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

Abstract

The three beta-agonists, salbutamol, ritodrine, and terbutaline have been shown to possess differing potentials to induce leiomyomas in rat costo-uterine muscle following chronic exposure (salbutamol greater than terbutaline greater than 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 beta 2-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 beta-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 beta-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 costo-uterine muscle following chronic exposure to the respective beta-agonists. These results indicate that the isolated rat costo-uterine muscle is a sensitive model for comparing the potency of beta-agonists, and may assist in establishing the risk of costo-uterine leiomyoma formation in chronic rat studies relative to agents such as salbutamol.

Growth Factors and Cytokines in Uterine Leiomyomas

“…Leiomyoma-like structures have been induced in animals with chronic β-receptor agonist treatment. 58,59 β-Receptor agonists also increase cAMP in the cells. The mechanism for the induction of the tumors in the rodent animals is un known.…”

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

“…The mechanism of the tumorigenic response elicited by nongenotoxic agents is an area of intensive current research effort. Much has been learned about the effect of chemicals administered to rodents at high doses for long periods of time over the [20][21][22][23][24][25][26][27][28][29][30] yr that this bioassay has been used. The examples discussed earlier have demonstrated the importance of a comprehensive approach to interpretation of the results of these studies.…”