Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1975 Dec;55(4):547–554. doi: 10.1111/j.1476-5381.1975.tb07431.x

Tolerance to sympathomimetic bronchodilators in guinea-pig isolated lungs following chronic administration in vivo.

C J Benoy, M S El-Fellah, R Schneider, O L Wade
PMCID: PMC1666729  PMID: 1212562

Abstract

1 Pretreatment of the guinea-pig subcataneously three times daily with either 5 mug/kg isoprenaline or adrenaline reduced the response of the isolated perfused histamine-constricted lung when challenged with either the same or a different sympathomimetic bronchodilator. The longer the animals were pretreated and the higher the dose of bronchodilator the greater was the degree of tolerance developed. 2 Tolerance was developed to aminophline in the same preparation when the guinea-pig had been pretreated with aminophyline or isoprenaline. Cross-tolerance also developed adrenaline when the guinea-pig had been pretreated with aminophyline. 3 Tolerance was still persistent in guinea-pigs one and two weeks after pretreatment three times daily with either isoprenaline of adrenaline (5 mu/kg s.c.) for seven days in the same preparation. Only after three weeks was the tolerance diminished. 4 These results suggest that asthmatic patients who use bronchodilators excessively may become refractory to the bronchodilator effect of these drugs. They also support the hypothesis that induced cross-resistance to endogenous sympathetic stimulation could lead to a deterioration of the asthmatic state in patients using the sympathomimetic bronchodilators and that this may explain the increase in asthma mortality rate. 5 A mechanism of tolerance to sympathomimetic bronchodilators is postulated.

