912. [DOI] [PubMed] [Google Scholar]
  23. Matsubara T., Tochino Y. Electron transport systems of lung microsomes and their physiological functions. I. Intracellular distribution of oxidative enzymes in lung cells. J Biochem. 1971 Dec;70(6):981–991. doi: 10.1093/oxfordjournals.jbchem.a129728. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Mills E., Jöbsis F. F. Mitochondrial respiratory chain of carotid body and chemoreceptor response to changes in oxygen tension. J Neurophysiol. 1972 Jul;35(4):405–428. doi: 10.1152/jn.1972.35.4.405. [DOI] [PubMed] [Google Scholar]
  26. Murray J. F., Karp R. B., Nadel J. A. Viscosity effects on pressure-flow relations and vascular resistance in dogs' lungs. J Appl Physiol. 1969 Sep;27(3):336–341. doi: 10.1152/jappl.1969.27.3.336. [DOI] [PubMed] [Google Scholar]
  27. Rosenthal M., Lamanna J. C., Jöbsis F. F., Levasseur J. E., Kontos H. A., Patterson J. L. Effects of respiratory gases on cytochrome A in intact cerebral cortex: is there a critical Po2? Brain Res. 1976 May 21;108(1):143–154. doi: 10.1016/0006-8993(76)90170-0. [DOI] [PubMed] [Google Scholar]
  28. Said S. I., Yoshida T., Kitamura S., Vreim C. Pulmonary alveolar hypoxia: release of prostaglandins and other humoral mediators. Science. 1974 Sep 27;185(4157):1181–1183. doi: 10.1126/science.185.4157.1181. [DOI] [PubMed] [Google Scholar]
  29. Strieder D. J., Barnes B. A., Aronow S., Russell P. S., Kazemi H. Xenon 133 study of ventilation and perfusion in normal and transplanted dog lungs. J Appl Physiol. 1967 Sep;23(3):359–366. doi: 10.1152/jappl.1967.23.3.359. [DOI] [PubMed] [Google Scholar]
  30. Sylvester J. T., McGowan C. The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction. Circ Res. 1978 Sep;43(3):429–437. doi: 10.1161/01.res.43.3.429. [DOI] [PubMed] [Google Scholar]
  31. Vaage J., Bjertnaes L., Hauge A. The pulmonary vasoconstrictor response to hypoxia: effects of inhibitors of prostaglandin biosynthesis. Acta Physiol Scand. 1975 Sep;95(1):95–101. doi: 10.1111/j.1748-1716.1975.tb10030.x. [DOI] [PubMed] [Google Scholar]
  32. Zakheim R. M., Mattioli L., Molteni A., Mullis K. B., Bartley J. Prevention of pulmonary vascular changes of chronic alveolar hypoxia by inhibition of angiotensin I-converting enzyme in the rat. Lab Invest. 1975 Jul;33(1):57–61. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES