Relaxation by beta 3-adrenoceptor agonists of the isolated human internal anal sphincter

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.

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.

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.

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.