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Archives of Toxicology

, Volume 65, Issue 7, pp 575–579 | Cite as

Relationship between in vitro relaxation of the costo-uterine smooth muscle and mesovarial leiomyoma formation in vivo by Β-receptor agonists

  • Walter E. Colbert
  • Billie F. Wilson
  • Patricia D. Williams
  • Gail D. Williams
Original Investigations

Abstract

The three Β-agonists, salbutamol, ritodrine, and terbutaline have been shown to possess differing potentials to induce leiomyomas in rat costo-uterine muscle following chronic exposure (salbutamol > terbutaline > ritodrine). It has been suggested that the potential to induce leiomyomas is related to the relaxant properties of these agonists in the costo-uterine muscle. In order to test this hypothesis, the potencies of salbutamol, terbutaline, and ritodrine were compared to isoproterenol and norepinephrine in vitro in the rat costo-uterine smooth muscle, a Β2-adrenergic receptor rich tissue. All compounds produced relaxation of potassium chloride (KCl) contracted costo-uterine smooth muscle. Significant differences in potency were observed, with isoproterenol being the most potent, followed in rank order by salbutamol, terbutaline and ritodrine. The relative potency of the non-selective Β-blocker propranolol in inhibiting the agonist mediated relaxant activity was similar for all agonists examined, indicative of interactions at the same receptor site (Tallarida and Jacob 1979). When tested for Β-agonist activity in the guinea pig atria, salbutamol and ritodrine were less potent in these tissues compared to the costo-uterine muscle.

In summary, the in vitro pharmacological potency of salbutamol, terbutaline and ritodrine correlated with the potential to induce leiomyoma formation in rat costouterine muscle following chronic exposure to the respective Β-agonists. These results indicate that the isolated rat costo-uterine muscle is a sensitive model for comparing the potency of Β-agonists, and may assist in establishing the risk of costo-uterine leiomyoma formation in chronic rat studies relative to agents such as salbutamol.

Key words

Ritodrine Salbutamol Terbutaline Costouterine Leiomyoma 

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References

  1. Apperly GH, Brittain RT, Coleman RA, Kennedy I, Levy GP (1978) Characterization of the Β-adrenoreceptors in the mesovarium of the rat. Br J Pharmacol 63: 345–346Google Scholar
  2. Arch JRS, Ainsworth AT, Cawthorne MA, Piercy V, Sennitt MV, Thody VE, Wilson C, Wilson S (1984) Atypical Β-adrenoreceptor on brown adipocytes as target for anti-obesity drugs. Nature 309: 163–165CrossRefPubMedGoogle Scholar
  3. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14: 48–58PubMedGoogle Scholar
  4. Bieth N, Bruno R, Schwartz J, Velly J (1980) Comparison of pharmacological and binding assays for ten Β-adrenoreceptor blocking agents and two Β-adrenoreceptor agonists. Br J Pharmacol 68: 563–569PubMedGoogle Scholar
  5. Emery PW, Rothwell NJ, Stock JM, Winter PD (1984) Chronic effects of Β2-adrenergic agonists on body composition and protein synthesis in the rat. Biosci Rep 4: 83–91CrossRefPubMedGoogle Scholar
  6. Garber AJ, Karl IE, Kipnis DM (1976) Alanine and glutamine synthesis and release from skeletal muscle. IV. Β-Adrenergic inhibition of amino acid release. J Biol Chem 251: 851–857PubMedGoogle Scholar
  7. Gard DL, Lazarides E (1982) Cyclic AMP-modulated phosphorylation of intermediate filament proteins in cultured avian myogenic cells. Mol Cell Biol 2: 1104–1114PubMedGoogle Scholar
  8. Gerritse R, Revwer PJHM, Rinas IM, Bever HJM, Charbon GA, Naspels AA (1985) Cardiovascular effects of ritodrine are blocked by metoprolol in the anesthetized dog. Arch Int Pharmacodyn 278: 97–106PubMedGoogle Scholar
  9. Hartley ML, Pennefather JN (1984) The rat costo-uterine muscle: A preparation of smooth muscle containing a homogeneous population of Β-adrenoreceptors. J Auton Pharmacol 4: 101–107PubMedGoogle Scholar
  10. Hen R, Axel R, Obici S (1989) Activation of the Β2-adrenergic receptor promotes growth and differentiation in thyroid cells. Proc Natl Acad Sci 86: 4785–4788PubMedGoogle Scholar
  11. Jack D, Poynter D, Spurling NW (1983) Beta-adrenoreceptor stimulants and mesovarian leiomyomas in the rat. Toxicology 2: 315–320CrossRefGoogle Scholar
  12. Li JB, Jefferson LS (1977) Effect of isoproterenol on amino acid levels and protein turnover in skeletal muscle. Am J Physiol 232: E243-E249PubMedGoogle Scholar
  13. McElligott MA, Barreto A Jr, Chaung LY (1989) Effect of continuous and intermittent clenbuterol feeding on rat growth rate and muscle. Comp Biochem Physiol 92C: 135–138Google Scholar
  14. Medical Economics Co. Inc. (1991) Physicians' desk reference. Medical Economics Data, Oradell, New Jersey, pp 632–633, 1288–1289, 2330–2331Google Scholar
  15. Piercy V (1987) The Β-adrenoreceptors mediating uterine relaxation throughout the oestrus cycle of the rat are predominantly of the Β2-subtype. J Auton Pharmacol 8: 11–18Google Scholar
  16. Tallarida RJ, Jacob LS (1979) The dose-response relation in pharmacology. Springer-Verlag New York Inc., New York, NY, PP 61–64.Google Scholar
  17. Zeman RJ, Ludemann R, Easton TG, Etlinger JD (1988) slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a Β2-receptor agonist. Am J Physiol 254: E726-E732PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Walter E. Colbert
    • 1
  • Billie F. Wilson
    • 1
  • Patricia D. Williams
    • 1
  • Gail D. Williams
    • 1
  1. 1.Toxicology Research Laboratories, Lilly Research LaboratoriesEli Lilly and CompanyGreenfieldUSA

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