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Effects of Ritodrine Hydrochloride, a Beta2-Adrenoceptor Stimulant, on Uterine Motilities in Late Pregnancy

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Effects of Ritodrine Hydrochloride, a Beta2-Adrenoceptor Stimulant, on Uterine Motilities in Late Pregnancy Japan. J. Pharmacol. 35, 319-326 (1984) 319 Effects of Ritodrine Hydrochloride, a Beta2-Adrenoceptor Stimulant, on Uterine Motilities in Late Pregnancy Shigeru IKEDA, Hiroshi TAMAOKI, Masuo AKAHANE and Yoshifumi NEBASHI Central ResearchLaboratories, Kissei Pharmaceutical Co., Ltd. 19-48 Yoshino,Matsumoto 399-65, Japan Accepted April7, 1984 Abstract•\Ritodrine hydrochloride (ritodrine) is a beta2-adrenoceptor stimulant which has been effectively prescribed for the prevention of premature labor. The present studies were carried out to investigate the effects of ritodrine on uterine motility in rats and rabbits during gestation, as compared with those of isoproterenol and isoxsuprine. The results were as follows: 1) Spontaneous movements and evoked contractile responses of isolated rat uterus (19-20th days of gestation) were suppressed by 10-9-1 0-6 M ritodrine. The potency of ritodrine was approximately 10 times more than that of isoxsuprine and 100-1,000 times less than that of iso- proterenol. 2) When these drugs were administered to pregnant rats or rabbits intravenously, the tocolytic potency was in the following order: isoproterenol> ritodrine>isoxsuprine. 3) Ritodrine induced hypotension and tachycardia, but these effects were less than those of isoproterenol and isoxsuprine. 4) The effects of isoproterenol and ritodrine were almost prevented by pretreatment with pro- pranolol, but those of isoxsuprine were only partially or not affected. These results suggest that ritodrine is effective in preventing the uterine contractions in rats and rabbits and that it has less effect on the circulatory system than isoproterenol and isoxsuprine. It is also concluded that ritodrine produces these effects through activation of beta-adrenoceptors. Ritodrine hydrochloride (ritodrine), a beta2-adrenoceptor stimulant, has been reported to be effective in inhibiting uterine contractions both in humans (1, 2) and in experimental animals (3, 4) and has the chemical structure shown in Fig. 1. Ritodrine has been introduced as a useful drug to prevent premature labor in obstetrics (5). The effects of ritodrine on uterine motility, the circulatory system and metabolism were mainly investigated using large animals, i.e., ewes (6, 7), and reports of investigations in rats or rabbits are limited (8). In the present study, we observed the effects of ritodrine on uterine activity, heart rate and blood pressure in rats and rabbits in comparison with isoxsuprine hydrochloride (isoxsuprine) and isoproterenol hydrochloride (isoproterenol). Fig. 1. Chemical structures of ritodrine hydro- chloride and related compounds. 320 S. Ikeda et al. quency for 5 min in rats and represented as Materials and Methods the integrated area under the records in Animals: Female Wistar strain rats, rabbits. weighing about 200 g, and female New The zero level was the bottom line after Zealand White rabbits weighing about 4 kg administration of 10 ƒÊg/kg (i.v.) of iso- were used. proterenol. When uterine contractions were Measurement of uterine motility in vitro: induced with oxytocin, it was infused at The experiments were carried out using 50 mU/kgimin in rats and 2.5 mU/kg/min uterine muscle strips from rats on the 19-20th in rabbits. When uterine contractions were days of gestation. The zero day of pregnancy induced with prostaglandin F2,6 (PGF2.), it was estimated by the presence of the plug was infused at 20 fig/kg/min in rats and after overnight housing with male rats. The administered at 500 fig into the intrauterine tissues were dissected to be 2-3 mm in width cavity in rabbits. and 18-20 mm in length, except for the Measurements of uterine motility, blood placental region. These preparations were pressure and heart rate in conscious rats: kept in an organ bath containing nutrient Pregnant rats on the 19-20th days of solution at 37•Ž (Krebs-Henselite bicarbonate gestation were anesthetized with ether, and a solution for spontaneous motility and balloon connected polyethylene catheter was modified Locke-Ringer solution for evoked inserted into the right uterine horn after respnses). The compositions of the nutrient removal of one fetus. solutions were as follows: Krebs-Henselite A polyethylene catheter for measurement bicarbonate solution (g/1) contained NaCI, of blood pressure was then inserted into the 34.5; KCI, 1.75; CaCl2, 2.75; KH2PO4, 0.8; left common carotid artery and the other one MgSO4.7H20, 1.45; Glucose, 5.0; NaHCO3, inserted for the administration of drugs into 10.5 and Modified Locke-Ringer solution the fore-stomach. All catheters were ex- (g/1) contained NaCI, 8.8; KCI, 0.4; CaCl2, teriorized from a skin incision in the maternal 0.04; MgCl2, 0.018; NaHCO3, 0.4; KH2PO4, cranial site through a subcutaneous tunnel. 