• The Korean Journal of Physiology and Pharmacology
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• v.21 no.4
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• pp.429-437
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• 2017

The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4- dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)- 3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-$F2{\alpha}$ ($PGF2{\alpha}$)-induced phasic, $K^+$-induced tonic, and $Ca^{2+}$-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ ($TNF{\alpha}$) and interleukin (IL)-$1{\beta}$, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced $TNF{\alpha}$ and $IL-1{\beta}$ uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

• The Korean Journal of Pharmacology
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• v.17 no.1 s.28
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• pp.9-15
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• 1981

Aconiti tuber butanol fraction, which is isolated from the chloroform insoluble and water soluble extract of Aconitum volubile, has been recently known to have a potent positive inotropic effect in the isolated cardiac muscle preparations of various animals. The positive inotropic mechanism of Aconiti tuber butanol fraction, in relation with the external calcium, was studied using the isolated cat papillary muscle. The positive inotropic effect was dependent on the calcium concentration in the nutrient medium, and a synergistic relation could be demonstrated between Aconiti tuber butanol fraction and the external calcium. The inotropic effect of $10^{-4}g/ml$ of Aconiti tuber butanol fraction was equivalent to that of 0.06mM of calcium in the medium. After the treatment with a calcium influx inhibitor, Verapamil$(2{\pm}10^{-7}-10^{-6}M)$, the contractile force of the papillary muscle was markedly inhibited. In these preparations, Aconiti tuber butanol fraction restored the decreased contractility in a dose-dependent manner. It was suggested that the positive inotropic effect of Aconiti tuber butanol fraction might be related with the stimulating action on the calcium influx through the slow inward calcium channels in the cardiac cell membrane. In contrast with digitalis cardiac glycoside, Aconiti tuber butanol fraction infused intravenously into the anesthetized rabbit decreased the systemic arterial blood pressure and increased the carotid blood flow, but produced no prominent changes in the heart rate.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.191-203
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• 1994

$K^+$ channel openers (KCOs) are known to have a wide range of effects by opening the $K^+$ channel in plasma membranes of various smooth muscles, cardiac muscle and pancreatic ${\beta}-cell$. In the present study, we investigated the effects of 5 types of KCOs, cromakalim, RP49356, pinacidil, nicorandil and diazoxide on the contractility of isolated rat uterus. All KCOs tested inhibited the uterine contraction induced by 0.2 nM oxytocin in a dose-dependent manner. Individual KCO and its $pD_2$ values were cromakalim 6.5, RP49356 6.3, pinacidil 5.92, nicorandil 4.43 and diazoxide 4.18. The relaxant effects of KCO were inhibited by glibenclamide (0.3, 1 and $10\;{\mu}M$) with $pA_2$ values of cromakalim 6.91, RP49356 6.59, pinacidil 6.55, nicorandil 5.97 and diazoxide 6.37. In addition, the relaxant effect of cromakalim or pinacidil was antagonised by TEA, a non-selective $K^+$ channel blocker, but not by apamin. Contractions induced by low concentration of KCI (< 40 mM) were inhibited by cromakalim $(100{\mu}M)$ and nicorandil $(300{\mu}M)$, but those evoked by higher concentration (> 40 mM) of KCI were little affected. In ovariectomized rat uterus, cromakalim dose-dependently inhibited oxytocin-induced contraction and glibenclamide $(10{\mu}M)$ inhibited the relaxant effect of cromakalim with $pD_2$ and $K_B$ values of 7.48 and $1.26{\times}10^{-7}M$, respectively. In estrogen-primed rat uterus, these values were 6.51 and $1.57{\times}10^{-7}M$, respectively, indicating that the cromakalim is less effective on the estrogen-treated uterine smooth muscle. Our results suggest that the KCO-sensitive $K^+$ channels participate in the motility of uterine smooth muscle and such channels are, at least in part, under the control of estrogen. In addition, our data Indicate that the type of $K^+$ channels activated by KCO is ATP-sensitive $K^+$ channels which is blocked by glibenclamide.

• Journal of Veterinary Clinics
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• v.32 no.5
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• pp.422-425
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• 2015

This study evaluated the myocardial performance on echocardiography after the sedation/anesthesia of medetomidine (D), the combination of medetomidine and tiletamine/zolazepam (DZ), and the combination of medetomidine, tiletamine/zolazepam and tramadol (DZT) in Beagle dogs. Ten healthy adult Beagle dogs (weighing $8.6{\pm}1.0kg$) were enrolled in this study. Heart rate (HR), fractional shortening (%FS), left ventricular ejection fraction (%LVEF), stroke volume (SV), cardiac output (CO), left ventricular internal diameter in systole (LVIDs) and left ventricular internal diameter in diastole (LVIDd) using M-mode echocardiography were measured prior to anesthesia, then every 10 min for 60 min. The HR, %FS, %LVEF, SV and CO were significantly decreased during sedation/anesthesia with D, DZ and DZT combination of anesthesia. Although those anesthetic protocols provided acceptable quality of sedation/anesthesia, levels of cardiovascular suppression were substantial and persistent and thus the continuous monitoring on vital signs should be accompanied in any situation. Close attention is required for dogs with pre-existing heart diseases, when those anesthetic protocols were applied.