Full text

PDF
553

Selected References

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

  1. Atuk N. O., Blaydes M. C., Westervelt F. B., Jr, Wood J. E., Jr Effect of aminophylline on urinary excretion of epinephrine and norepinephrine in man. Circulation. 1967 Apr;35(4):745–753. doi: 10.1161/01.cir.35.4.745. [DOI] [PubMed] [Google Scholar]
  2. COOKSON D. U., REED C. E. A COMPARISON OF THE EFFECTS OF ISOPROTERENOL IN THE NORMAL AND ASTHMATIC SUBJECT. A PRELIMINARY REPORT. Am Rev Respir Dis. 1963 Nov;88:636–643. doi: 10.1164/arrd.1963.88.5.636. [DOI] [PubMed] [Google Scholar]
  3. Conolly M. E., Davies D. S., Dollery C. T., George C. F. Resistance to -adrenoceptor stimulants (a possible explanation for the rise in ashtma deaths). Br J Pharmacol. 1971 Oct;43(2):389–402. [PMC free article] [PubMed] [Google Scholar]
  4. Fireman P. Metabolic abnormalities in asthma--decreased urinary cycle AMP. Int Arch Allergy Appl Immunol. 1973;45(1):123–127. doi: 10.1159/000231014. [DOI] [PubMed] [Google Scholar]
  5. Fleisch J. H., Titus E. The prevention of isoproterenol desensitization and isoproterenol reversal. J Pharmacol Exp Ther. 1972 Jun;181(3):425–433. [PubMed] [Google Scholar]
  6. Franklin T. J., Foster S. J. Hormone-induced desensitisation of hormonal control of cyclic AMP levels in human diploid fibroblasts. Nat New Biol. 1973 Dec 5;246(153):146–148. doi: 10.1038/newbio246146a0. [DOI] [PubMed] [Google Scholar]
  7. Fraser P. M., Speizer F. E., Waters S. D., Doll R., Mann N. M. The circumstances preceding death from asthma in young people in 1968 to 1969. Br J Dis Chest. 1971 Apr;65(2):71–84. [PubMed] [Google Scholar]
  8. Herxheimer H. Asthma mortality. Am Rev Respir Dis. 1973 Feb;107(2):306–307. doi: 10.1164/arrd.1973.107.2.306a. [DOI] [PubMed] [Google Scholar]
  9. Hitchcock M. Adenosine 3',5'-cyclic monophosphate phosphodiesterase in guinea-pig lung--properties and effect of adrenergic drugs. Biochem Pharmacol. 1973 Apr 15;22(8):959–969. doi: 10.1016/0006-2952(73)90220-7. [DOI] [PubMed] [Google Scholar]
  10. Inman W. H., Adelstein A. M. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet. 1969 Aug 9;2(7615):279–285. doi: 10.1016/s0140-6736(69)90051-8. [DOI] [PubMed] [Google Scholar]
  11. Keighley J. F. Iatrogenic asthma associated with adrenergic aerosols. Ann Intern Med. 1966 Nov;65(5):985–995. doi: 10.7326/0003-4819-65-5-985. [DOI] [PubMed] [Google Scholar]
  12. Lockey S. D., Jr, Glennon J. A., Reed C. E. Comparison of some metabolic responses in normal and asthmatic subjects to epinephrine and glucagon. J Allergy. 1967 Dec;40(6):349–354. doi: 10.1016/0021-8707(67)90024-x. [DOI] [PubMed] [Google Scholar]
  13. Logsdon P. J., Middleton E., Jr, Coffey R. G. Stimulation of leukocyte adenyl cyclase by hydrocortisone and isoproterenol in asthmatic and nonasthmatic subjects. J Allergy Clin Immunol. 1972 Jul;50(1):45–56. doi: 10.1016/0091-6749(72)90078-4. [DOI] [PubMed] [Google Scholar]
  14. Middleton E., Jr, Finke S. R. Metabolic response to epinephrine in bronchial asthma. J Allergy. 1968 Nov;42(5):288–299. doi: 10.1016/0021-8707(68)90022-1. [DOI] [PubMed] [Google Scholar]
  15. Nelson H. S. The effect of ephedrine on the response to epinephrine in normal men. J Allergy Clin Immunol. 1973 Apr;51(4):191–198. doi: 10.1016/0091-6749(73)90138-3. [DOI] [PubMed] [Google Scholar]
  17. Paterson J. W., Conolly M. E., Davies D. S., Dollery C. T. Isoprenaline resistance and the use of pressurised aerosols in asthma. Lancet. 1968 Aug 24;2(7565):426–429. doi: 10.1016/s0140-6736(68)90467-4. [DOI] [PubMed] [Google Scholar]
  18. Peach M. J. Stimulation of release of adrenal catecholamine by adenosine 3':5'-cyclic monophosphate and theophylline in the absence of extracellular Ca 2+ . Proc Natl Acad Sci U S A. 1972 Apr;69(4):834–836. doi: 10.1073/pnas.69.4.834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Robison G. A., Butcher R. W., Sutherland E. W. Adenyl cyclase as an adrenergic receptor. Ann N Y Acad Sci. 1967 Feb 10;139(3):703–723. doi: 10.1111/j.1749-6632.1967.tb41239.x. [DOI] [PubMed] [Google Scholar]
  20. Speizer F. E., Doll R., Heaf P. Observations on recent increase in mortality from asthma. Br Med J. 1968 Feb 10;1(5588):335–339. doi: 10.1136/bmj.1.5588.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Speizer F. E., Doll R., Heaf P., Strang L. B. Investigation into use of drugs preceding death from asthma. Br Med J. 1968 Feb 10;1(5588):339–343. doi: 10.1136/bmj.1.5588.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Stolley P. D. Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. Am Rev Respir Dis. 1972 Jun;105(6):883–890. doi: 10.1164/arrd.1972.105.6.883. [DOI] [PubMed] [Google Scholar]
  23. Westfall D. P., Fleming W. W. Sensitivity changes in the dog heart to norepinephrine, calcium and aminophyline resulting from pretreatment with reserpine. J Pharmacol Exp Ther. 1968 Jan;159(1):98–106. [PubMed] [Google Scholar]
  24. Wooten G. F., Thoa N. B., Kopin I. J., Axelrod J. Enhanced release of dopamine -hydroxylase and norepinephrine from sympathetic nerves by dibutyryl cyclic adenosine 3', 5'-monophosphate and theophylline. Mol Pharmacol. 1973 Mar;9(2):178–183. [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES