Agents and Actions

, Volume 9, Issue 1, pp 18–23 | Cite as

Combination bronchodilators: Antagonism of airway smooth muscle contractions in vitro

  • Christopher J. Hanna
  • Sheldon H. Roth
Histamine and Kinins

Abstract

The component drugs of fixed-dose combination bronchodilators may interact in a synergistic manner to antagonize airway contractions. To examine this hypothesis, combinations of ephedrine (E) and theophylline (Th) or salbutamol (S) and theophylline were tested for their ability to relax contracted guinea-pig airway smooth muscle in vitro. The combination bronchodilator effect was compared to the summed effects of the component drugs given individually (i.e. a theoretical additive response, Ta). Relaxation responses to combination bronchodilators were considered less-than-additive if significantly less than Ta, additive if non-significant and greater-than-additive or synergistic if the values were significantly greater than Ta.

It was found that the E-Th combinations interacted primarily in an additive fashion to relax contractions induced by histamine, acetylcholine and 5-hydroxytryptamine at concentrations that produced one-half maximal contractile response (ED50). Similarly S-Th combinations interacted in an additive manner to reverse histamine and acetylcholine contractions. In the case of both E-Th and S-Th combinations, the drugs were more effective in reducing the smooth muscle contractions when given during rather than prior to the response. It may be concluded that beta-sympathomimetics and methylxanthines when combined do not interact in a synergistic fashion to produce relaxation of contracted airway smooth muscle.

Keywords

Histamine Theophylline Salbutamol Airway Smooth Muscle Ephedrine 

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References

  1. [1]
    E.W. Sutherland, G.A. Robison andR.W. Butcher,Some Aspects of the Biological Role of Adenosine 3′5′-Monophosphate (Cyclic AMP), Circulation37, 279–306 (1968).Google Scholar
  2. [2]
    L.M. Lichtenstein andS. Margolis,Histamine Release In Vitro: Inhibition by Catecholamines and Methylxanthines, Science161, 902–903 (1968).PubMedGoogle Scholar
  3. [3]
    R.P. Orange, W.G. Austen andK.F. Austen,Immunological Release of Histamine and Slow-reacting Substance of Anaphylaxis from Human Lung. I. Modulation by Agents Influencing Cellular Levels of Cyclic 3′,5′-Adenosine Monophosphate. J. Exp. Med.134, 136s-148s (1971).PubMedGoogle Scholar
  4. [4]
    H.R. Bourne, L.M. Lichtenstein andK.L. Melmon,Pharmacologic Control of Allergic Release in Vitro: Evidence for an Inhibitory Role of 3′,5′-Adenosine Monophosphate in Human Leukocytes. J. Immunol.108, 695–705 (1972).PubMedGoogle Scholar
  5. [5]
    R.G. Coffey andE. Middleton,Release of Histamine from Rat Mast Cells by Lysosomal Cationic Proteins: Possible Involvement of Adenylate Cyclase and Adenosine Triphosphatase in Pharmacologic Regulation. Int. Arch. Allergy45, 593–611 (1973).PubMedGoogle Scholar
  6. [6]
    Y. Tomita, R. Patterson andI.M. Suszko,Respiratory Mast Cells and Basophiloid Cells, Int. Arch. Allergy47, 261–272 (1974).PubMedGoogle Scholar
  7. [7]
    J.W. Dobbs andG.A. Robision,Functional Biochemistry of Beta-receptors in the Uterus. Fed. Proc.27, 352 (1968).Google Scholar
  8. [8]
    J.W. Lamble,The Effect of Isoprenaline, Theophylline and Adenosine 3′,5′-Monophosphate on the Isolated Vas Deferens of the Guinea-pig, Life Sciences9, 463–470 (1970).CrossRefGoogle Scholar
  9. [9]
    L. Triner, G.G. Nahas, Y. Vulliemoz, N. Overweg, M. Verosky, D. Habif andS. Ngai,Cyclic AMP and Smooth Muscle Function, Ann. N.Y. Acad. Sci.185, 458–476 (1971).PubMedGoogle Scholar
  10. [10]
    Y. Vulliemoz, M. Verosky andL.L. Triner,Effect of Albuterol and Terbultaline, Synthetic Beta-adrenergic Stimulants, on the Cyclic 3′,5′-Adenosine Monophosphate System in Smooth Muscle. J. Pharmacol. Exp. Ther.195, 549–556 (1975).PubMedGoogle Scholar
  11. [11]
    A. Bertelli, C. Bianchi andL. Beani,Interaction Between β-Adrenergic Stimulant Phosphodiesterase Inhibiting Drugs on the Bronchial Muscle, Experientia29, 300–302 (1973).CrossRefPubMedGoogle Scholar
  12. [12]
    K. Pihlajamäki, J. Kanto andE. Iisalo,Human and Animal Studies on the Interactions Between Glycphylline and Isoprenaline, J. Asthma Res.9, 255–261 (1972).PubMedGoogle Scholar
  13. [13]
    H. Herxheimer andE. Stresemann,Protection Against Anaphylactic Shock by Ephedrine-Theophylline Combinations, Arch. int. Pharmacodyn.125, 265–271 (1960).PubMedGoogle Scholar
  14. [14]
    M. Oskoui, D.M. Aviado andS. Bellet,Bronchopulmonary Effects of Caffeine in the Anesthetized Dog. Respiration27, 63–73 (1970).Google Scholar
  15. [15]
    W.F. Taylor, E.M. Heimlich, L. Strick andR. Busser,Ephedrine and Theophylline in Asthmatic Children: Quantitative Observations on the Combination and Ephedrine Tachyphylaxis, Ann. Allergy23, 437–440 (1965).PubMedGoogle Scholar
  16. [16]
    L.A. Howard,The Effect of Oral Theophylline on Bronchospams. J. Asthma Res.8, 111–114 (1971).PubMedGoogle Scholar
  17. [17]
    C.W. Bierman, W.E. Pierson, G.G. Shapiro andP.P. Van Arsdel,The Pharmacological Assessment of Single Drugs and Drug Combinations in Exercise-induced Asthma, J. All. Clin. Immunol.51, 88 (1973).Google Scholar
  18. [18]
    M.M. Weinberger andE.A. Bronsky,Evaluation of Oral Bronchodilator Therapy in Asthmatic Children. J. Pediatrics84, 421–427 (1974).Google Scholar
  19. [19]
    M.M. Weinberger, E.A. Bronsky, G.W. Bensch, G.N. Bock andJ.J. Yecies,Interaction of Ephedrine and Theophylline. Clin. Pharmacol. Ther.17, 585–592 (1975).PubMedGoogle Scholar
  20. [20]
    B. Badiei, J. Facianne andR.M. Sly,Effect of Theophylline, Ephedrine and Their Combination Upon Exercise-induced Airway Obstruction, Ann. Allergy35, 32–36 (1975).PubMedGoogle Scholar
  21. [21]
    C.J. Hanna andS.H. Roth,The Guinea-pig Tracheo-bronchial Spiral Strip: Responses to Selected Agonists, Can. J. Physiol. Pharmacol.56, 823–827 (1978).PubMedGoogle Scholar
  22. [22]
    Y. Vulliemoz, M. Verosky, G.G. Nahas andL. Triner,Adenyl Cyclase-phosphodiesterase System in Bronchial Smooth Muscle, Pharmacologist13, 256 (1971).Google Scholar
  23. [23]
    L. Triner, Y. Vulliemoz andM. Verosky,Cyclic 3′,5′-Adenosine Monophosphate and Bronchial Tone, Eur. J. Pharmacol.41, 37–46 (1977).CrossRefPubMedGoogle Scholar
  24. [24]
    R.G.G. Andersson,Cyclic AMP and Calcium Ions in Mechanical and Metabolic Responses of Smooth Muscles; Influence of Some hormones and Drugs. Acta Physiol. Scand. Supp.382, 1–59 (1972).Google Scholar
  25. [25]
    Y.S. Lau andB.K.B. Lum,Role of Cyclic AMP in Adrenergically Induced Tracheal Smooth Muscle Relaxation, Proc. West. Pharmacol. Soc.20, 33 (1977).PubMedGoogle Scholar

Copyright information

© Birkhäuser-Verlag 1979

Authors and Affiliations

  • Christopher J. Hanna
    • 1
  • Sheldon H. Roth
    • 1
  1. 1.Division of Pharmacology and Therapeutics, Faculty of MedicineUniversity of CalgaryCalgaryCanada

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