• The Korean Journal of Physiology and Pharmacology
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• v.26 no.4
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• pp.255-262
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• 2022

Oxytocin is a neuropeptide produced primarily in the hypothalamus and plays an important role in the regulation of mammalian birth and lactation. It has been shown that oxytocin has important cardiovascular protective effects. Here we investigated the effects of oxytocin on vascular reactivity and underlying the mechanisms in human umbilical vein endothelial cells (HUVECs) in vitro and in rat aorta ex vivo. Oxytocin increased phospho-eNOS (Ser 1177) and phospho-Akt (Ser 473) expression in HUVECs in vitro and the aorta of rat ex vivo. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), inhibited oxytocin-induced Akt and eNOS phosphorylation. In the rat aortic rings, oxytocin induced a biphasic vascular reactivity: oxytocin at low dose (10^-9-10^-8 M) initiated a vasorelaxation followed by a vasoconstriction at high dose (10^-7 M). L-NAME (a nitric oxide synthase inhibitor), endothelium removal or wortmannin abolished oxytocin-induced vasorelaxation, and slightly enhanced oxytocin-induced vasoconstriction. Atosiban, an oxytocin/vasopressin 1a receptor inhibitor, totally blocked oxytocin-induced relaxation and vasoconstriction. PD98059 (ERK1/2 inhibitor) partially inhibited oxytocin-induced vasoconstriction. Oxytocin also increased aortic phospho-ERK1/2 expression, which was reduced by either atosiban or PD98059, suggesting that oxytocin-induced vasoconstriction was partially mediated by oxytocin/V1aR activation of ERK1/2. The present study demonstrates that oxytocin can activate different signaling pathways to cause vasorelaxation or vasoconstriction. Oxytocin stimulation of PI3K/eNOS-derived nitric oxide may participate in maintenance of cardiovascular homeostasis, and different vascular reactivities to low or high dose of oxytocin suggest that oxytocin may have different regulatory effects on vascular tone under physiological or pathophysiological conditions.

• The Korean Journal of Pharmacology
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• v.23 no.2
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• pp.133-141
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• 1987

The effects of verapamil and tetracaine on acetylcholine-and oxytocin-induced contraction of uterus from estrogen-treated rat were examined. Isometric tensions were recorded on the Physiograph and stored in TriGem 20XT computer as digitized data for off-line analysis of the components, which described the contraction patterns: trought tension (T), peak tension (P), contraction frequency (F), and duration (D). In the acetylcholine-induced contraction, verapamil $(0.25\;{\mu}M)$ significantly decreased P and D. In contrast, tetracaine $(42{\mu}M)$ decreased F, but increased D. In the low oxytocin-induced contraction, verapamil $(0.25\;{\mu}M)$ decreased P and D, and tetracaine $(42{\mu}M)$ decreased F but increased D. In the high oxytocin-induced contraction, verapamil decreased P and D, but tetracaine decreased P without affecting on other components. These results suggest that the analysis of effects of a certain inhibitor on the components of contraction allow to postulate its specific inhibitory mechanism of the smooth muscle contraction.

• Journal of Yeungnam Medical Science
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• v.9 no.2
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• pp.359-381
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• 1992

This study was designed to investigate the effect of diazepam on the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus. Female rat(Sprague-Dawley) pretreated with oophorectomy and 4 days administration of estrogen, weighing about 200 g, was sacrificed by cervical dislocation, and the uteruses were isolated. A longitudinal muscle strip was placed in temperature controlled($37^{\circ}C$) muscle chamber containing Locke's solution and myographied isometrically. Diazepam inhibited the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus in a concentration-dependent manner. GABA, muscimol, a GABA A receptor agonist, bicuculline, a competitive GAGA A receptor antagonist, picrotoxin, a non competitive GABA A receptor antagonist, baclofen, a GABA B receptor agonist, and delta-aminovaleric acid, a GABA B receptor antagonist, did not affect on the spontaneous and oxytocin induced contraction of the isolated rat uterus. The inhibitory actions of diazepam on the spontaneous and oxytocin induced contraction were not affected by all the GABA receptor agonists and antagonists, but exceptionally potentiated by bicuculline. This potentiation-effect by bicuculline was not antagonized by muscimol. In normal calcium PSS, addition of calcium restored the spontaneous contraction preinhibited by diazepam and recovered the contractile of oxytocin preinhibited by diazepam. A23187, a calcium inophore, enhanced the restoration of both the spontaneous and oxytocin induced contraction by addition of calcium. In calcium-free PSS, diazepam suppressed the restoration of spontaneous motility by addition of calcium but allowed the recovery of spontaneous motility to a considerable extent. Diazepam could not inhibit some development of contractility by oxytocin in calcium-free PSS, but inhibited the increase in contractility by subsequent addition of calcium. These results suggest that the inhibitory action of diazepam on the rat uterine motility does not depend on or related to GABA receptors and that diazepam inhibits the extracellular calcium influx to suppress the spontaneous and oxytocin induced contractilities.

