Selective and full beta 1-adrenoceptor agonist action of a catechol derivative of denopamine (T-0509) in the guinea-pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline.
1. The pharmacological actions of T-0509, a 3-hydroxy derivative of denopamine, were studied in various guinea-pig tissues; these effects were compared with those of isoprenaline, denopamine and xamoterol. 2. The intrinsic activities of the positive inotropic actions of T-0509, denopamine and xamoterol compared with isoprenaline (= 100%) in the papillary muscle were 99%, 83% and 28%, respectively, while their relative potencies (EC50 agonist EC50 isoprenaline) were 0.23, 33 and 1.4, respectively. The intrinsic activities of T-0509, denopamine and xamoterol as positive chronotropic agents in the right atria were 98%, 69% and 48%, respectively, and their equipotent concentrations (isoprenaline = 1) were 0.24, 50 and 4, respectively. 3. The positive chronotropic actions of T-0509 and denopamine were antagonized by bisoprolol (3 x 10(-8) M), but not by ICI 118,551 (3 x 10(-8) M). 4. The intrinsic activity of T-0509 in histamine-contracted tracheae was similar to that of isoprenaline, but its equipotent concentration was 38; the effects of both agents were antagonized by ICI 118,551 (3 x 10(-8) M), but not by bisoprolol (3 x 10(-8) M). Denopamine and xamoterol did not show any agonist activity on guinea-pig trachea. 5. Denopamine and xamoterol antagonized the positive chronotropic (pA2, denopamine: 6.98, xamoterol: 7.75) and tracheal relaxant (pA2, denopamine: 5.39, xamoterol: 6.25) effects of isoprenaline. 6. Isoprenaline, T-0509 and denopamine, but not xamoterol, contracted the guinea-pig aorta in a decreasing order in the presence of propranolol (10(-6) M).7. Based on the above studies, T-0509 appears to be a highly selective betaI-adrenoceptor agonist with full agonist properties, while denopamine and xamoterol appear to be selective, but partial betaI-adrenoceptor agonists.
Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
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Yabana
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Watanabe
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Narita
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Nagao
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017298:Bisoprolol / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D017307:Xamoterol / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011412:Propanolamines; C026777:ICI 118551; C025342:RP333; D017307:Xamoterol; D006632:Histamine; D007545:Isoproterenol; C037293:denopamine; D017298:Bisoprolol