| Objective: This study is to investigate the effects on rat myometrial contractions in vitro and in vivo, and provide a preliminary experimental basis for developing a new drug for the treatment of preterm labor.Methods:1 In vitro study, the effect of betaphrine on the isolated rat uterine contraction was observed。(1) The isolated non-pregnant rat myometrial strips were made and the effects of betaphrine and ritodrine on spontaneous contraction of myometrial strips was observed.(2) The isolated pregnant rat myometrial strips were made and the effects of betaphrine and ritodrine on spontaneous contraction , and contraction induced by agonists(oxytocin,PGF2αand KCl ) was observed.(3) We evaluated the effect of increasing concentrations of betaphrine on contractions of myometrial strips pretreated with metoprolol, ICI 118.551 and SR 59230A (selectiveβ1,β2,β3-AR antagonist, respectively Each antagonist was added 15 min before treatment with betaphrine). The results obtained were subjected to Schild plot analysis, and the pA2 values were obtained.2 In vivo study, betaphrine (0.1μg/kg/min-10μg/kg/min) and ritodrine(1μg/kg/min-100μg/kg/min)was administered by sequential intravenous infusion,the dose being increased per 15 min.Results:(1) Betaphrine and ritodrine decreased the amplitude of non-pregnant rat uterine spontaneous contractions in a dose-dependent manner.pIC50 value (7.74±0.12) and Emax value (80.32±5.49%) of betaphrine was increased significantly more than Emax value (63.63±6.28%) and pIC50 value (7.28±0.07) of ritodrine (P < 0.05).(2) Betaphrine and ritodrine decreased the amplitude of pregnant rat uterine spontaneous contractions in a dose-dependent manner.pIC50 value (7.74±0.12) and Emax value (80.32±5.49%) of betaphrine were increased significantly more than the Emax value (63.63±6.28%) and pIC50 value (7.28±0.07 of ritodrine (P < 0.05). Betaphrine and ritodrine also produced dose-dependent inhibitions of the uterine contractions elicited by oxytocin, PGF2α, and KCl. However, the potency of betaphrine and ritodrine was less against PGF2α(pIC50=6.77±0.06) than oxytocin (pIC50=7.69±0.11) or KCl (pIC50=7.74±0.45)-induced contraction.(3) Selectiveβ3-AR antagonist SR59230A (3×10-8-3×10-7M,pA2=9.1 ) competitively antagonized the betaphrine-induced inhibition of spontaneous uterine contractions, but Metoprolol (3×10-8-3×10-7M) and ICI-118551 (3×10-8-3×10-7M)did not.(4) In vivo study, betaphrine (0.1μg/kg/min-10μg/kg/min,iv,infusion) produced significant inhibition of spontaneous uterine contractions: ED30 value for betaphrine was 0.17μg/kg/min, a potency about 70 times greater than ritodrine. In contrast, the positive chronotropic effect was minimal in betaphrine -treated rats.Conclusions:(1) Betaphrine dose-dependently inhibits rat uterine contraction without causing severe cardiovascular side effects, such as tachycardia and hypotension.(2) Betaphrine produced its inhibitory effect on rat uterine contractions ,mainly by inhibiting the influx of extracelluar Ca2+ and the release of Ca2+ from intracellular stores via stimulation ofβ3-AR subtype.(3)β3-AR agonist betaphrine may become a type of drug for the treatment of preterm labor. |
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