A FUNCTIONAL BETA-2-ADRENOCEPTOR-MEDIATED CHRONOTROPIC RESPONSE IN ISOLATED GUINEA-PIG HEART-TISSUE - SELECTIVITY OF THE POTENT BETA-2-ADRENOCEPTOR AGONIST TA-2005

Responses were measured of the highly potent beta-2 adrenoceptor agoni st TA 2005, a new bronchodilator, on isolated guinea pig right and lef t atria and papillary muscle. The main objectives of the study were to investigate the selectivity of the compound and to determine whether guinea pig isolated heart tissues could be used as a model for investi gating mechanisms of clinical cardiac side effects. It was found that the inotropic responses in all tissues were mediated by the beta-1 adr enoceptor only. TA 2005 was a partial agonist for the inotropic respon se compared with I-isoprenaline. For the right atrial chronotropic res ponse, however, TA 2005 exerted a biphasic effect and reached 84% of t he I-isoprenaline response. The first phase was mediated by the beta-2 adrenoceptor, whereas the second phase was beta-1 adrenoceptor mediat ed. Approximately 64% of the TA 2005 chronotropic response was exerted via the beta-2 adrenoceptor. Addition of the beta-2-selective antagon ist ICI 188.551 blocked the beta-2 adrenoceptor-mediated response, pro viding only a monophasic response. Addition of the beta-1-selective an tagonist ICI 89.406 resulted in further separation of the phases. The finding that a beta-2-mediated chronotropic response exists on the rig ht atrium of the guinea pig sheds new light on selectivity studies. It is suggested that quantification of beta-1/beta-2 selectivity of beta adrenoceptor agonists be performed not on the basis of measurement of guinea pig right atrial chronotropism but rather on the basis of meas urement of guinea pig left atrial inotropism. On the other hand, becau se in human heart beta-2 adrenoceptors have a functional role, the gui nea pig might be a suitable model for the examination of the cardiac s ide effects of bronchodilators. TA 2005 was found to be a beta-2-selec tive compound with a beta-2/beta-1 selectivity ratio of 256.