Diversity of inhibitory responses to beta2-stimulants shown by term-pregnant human myometria in vitro is partly due to differences in receptor density.
OBJECTIVE
The aims of this study were (1) to evaluate the usefulness of the new beta2-adrenergic stimulant KUR-1246 as a tocolytic agent and (2) to clarify the mechanisms that underlie the diverse inhibitory effects of beta2-stimulants that are seen in human myometria in vitro.


METHODS
The displacement of tritiated ([3H]) (-)CGP 12177 (0.4 nmol/L) by KUR-1246 and other beta2-stimulants was examined with human beta(1)- and beta2-receptors present on membrane fractions. The inhibitory effects of these beta2-stimulants on the term-pregnant human myometrium were compared with the use of isometric tension recording and microelectrode methods. Finally, the relationship between [3H]dihydroaloprenolol binding and the magnitude of the tocolytic effect of isoproterenol was examined.


RESULTS
KUR-1246 was approximately 80 times and 7 times more selective for beta2-receptors than isoproterenol and ritodrine, respectively. The inhibitory effect of KUR-1246 was as strong as the inhibitory effect of the conventional beta2-adrenergic stimulants. A wide range of inhibitory effects was observed, even when high concentrations of isoproterenol or KUR-1246 were applied. There was a correlation between the degree to which isoproterenol suppressed contractions and the number of [3H]dihydroaloprenolol binding sites on the membrane in each muscle strip.


CONCLUSIONS
KUR-1246 should be a very useful beta2-adrenergic stimulant for use as a tocolytic agent because of its high selectivity for the beta2-receptor and its potent inhibitory effect. The diversity of the inhibitory effects that are induced by beta2-stimulants is at least partly due to differences in beta2-receptor density among term-pregnant human myometria.
Sakakibara
Tomoko
T
Department of Obstetrics and Gynecology, School of Medicine, Fukuoka University, Japan.
Inoue
Yoshihito
Y
Uzue
Satoshi
S
Tsukamoto
Takuji
T
Kobayashi
Mamoru
M
Kojima
Masami
M
Akahane
Masuo
M
Kitamura
Kenji
K
Kawarabayashi
Tatsuhiko
T
D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000328:Adult; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D036861:Delivery, Obstetric; D004082:Dihydroalprenolol / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects* / Q000502:physiology; D009281:Naphthalenes / Q000378:metabolism / Q000494:pharmacology*; D009994:Osmolar Concentration; D011247:Pregnancy / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015149:Tocolytic Agents / Q000378:metabolism / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*
D000081:Acetamides; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D009281:Naphthalenes; D011943:Receptors, Adrenergic, beta; D015149:Tocolytic Agents; C425888:bedoradrine; D004082:Dihydroalprenolol; D007545:Isoproterenol