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  • Title: Relaxation by beta 3-adrenoceptor agonists of the isolated human internal anal sphincter.
    Author: Ballester C, Sarriá B, García-Granero E, Mata M, Milara J, Morcillo EJ, Lledó S, Cortijo J.
    Journal: Life Sci; 2010 Feb 27; 86(9-10):358-64. PubMed ID: 20093127.
    Abstract:
    AIMS: In this study, responses of beta(3)-adrenoceptor agonists were examined on human isolated internal anal sphincter (IAS) in order to explore their relaxant effects on hypertonicity of IAS. MAIN METHODS: The relaxant efficacy (E(max)) and potency (-logIC(50)) of BRL37344 and SR58611A, beta(3)-adrenoceptor agonists, were examined in contracted IAS muscle strips. The presence of beta(3)-adrenoceptors, and changes in intracellular calcium and cyclic nucleotide levels in IAS muscle were tested by Western blotting, epifluorescence microscopy and enzyme immunoassay, respectively. KEY FINDINGS: BRL37344 and SR58611A relaxed contracted IAS muscle (E(max)=27+/-3% and 35+/-3%; -logIC(50)=6.26+/-0.24 and 4.87+/-0.13; respectively). These relaxant responses were blocked by SR59230A, a selective beta(3)-antagonist but not by beta(1)/beta(2)-selective antagonists, neuronal inhibitor or inhibition of nitric oxide synthase. The E(max) of beta(3)-agonists was similar to that of beta(2)-selective agonists but smaller than that of isoprenaline (nonselective agonist) or beta(1)-selective agonists. BRL37344 (100 microM) increased cAMP (1.5-fold) without cGMP change, and depressed intracellular calcium signal. beta(3)-Adrenoceptor expression was smaller than that of beta(1)- and beta(2)-adrenoceptors. SIGNIFICANCE: This is the first study demonstrating the presence of beta(3)-adrenoceptor in human IAS muscle and beta(3)-mediated relaxation of augmented sphincter tone. However, direct beta(3)-relaxation appears smaller than that obtained for nonselective agonists which may limit their potential use in the treatment of anorectal hypertonicity disorders.
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