• Korean Journal of Veterinary Research
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• v.34 no.3
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• pp.493-500
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• 1994

The purpose of this study was to investigate the effects of neurotransmitters and the source of $Ca^{2+}$ in the effects of neurotransmitters on the motility of pig oviductal isthmic smooth muscle. The motility of the isolated smooth muscle was recorded by using physiological recording system. The results were summarized as follows; Acetylcholine, norepinephrine, histamine and prostaglandin $F_{2{\alpha}}(PGF_{2{\alpha}})$ caused the contraction and the contractile responses were increased in a dose-dependent manner from the concentration of $10^{-7}$ to $10^{-4}M$. The maximum contractility of acetylcholine, norepinephrine, histamine and $PGF_{2{\alpha}}$ was 65.99, 28.66, 83.99 and 47.33% of 100 mM K contraction, respectively. The contractile response induced by acetylcholine$(10^{-6}M)$ was completely blocked by the pretreatment with cholinergic receptor blocker, atropine$(10^{-6}M)$, the contractile response induced by norepinephrine$(10^{-5}M)$ was blocked by the pretreatment with ${\alpha}$-adrenergic receptor blocker, phentolamine$(10^{-6}M)$ but was not blocked and rather increased by the pretreatment with ${\beta}$-adrenergic receptor blocker. propranolol$(10^{-6}M)$, the contractile response induced by histamine$(10^{-6}M)$ was completely blocked by the pretreatment with $H_1$-histaminergic receptor blocker, pyrilamine$(10^{-6}M)$ but was increased by the pretreatment with $H_2$-histaminergic receptor blocker, cimetidine$(10^{-6}M)$. The contractile response induced by acetylcholine$(10^{-6}M)$, norepinephrine$(10^{-5}M)$ and histamine$(10^{-6}M)$ was weakly contracted response in $Ca^{2+}$-free medium, but the contractile response induced by $PGF_{2{\alpha}}(10^{-6}M)$ was disappeared. The contractile response induced by acetylcholine$(10^{-6}M)$, norepinephrine$(10^{-5}M)$ and histamine$(10^{-6}M)$ was powerfully depressed by the pretreatment with $Ca^{2+}$-channel blocker, verapamil$(10^{-5}M)$ but the contractile response induced by $PGF_{2{\alpha}}(10^{-6}M)$ was completely inhibited.

• The Korean Journal of Nuclear Medicine
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• v.27 no.2
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• pp.155-160
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• 1993

The identification of viable myocardium in patients with coronary artery disease and left ventricular dysfunction is an issue of increasing clinical relavance in the current era of myocardial revascularization. There are at least two forms of reversible myocardial dysfunction. Early reperfusion does not always lead to immediate functional improvement; rather, the return of contractility in tissue salvaged by reperfusion is delayed for hours, days or even weeks, a phenomenon that has been termed "stunned myocardium". Some patients with coronary artery disease show myocardial dysfunction at rest which are associated with reduced perfusion, and which disappear after revascularization; this phenomenon has been termed "hibernating myocardium". Recently, cardiac imaging techniques that evaluate myocardial viability on the basis of perfusion-contraction mismatch and inotropic reserve have gained substantial popularity and clinical success. This review focus on the application of $^{201}TI$ and $^{99m}Tc-MIBI$ to address myocardial viability in patients with hibernating and stunned myocardium. It is clear that 4-hour redistribution images of $^{201}TI$ underestimate ischemia and overestimate scar. Delayed imaging and reinjection imaging have been developed for the assessment of viability. Among many protocols suggested, stress-redistribution-reinjection imaging gained most popularity. Although $^{99m}Tc-MIBI$ could identify myocardial viability, $^{201}TI$ reinjection technique was regarded as superior to it. In conclusion, $^{201}TI$ stress, 4-hr rest redistribution, and reinjection imaging technique may be the most preferable method for evaluation of myocardial viability.

• Development and Reproduction
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• v.13 no.2
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• pp.79-87
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• 2009

Due to its well-known function in parturition and milk ejection, oxytocin (OT) has been considered as a 'female neurohypophyseal hormone'. Recent studies, however, clearly indicate that OT has some local roles in male reproduction via both central and peripheral routes. In experimental rodents, OT is released within distinct brain regions in response to social stimuli, and the brain OT receptor (OTR) mediated actions were strongly involved in the regulation of a variety of male behaviors such as mating-associated behaviors. In particular, OT and/or OTR knockout mice provide important clues about the molecular regulatory mechanism of the socio-sexual behaviors. Several lines of evidence also show that OT is synthesized within rodents testis, epididymis and prostate, and the presence of OTRs in these organs. In rodent testes, OT might have a role in the modulation of steroidogenesis via stimulation of the conversion of testosterone (T) to dihydrotestosterone (DHT) by 5alpha-reductase. Similar effects of OT on this androgen conversion were observed in epididymis and prostate suggesting the OT's modulatory role, such as contractility induction, in these androgen-dependent organs. In this context, further investigations on the OT's role in male CNS and reproductive organs are likely to provide better understanding on the complex socio-sexual behaviors and a platform for development of therapeutics to treat some psychological and/or andrological problems.