• CELLMED
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• v.10 no.1
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• pp.2.1-2.8
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• 2020

Uterotonics have the ability to contract uterus. Such plants might be useful in augmenting or inducing labour, expelling retained afterbirth and for abortifacient purposes. Limitations associated with conventional treatments have made herbal medicines a feasible alternative for the management of these conditions. The aim of this study was to evaluate the contractile effects of Uvariodendron kirkii extracts on isolated uterine strips of female Wistar rats. Isolated strips of Wistar rats' uteri were treated with 20, 40, 80 and 160 mg/ml concentrations of Uvariodendron kirkii aqueous extract. The plant extract was also tested against prostaglandin and oxytocin induced uterine contractions. Uvariodendron kirkii extract concentrations (20, 40, 80 and 160 mg/ml) increased the frequency of uterine contraction (16.53, 25.12, 33.48 and 56.39 percentages respectively) compared to the control. The graded extract concentrations caused a significant increase in amplitude (force) of uterine contractions by 2.87, 9.22, 16.37 and 24.32 percentages respectively. The concentrations significantly increased the frequency of oxytocin induced uterine contractions by 6.92; 28.31; 47.06, 58.78 percentages respectively. The graded extract concentrations also significantly increased the amplitude of oxytocin induced uterine contractions by 6.07; 9.40; 15.19 and 23.56 percentages respectively. Uvariodendron kirkii extract concentrations significantly increased the frequency and amplitude of prostaglandin induced contractions. The percentage increase in frequency was 11.44, 8.92, 20.65 and 35.71 at 20, 40, 80 and 160 mg/ml respectively. The mean amplitude of prostaglandin induced uterine contractions also increased (4.75, 3.89, 8.29 and 15.91% at 20. 40, 80 and 160 mg/ml respectively). The extract caused a dose dependent increase in uterine frequency and amplitude of contraction. The findings of thisstudy are useful in generating a novel uterotonic agent that will be useful in augmenting labour or in expelling retained after birth in cattle. More studies at molecular level will further elucidate the plant mechanism of action.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.173-182
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• 2018

Recent studies have provided several lines of evidence that peripheral administration of oxytocin induces analgesia in human and rodents. However, the exact underlying mechanism of analgesia still remains elusive. In the present study, we aimed to identify which receptor could mediate the analgesic effect of intraperitoneal injection of oxytocin and its cellular mechanisms in thermal pain behavior. We found that oxytocin-induced analgesia could be reversed by $d(CH_2)_5[Tyr(Me)^2,Dab^5]$ AVP, a vasopressin-1a (V1a) receptor antagonist, but not by $desGly-NH_2-d(CH_2)_5[D-Tyr^2,Thr^4]OVT$, an oxytocin receptor antagonist. Single cell RT-PCR analysis revealed that V1a receptor, compared to oxytocin, vasopressin-1b and vasopressin-2 receptors, was more profoundly expressed in dorsal root ganglion (DRG) neurons and the expression of V1a receptor was predominant in transient receptor potential vanilloid 1 (TRPV1)-expressing DRG neurons. Fura-2 based calcium imaging experiments showed that capsaicin-induced calcium transient was significantly inhibited by oxytocin and that such inhibition was reversed by V1a receptor antagonist. Additionally, whole cell patch clamp recording demonstrated that oxytocin significantly increased potassium conductance via V1a receptor in DRG neurons. Taken together, our findings suggest that analgesic effects produced by peripheral administration of oxytocin were attributable to the activation of V1a receptor, resulting in reduction of TRPV1 activity and enhancement of potassium conductance in DRG neurons.

