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 agonist TA 2005, a new bronchodilator, on isolated guinea pig right and left 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 investigating mechanisms of clinical cardiac side effects. It was found that the inotropic responses in all tissues were mediated by the beta-1 adrenoceptor only. TA 2005 was a partial agonist for the inotropic response compared with I-isoprenaline. For the right atrial chronotropic response, however, TA 2005 exerted a biphasic effect and reached 84% of the I-isoprenaline response. The first phase was mediated by the beta-2 adrenoceptor, whereas the second phase was beta-1 adrenoceptor mediated. Approximately 64% of the TA 2005 chronotropic response was exerted via the beta-2 adrenoceptor. Addition of the beta-2-selective antagonist ICI 188.551 blocked the beta-2 adrenoceptor-mediated response, providing only a monophasic response. Addition of the beta-1-selective antagonist ICI 89.406 resulted in further separation of the phases. The finding that a beta-2-mediated chronotropic response exists on the right 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 measurement of guinea pig left atrial inotropism.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacochemistry, Leiden/Amsterdam Center for Drug Research, The Netherlands.
H P
HP
Voss
S
S
Shukrula
T S
TS
Wu
D
D
Donnell
A
A
Bast
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D006912:Hydroxyquinolines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015363:Quinolones / Q000494:pharmacology*; D011869:Radioligand Assay; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000662:Amphetamines; D006912:Hydroxyquinolines; D015363:Quinolones; D018343:Receptors, Adrenergic, beta-2; C074413:carmoterol