In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical beta-adrenoceptors in rat colon.
1. The new compounds phenylethanolaminotetralines (PEAT), unlike the reference beta-adrenoceptor agonists isoprenaline (Iso), ritodrine (Ri) and salbutamol (Sal), produced half-maximal inhibition of spontaneous motility of rat isolated proximal colon at substantially lower concentrations (EC50 2.7-30 nM) than those inducing beta 2-adrenoceptor-mediated responses (relaxation of guinea-pig isolated trachea and rat uterus) and had virtually no chronotropic action (EC50 greater than 3 x 10(5) M) on the guinea-pig isolated atrium (a beta 1-adrenoceptor-mediated response). 2. The nonselective beta-adrenoceptor antagonists alprenolol and propranolol prevented the inhibition of rat colon motility by the PEAT with low and different potencies (pA2 values around 7.5 and 6.5 respectively). Conversely alprenolol and propranolol had a higher and similar potency (pA2 values around 9.0) in preventing typical beta 1 or beta 2-responses (increase in atrial frequency by Iso or tracheal relaxation by Ri or Sal). 3. The selective beta-adrenoceptor antagonists CGP 20712A (beta 1) and ICI 118,551 (beta 2) either alone or in combination, did not prevent rat colon motility inhibition by the representative PEAT SR 58611A, which was also fully resistant to alpha-adrenoceptor, acetylcholine, dopamine, histamine, opioid and 5-hydroxytryptamine antagonists. 4. These results indicate that the PEAT are a new class of beta-adrenoceptor agonists and suggest that their preferential intestinal action may be accounted for by selectivity for atypical beta-adrenoceptors, abundant in the rat colon and distinct from the currently recognized beta 1 and beta 2 subtypes.
Bianchetti
A
A
Research Center Sanofi-Midy S.p.A., Milan, Italy.
Manara
L
L
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects; D014599:Uterus / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D013764:Tetrahydronaphthalenes