• The Korean Journal of Pharmacology
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• v.32 no.2
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• pp.221-231
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• 1996

The properties of cytosolic $Ca^{2+}$ level$([Ca^{2+}]_i)$ movement of high KCl, carbachol and oxytocin were examined with myometrium isolated from non-pregnant rat(estrus cycle). High concentration of KCl$({\leq}23.3mM)$ induced rhythmic increases in $[Ca^{2+}]_i$ and muscle contraction. However, sustained $[Ca^{2+}]_i$ and contracion were obtained at higher KCl concentration $({\geq}30.3mM)$ The rhythmic and sustained contraction closely associated with changes in $[Ca^{2+}]_i$ induced by high KCl. Carbachol $(3{\sim}30{\mu}M$ generated rhythmic increases with tonic component in $[Ca^{2+}]_i$ and muscle contraction. Myometrial contraction stimulated by carbachol was also closely correlated with change in $[Ca^{2+}]_i$. And the $[Ca^{2+}]_i/contraction$ relationships were similar when muscle strips were stimulated by high KCl and carbachol. Maximal concentration of carbachol $(10{\mu}M)$ and oxytocin(100 nM) increased $[Ca^{2+}]_i$ and contraction which were slightly greater than that of high KCl in non-pregnant myometrium, respectively. However, the $[Ca^{2+}]_i$ and contraction were strongly inhibited by verapamil $(10{\mu}M)$, a 1-type $Ca^{2+}$ channel blocker, as in the case of high KCl. Additionally, although carbachol further increased $[Ca^{2+}]_i$ and contraction induced by high KCl, these changes also strongly inhibited by application of verapamil. These results suggest that uterotonic agents, carbachol and oxytocin, induced contraction by increase in $[Ca^{2+}]_i$ through $Ca^{2+}$ influx than by a regulation of $Ca^{2+}-sensitization$ in non-pregnant myometrium.

• Clinical and Experimental Reproductive Medicine
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• v.43 no.4
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• pp.233-239
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• 2016

Objective: Uterine contraction induced by the embryo transfer (ET) process has an adverse effect on embryo implantation. The aim of this study was to determine the effect of oxytocin antagonist supplementation on the day of ET on in vitro fertilization outcomes via a meta-analysis. Methods: We performed a meta-analysis of randomized controlled trials (RCTs). Four online databases (Embase, Medline, PubMed, and Cochrane Library) were searched through May 2015 for RCTs that investigated oxytocin antagonist supplementation on the day of ET. Studies were selected according to predefined inclusion criteria and meta-analyzed using RevMan 5.3. Only RCTs were included in this study. The main outcome measures were the clinical pregnancy rate, the implantation rate, and the miscarriage rate. Results: A total of 123 studies were reviewed and assessed for eligibility. Three RCTs, which included 1,020 patients, met the selection criteria. The implantation rate was significantly better in patients who underwent oxytocin antagonist infusion (19.8%) than in the control group (11.3%) (n = 681; odds ratio [OR], 1.92; 95% confidence interval [CI], 1.25-2.96). No significant difference was found between the two groups in the clinical pregnancy rate (n = 1,020; OR, 1.57; 95% CI, 0.92-2.67) or the miscarriage rate (n = 456; OR, 0.76; 95% CI, 0.44-1.33). Conclusion: The results of this meta-analysis of the currently available literature suggest that the administration of an oxytocin antagonist on the day of ET improves the implantation rate but not the clinical pregnancy rate or miscarriage rate. Additional, large-scale, prospective, randomized studies are necessary to confirm these findings.

• Korean Journal of Veterinary Research
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• v.36 no.1
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• pp.83-91
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• 1996