• The Korean Journal of Pharmacology
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• v.26 no.1
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• pp.25-33
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• 1990

The responsiveness of various arterial smooth muscles isolated from rabbit to peptide YY (PYY) and the calcium source responsible for the muscles to contract were studied in vitro. PYY contracted the muscle strips of femoral, basilar and common iliac arteries more sensitively than renal, superior mesenteric and common carotid arteries. Common carotid and renal arteries were less sensitive to PYY $(p{\leqslant}0.05)$ than to NE; and basilar artery was more sensitive to PYY$(p{\leqslant}0.01)$ than to NE. A calcium channel blocker, verapamil and an inhibitor of intracellular calcium release, 3, 4, 5-Trime-thoxybenzoic arid 8-(diethylamino)octyl ester [TMB-8] significantly $(p{\leqslant}0.001)$ suppressed the concentration-response of the strips from femoral artery to PYY. When both verapamil and TMB-8 existed in normal PSS, the concentration-response to PYY was inhibited almost completely; and a similar suppression was observed when the muscle was incubated in calcium-free, ethyleneglycol-bis-(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid [EGTA] containing PSS. The results of these experiments suggest that increased PYY activity in circulation may result in the more sensitive increase in the intracranial vascular resistance and the cerebral arterial pressure than the increased sympathetic activity and that both intra- and extracellular calcium are to be utilized for the PYY-induced contraction on arterial smooth muscle.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.1
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• pp.37-44
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• 2017

Regulation of vascular smooth muscle cell (VSMC) phenotype plays an essential role in many cardiovascular diseases. In the present study, we provide evidence that $kr{\ddot{u}}ppel$-like factor 8 (KLF8) is essential for tumor necrosis factor ${\alpha}$ ($TNF{\alpha}$)-induced phenotypic conversion of VSMC obtained from thoracic aorta from 4-week-old SD rats. Stimulation of the contractile phenotype of VSMCs with $TNF{\alpha}$ significantly reduced the VSMC marker gene expression and KLF8. The gene expression of KLF8 was blocked by $TNF{\alpha}$ stimulation in an ERK-dependent manner. The promoter region of KLF8 contained putative Sp1, KLF4, and $NF{\kappa}B$ binding sites. Myocardin significantly enhanced the promoter activity of KLF4 and KLF8. The ectopic expression of KLF4 strongly enhanced the promoter activity of KLF8. Moreover, silencing of Akt1 significantly attenuated the promoter activity of KLF8; conversely, the overexpression of Akt1 significantly enhanced the promoter activity of KLF8. The promoter activity of SMA, $SM22{\alpha}$, and KLF8 was significantly elevated in the contractile phenotype of VSMCs. The ectopic expression of KLF8 markedly enhanced the expression of SMA and $SM22{\alpha}$ concomitant with morphological changes. The overexpression of KLF8 stimulated the promoter activity of SMA. Stimulation of VSMCs with $TNF{\alpha}$ enhanced the expression of KLF5, and the promoter activity of KLF5 was markedly suppressed by KLF8 ectopic expression. Finally, the overexpression of KLF5 suppressed the promoter activity of SMA and $SM22{\alpha}$, thereby reduced the contractility in response to the stimulation of angiotensin II. These results suggest that cross-regulation of KLF family of transcription factors plays an essential role in the VSMC phenotype.

• The Korean Journal of Pharmacology
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• v.24 no.2
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• pp.189-195
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• 1988

This study aimed to investigate the autonomic innervations of human vas deferens and the effect of diazepam, a benzodiazepine sedative antianxiety drug, on the smooth muscle contractility of vas deferens. The specimens were obtained from healthy volunteers undergoing elective vasectomy with local anesthesia. The muscle preparation did not show any spontaneous contraction, but showed a good contraction induced by norepinephrine exerting the strongest response at $33^{\circ}C$. Phentolamine inhibited the norepinephrine-induced contraction concentration-dependently. Isoproterenol, a beta-adrenergic agonist evoked a considerable extent of contraction, and this contractile activity was antagonized by propranolol, a beta-adrenergic blocking agent. Acetylcholine induced a dashing contraction of the human vas deferens, and atropine, a muscarinic receptor blocking agent abolished the acetylcholine-induced contraction. Diazepam inhibited the norepinephrine-induced contraction in a concentration dependent manner. These results suggest that the smooth muscle of human vas deferens has cholinergic muscarinic and beta adrenergic receptors as well as the predominant alpha adrepergic receptor. Diazepam inhibits the motility, especially norepinephrine-induced contraction of human vas deferens.