Partial agonism and functional selectivity: a study on beta-adrenoceptor mediated effects in tracheal, cardiac and skeletal muscle.
Colterol, procaterol, sulfonterol, terbutaline and three monophenolic derivatives of terbutaline were examined with respect to their ability to react in vitro on beta-adrenoceptors in tissues isolated from guinea-pig. The effects measured were a) relaxation of the tracheal smooth muscle (mostly beta 2), b) depression of subtetanic contractions of the soleus muscle (beta 2), and c) increase in the force of the papillary muscle of the left ventricle (beta 1). Antagonistic effects were measured against isoprenaline as an agonist. The compounds studied showed a wide variation in selectivity, potency and intrinsic activity. All agonists showed a pronounced beta 2-selectivity, in general characterized by a higher intrinsic activity at beta 2- than at beta 1-adrenoceptors, while differences in affinity, as judged from the pA2-values were small. Partial agonists, such as sulfonterol, which did not cause a complete relaxation of a moderately contracted tracheal muscle, produced identical concentration-response curves from the trachea and soleus muscle. It is concluded that partial agonism at beta 1-adrenoceptors is an important factor for functional selectivity of beta 2-adrenoceptor agonists. On the other hand there seems to be no useful differences between the maximum effect elicited by a partial beta 2-adrenoceptor agonist on the skeletal muscle as compared with airway smooth muscle.
Waldeck
B
B
Jeppsson
A B
AB
Widmark
E
E
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001592:Benzyl Alcohols / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009132:Muscles / Q000187:drug effects*; D008771:Nordefrin / Q000031:analogs & derivatives / Q000494:pharmacology; D017265:Procaterol; D013726:Terbutaline / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D004983:Ethanolamines; C049307:KWD 2078; C011595:colterol; D006632:Histamine; C078462:fepradinol; D002217:Carbachol; C049308:KWD 2066; D013726:Terbutaline; D008771:Nordefrin; D017265:Procaterol; C028820:sulfonterol