Activation of $K^+$ channels induces relaxation of smooth muscles by reducing electrical excitability and cytosolic free $Ca^{2+}$ level. ${\beta}$-adrenergic agonist isoproterenol is known to induce relaxation of the uterine smooth muscle by membrane hyperpolarization and $K^+$ efflux. Recently it is suggested that the activity of $Ca^{2+}$-activated $K^+$ channel was increased by isoproterenol in the uterine myocytes isolated from myometrium of the pregnant rat. However, the type of $K^+$ channel mediating the relaxant effect of isopreterenol in the tissue level has not yet studied. In this work, we investigated the type of $K^+$ channels involved in the isoproterenol-induced relaxation of uterine smooth muscle by measuring the integrated insometric tension of the estrogen-treated isolated nonpregnant rat uterus. Contraction of uterine tissue was induced by oxytocin (0.2nM, 2~3 contractions/min) or high KCl(20~80mM). The result are as follows : 1. Isoproterenol($10^{-10}{\sim}10^{-4}M$) inhibited oxytocin-induced contraction of isolated rat uterus($EC_{50}=1.17{\times}10^{-10}M$). 2. Isoproterenol($10^{-10}{\sim}10^{-4}M$) effectively inhibited uterine contraction induced by low KCl(20~40mM) but little those induced by high KCl(60~80mM). 3. Relaxant effect of isoproterenol($10^{-10}{\sim}10^{-4}M$) on 0.2nM oxytocin-induced contraction was effectively reduced by 4-aminopyridine(3, 10mM) but little by TEA(10~30mM), $Ba^{2+}$($1{\sim}30{\mu}M$) and glibenclamide($100{\mu}M$). Our data suggest that the relaxant effect of isoproterenol is mediated by the $K^+$ channel(s) which can be blocked by 4-aminopyridine.

• The Korean Journal of Pharmacology
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• v.24 no.1
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• pp.103-109
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• 1988

Cyclobuxine D, extracted from Buxus microphylla var. koreana Nakai, is a steroidal alkaloid. Many pharmacological effects of cyclobuxine D were examined in our Lab. Cyclobuxine D showed a significant bradycardic effect in the rat heart and an inhibitory action on acetylcholine and $Ba^{++}-induced$ contraction of the longitudinal muscle isolated from the rabbit jejunum. In this study, we investigated the effect of cyclobuxine D on the contractile response-elicited by acetylcholine, oxytocin and $Ba^{++}$ in rat uterine. In order to analyse the inhibitory action of cyclobuxine D on the smooth muscle, we examined the inhibitory action of cyclobuxine D against the contractile response of the high potassium-depolarized rat ileum to calcium. Concentration-dependent decrease in the peak tension and duration of the acetylcholine, oxytocin and $Ba^{++}-induced$ contraction in the isolated rat uterus was observed when cyclobuxine D was added to the organ bath. The isolated longitudinal muscle from the rat ileum was immersed calcium-depleted potassium-depolarizing solution. Ten minutes after, 1.8 mM $CaCl_2$ was added to muscle bath and elicited a biphasic increase in muscle tension. Cyclobuxine D $(6.2{\times}10^{-5}\;M)$ produced an appreciable inhibition of both components of the mechanical response. In addition, $3.1{\times}10^{-4}\;M$ cyclobuxine D, introduced at a point when the tonic response had reached its maximum level, caused the muscle to exhibit a rapid lose of tension. Based on these experimental results, we propose the possibility that the inhibitory action of cyclobuxine D on the acetylcholine, oxytocin and $Ba^{++}-induced$ contraction in the isolated rat uterus may be due to blocking potassium-activated calcium channels, voltage-sensitive calcium channels.

• Clinical and Experimental Pediatrics
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• v.60 no.12
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• pp.385-389
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• 2017

Purpose: This study aimed to assess whether different anesthetic techniques and oxytocin use applied during delivery affect transcutaneous bilirubin levels during the first 24 hours in neonates. Methods: A total of 1,044 neonates delivered by either caesarian section (C/S) or normal vaginal delivery (NVD) were included in the study. They were classified into 5 groups as follows: group 1: born by C/S using general anesthesia, group 2: C/S using spinal anaesthesia, group 3: C/S using general anesthesia after failed spinal block, group 4: by NVD without anesthesia, and group 5: oxytocin-induced vaginal delivery without anesthesia. Transcutaneous total bilirubin levels (TBLs) were measured during the first 24 hours and on the fifth and eighth days of life and the levels in different groups were compared. Results: The TBLs were significantly higher in neonates delivered by C/S using general anesthesia rather than spinal anesthesia (P<0.001), and both groups had higher levels than those born by NVD without anesthesia ($P{\leq}0.001$). However, the group receiving general anesthesia after failed spinal block was found to have the highest bilirubin level. Moreover, TBLs were significantly higher with the use of oxytocin ($P{\leq}0.001$). Conclusions: C/S and general anesthesia adversely affect the bilirubin levels in neonates, and the use of oxytocin during vaginal delivery also increases TBLs in neonates.