IN-VITRO INHIBITION OF HUMAN COLONIC MOTILITY WITH SR 59119A AND SR 59104A - EVIDENCE OF A BETA(3)-ADRENOCEPTOR-MEDIATED EFFECT

The new beta(3)-adrenoceptor is present in the gastrointestinal tract of various species. This study aimed to show that this receptor modula tes human colonic motility in vitro. We used circular muscle strips fr om the human colon suspended in single organ baths containing Krebs so lution and subjected to an initial 1.5-2 g tension. We measured the ef fects of different beta(3)-adrenoceptor agonists, including SR 59104A ( N-[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-(2 R)-2-yl)methyl]-(2 R)- 2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), SR 59119A (N-[( 7-methoxy-1,2,3,4-tetrahydronaphthalen(2 R)-2-yl)methyl]-(2 R)-2-hydro xy-2-(3-chlorophenyl)ethanamine hydrochloride), BRL 37344 (R,R+S,S) [4 -[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl] phenoxy] aceti c acid), acid of isoprenaline and salbutamol in the absence or in the presence of propranolol alone or in combination with the beta(3)-adren oceptor antagonist SR 59230A 4-tetrahydro-naphthalen-1-ylamino]-(2S)-2 -propanol oxalate) on amplitude of spontaneous contractions. To evalua te a possible beta(2)-adrenoceptor-mediated effect, we studied the act ion of these compounds on human isolated bronchi. On the human isolate d colon, SR 59119A, SR 59104A and isoprenaline reduced the initial amp litude of spontaneous contractions by 60%. The curves obtained in the presence of antagonists suggested an action mediated by beta(3)-adreno ceptor stimulation, since propranolol did not antagonize the action of SR 59119A and SR 59104A, whereas the combination of propranolol and S R 59230A significantly displaced the concentration-response curve of t hese agonists to the right. This study provides pharmacological eviden ce of modulation of human colonic motility, and especially of the ampl itude of spontaneous contractions, by the atypical beta-adrenoceptor, the beta(3)-adrenoceptor. (C) 1998 Elsevier Science B,V. All rights re served.