0.02; Na2HPO4, 0.08; Glucose, 0.5. The Measurements were performed at least 3 hr contractions of preparations were recorded after the operation. isometrically on an ink-writing rectigraph Drugs used in this experiment: The main (Type 8-S, Sanei) through a force-displace- drugs used in this experiment were ritodrine ment transducer (SB-1TH, Nihon Kohden). HCI (Duphar), isoxsuprine HCI (Duvadilan, Measurements of uterine motility, blood Daiichi), isoproterenol HCI (Nakarai), pro- pressure and heart rate in anesthetized pranolol HCI (I nderal, ICI-Sumitomo), animals: Pregnant rats on the 19-20th days oxytocin (Syntocinon, Sandoz-Sankyo) and of gestation and rabbits on the 29-30th days prostaglandin F2ƒ¿ (Prostarmon-F, Ono). of gestation were anesthetized with urethane Results (1.5 g/kg, s.c.), and a balloon connected polyethylene catheter was inserted into the Effects on motilities of isolated rat uterus: right uterine horn after removal of one fetus. Spontaneous movements of isolated rat A polyethylene catheter was then inserted uterus were suppressed by ritodrine (10w- into the left common carotid artery. Blood 10-6 M), isoxsuprine (10-9-10-8 M) and pressure and uterine motility (balloon isoproterenol (10-11-10-8 M), in a dose- pressure) were measured with pressure dependent manner (Fig. 2). Contractile transducers (MPU-0.5A, Nihon Kohden), responses evoked by oxytocin (1 x10-2 U/ and the heart rates were taken from a cardio- ml), PGF2ƒ¿, (3 •~ 10-6 M), acetylcholine tachometer (2140. Sanei) triggered by the (1•~10-7 g/ml), KCI (40 mM) or electrical pulse pressure of the artery. These parameters field stimulation (20 V. 5 msec, 2 Hz of were recorded on an ink-writing rectigraph rectangular pulses for 10 sec) were also (Type 8S, Sanei). depressed dose-dependently by the drugs The uterine activity was represented as tested. The pD2 values calculated from dose- the product of contractile height and fre- response relationships are shown in Table 1. Effects of Ritodrine on Uterine Motilities 321 The potency of ritodrine was about 10 times When ritodrine was administered at 10 mg/kg more than that of isoxsuprine and 1 00-1 000 (i.v.), the maximal suppression was about times less than that of isoproterenol. 60%, and this suppression was restored after Figure 3 shows the interaction of these 120 min. lsoxsuprine (1 mg/kg, i.v.) also three drugs with propranolol. Parallel shifts depressed uterine activity by about 50% for of the dose-response curves to the right were 2 hr. When isoxsuprine was administered at seen for ritodrine, isoxsuprine and iso- 10 mg/kg (i.v.), the suppressive response was proterenol in the presence of propranolol. similar to that of 1 mg/kg administration, but Effects on uterine activity in anesthetized some rats died after 2 hr. lsoproterenol (10 rats: Figure 4 shows the effects of ritodrine, μg/kg,i.v.) showed about 90% suppression isoxsuprine and isoproterenol on uterine of uterine activity, but this response was activity when administered intravenously to immediately restored. rats. Ritodrine (1 mg/kg, i.v.) suppressed The maximal inhibition by ritodrine of the uterine activity by approximately 50%, but uterine activity at 1000 ƒÊg/kgimin infusion this suppression was restored after 30 min. was about 60% at the end of administration. Fig. 2. Effects of ritodrine, isoproterenol and isoxsuprine on spontaneous movements of isolated pregnant rat uterus (19-20th days of gestation). Table 1. Tocolytic effects of the drugs tested which are represented as pD2 values in various preparations of pregnant rat uterus (19-20th days of gestation) Spont: Spontaneous movement; Oxytocin: Oxytocin, 10-2 U/mI; PGF2a: Prostaglandin F2a, 3•~10-6 M; Ach: Acetylcholine, 10-7 g/ml; KCI: KCI, 40 mM; E.S.: Electrical field stimulation; 20 V. 5 msec, 2 Hz, rectangular pulses for 10 sec. 322 S. Ikeda et al. (B) Amplitude (A) Amplitude (C) Amplitude Fig. 3. Concentration-response relationships of ritodrine, isoproterenol and isoxsuprine with and without propranolol in pregnant rat uterus (N=14-20). Fig. 4. Effects of ritodrine, isoproterenol and isoxsuprine on uterine activity in pregnant rats (19-20th days of gestation), N=5. The drugs tested were administered intravenously. Inhibition by isoxsuprine infusion (300 ƒÊg/ 80% depression of uterine activity immediately kg/min) was less than 40%, and no effect after the start of administration, but it was was seen at the end of infusion. Isoproterenol restored gradually even during infusion. infusion (1-10 ,ƒÊg/kg/min) showed about Ritodrine also depressed oxytocin (50 mU/ Effects of Ritodrine on Uterine Motilities 323 kg/min, infusion) induced uterine motility in even at 10 ƒÊg/kg/min infusion, while the a dose-dependent manner. A 10 mg/kg heart rate was markedly decreased. intravenous administration or 1000 ƒÊg/kg/ Table 3 shows the effects of the drugs min infusion of ritodine showed about 70% tested on uterine activity and heart rate in the inhibition. Isoproterenol showed about 80% presence of propranolol. inhibition at 10 ƒÊg/kg (i.v.) and about 90% The actions of ritodrine (1 mg/kg, i.v.) and with a 1 ƒÊg/kg/min infusion, but these isoproterenol (1 ƒÊg/kg, i.v.) were almost inhibitions recovered faster than that of completely abolished by pretreatment with ritodrine.
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