Dissociation constants of isoprenaline and orciprenaline and their relative efficacies on guinea-pig isolated atria determined by use of an irreversible beta-adrenoceptor antagonist.
1. Dissociation constant (KA) of isoprenaline and orciprenaline were determined for the positive inotropic and chronotropic responses of guinea-pig isolated atria. Cumulative dose-response curves to the agonists were constructed before and after incubation with and washout of the irreversible beta-adrenoreceptor antagonist, Ro 03-7894 1-(5-chloracetylaminobenzfuran-2-yl)-2-isopropylaminoethanol). 2. After 20 min washout, the curves were displaced to the right with depression of the maxima. After 3 h washout, there was only depression of the maxima. 3. Dissociation constants were determined by plotting reciprocals of molar concentrations before Ro 03-7894 (1/A) against reciprocals of the equiactive concentrations after Ro 03-7894 (1/A'). KA = (slope - 1)/ intercept. 4. Isoprenaline had a greater affinity (KA) than orciprenaline on both rate and tension. The affinity for rate and tension was identical for both agonists, indicating that the beta-adrenoceptors were identical. 5. Isoprenaline and orciprenaline produced identical rate response maxima when compared in the same preparation but the orciprenaline tension maximum was only 92.0 +/- 0.3% that of isoprenaline. 6. These dose-response curves were replotted as response against -log RA/Rt (fraction of receptors occupied) for each agonist concentration, calculated from the equation RA/Rt = (A)/(KA + (A)). The antilogarithm of the distance along the -log RA/Rt axis gave the efficacy of orciprenaline relative to isoprenaline. It had a greater efficacy (2.24) for rate but a lower efficacy for tension responses (0.5).
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009921:Metaproterenol / Q000378:metabolism* / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D001572:Benzofurans; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D009921:Metaproterenol; C018430:Ro 03-7894; D007545:Isoproterenol