• Biomolecules & Therapeutics
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• v.10 no.1
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• pp.19-24
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• 2002

The effects of a newly synthesized $H^+/K^+$ ATPase inhibitor,1-(2-methyl-4-methoxypheny)-4-[(3-hy-droxypropyl)amino] -6-methyl-2,3-dihydropyrrolo (3,2-c) quinoline (DBM-819) , on the central nervous system, isolated smooth muscle, cardiovascular and digestive systems and renal function were investigated in various experimental animals. Oral administration of DBM-819 had no effect on the central nervous system except body temperature of mice slightly decreased at doses of 15 and 50 mg／kg. DBM-819 produced a moderate analgesic effect in acetic acid-induced writhing test in mice at 50 mg／kg (p.o.). In conscious rats, DBM-819 (15 and 50 mg／kg, p.o.) showed a slight increase in blood pressure and a small decrease in heart rate. DBM-819 had an significant effect on agonist-induced contraction of guinea pig ileum at $1.5{\times}10^{-5}g/ml.$ No significant effect of DBM-819 (5 and 15 mg／kg, i.p) on urinary volume or urinary excretion of $Na^+,\;K^+$ and Cl- was observed in rats. DBM-819 had no significant effect on intestinal transport of a semisolid meal in mice at 15 and 50 mg／kg (p.o.). These findings suggest that DBM-819 exerts no significant pharmacological effects on the central nervous system and renal function at 15 mg／kg (p.o.), but produces some effects on the smooth muscle and circulatory system.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.139-145
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• 2018

The present study was undertaken to investigate the influence of hypothermia on endothelium-independent vascular smooth muscle contractility and to determine the mechanism underlying the relaxation. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Hypothermia significantly inhibited fluoride-, thromboxane $A_{2-}$, phenylephrine-, and phorbol ester-induced vascular contractions regardless of endothelial nitric oxide synthesis, suggesting that another pathway had a direct effect on vascular smooth muscle. Hypothermia significantly inhibited the fluoride-induced increase in pMYPT1 level and phorbol ester-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxing effect of moderate hypothermia on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activities.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.3
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• pp.171-177
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• 2011

Tonic smooth muscle exhibit the latch phenomenon: high force at low myosin regulatory light chains (MRLC) phosphorylation, shortening velocity (Vo), and energy consumption. However, the kinetics of MRLC phosphorylation and cellular activation in phasic smooth muscle are unknown. The present study was to determine whether $Ca^{2+}$-stimulated MRLC phosphorylation could suffice to explain the agonist- or high $K^+$-induced contraction in a fast, phasic smooth muscle. We measured myoplasmic [$Ca^{2+}$], MRLC phosphorylation, half-time after step-shortening (a measure of Vo) and contractile stress in rabbit urinary bladder strips. High $K^+$-induced contractions were phasic at both $22^{\circ}C$ and $37^{\circ}C$: myoplasmic [$Ca^{2+}$], MRLC phosphorylation, 1/half-time, and contractile stress increased transiently and then all decreased to intermediate values. Carbachol (CCh)-induced contractions exhibited latch at $37^{\circ}C$: stress was maintained at high levels despite decreasing myoplasmic [$Ca^{2+}$], MRLC phosphorylation, and 1/half-time. At $22^{\circ}C$ CCh induced sustained elevations in all parameters. 1/half-time depended on both myoplasmic [$Ca^{2+}$] and MRLC phosphorylation. The steady-state dependence of stress on MRLC phosphorylation was very steep at $37^{\circ}C$ in the CCh- or $K^+$-depolarized tissue and reduced temperature flattend the dependence of stress on MRLC phosphorylation compared to $37^{\circ}C$. These data suggest that phasic smooth muscle also exhibits latch behavior and latch is less prominent at lower temperature.

• Molecules and Cells
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• v.22 no.3
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• pp.328-335
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• 2006

Imperatoxin A ($IpTx_a$), a 3.7 kDa peptide from the African scorpion Pandinus imperator, is an agonist of the skeletal muscle ryanodine receptor (RyR1). In order to study the structure of the toxin and its effect on RyR1, $IpTx_a$ cDNA was PCR-amplified using 3 pairs of primers, and the toxin was expressed in E. coli. The toxin was further purified by chromatography, and various point mutants in which basic amino acids were substituted by alanine were prepared by site-directed mutagenesis. Studies of single channel properties by the planar lipid bilayer method showed that the recombinant $IpTx_a$ was identical to the synthetic $IpTx_a$ with respect to high-performance liquid chromatography mobility, amino acid composition and specific effects on RyR1. Mutations of certain basic amino acids ($Lys^{19}$, $Arg^{23}$, and $Arg^{33}$) dramatically reduced the capacity of the peptide to activate RyRs. A subconductance state predominated when $Lys^8$ was substituted with alanine. These results suggest that some basic amino acid residues in $IpTx_a$ are important for activation of RyR1, and that $Lys^8$ plays an important role in regulating the gating mode of RyR1.

• Proceedings of the Ginseng society Conference
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• 2005.11a
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• pp.41-63
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• 2005

Ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. CTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, wehypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum (${\mu}$-receptors) and mouse vas deferens(${\delta}$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H (${\kappa}$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced CAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• Journal of Industrial Convergence
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• v.20 no.7
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• pp.131-137
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• 2022

In the study, we endeavored to assess the convergence effect of Silybum marianum-derived silymarin and epidemiologically-correlated alcohol intake on vascular contractility and to determine the mechanism involved. There were few reports addressing the question whether thin or thick filament modulation is included in ethanol and silymarin-induced regulation. We hypothesized that ethanol at a low concentration and silymarin play a role in agonist-dependent regulation of vascular contractility. Denuded arterial muscles of Sprague-Dawley male rats were suspended in organ baths and isometric tensions were transduced and recorded using isometric transducers and an automatic data acquisition system. Interestingly, both silymarin and ethanol didn't encourage silymarin alone-induced inhibition in agonists-induced contraction suggesting that endothelial nitric oxide synthesis might be involved in ethanol or silymarin-induced modulation of vascular contractility and additional pathways besides endothelial nitric oxide synthesis such as ROCK inactivation might be involved in the silymarin-induced modulation of vascular contractility.

• Journal of Life Science
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• v.20 no.4
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• pp.549-554
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• 2010

Increased external rotation and decreased internal rotation have been noted to occur progressively in the throwing shoulders of baseball pitchers. The purpose of this study was to provide descriptive data for terminal range eccentric antagonist/concentric agonist shoulder muscle strength in collegiate baseball pitchers with humeral head retroversion diagnosed through MRI. The dominant and non-dominant shoulders of 9 asymptomatic baseball pitchers were tested through a range of 20 degrees of external rotation to 90 degrees of internal rotation using the Biodex system 3 isokinetic dynamometer at speeds of $90^{\circ}/s$ and $180^{\circ}/s$. Differences between the dominant and non-dominant shoulders were assessed using the paired samples t-test. Total range of motion, measured at $90^{\circ}$ of glenohumeral abduction, was $180.1^{\circ}$ for dominant shoulders and $183.7^{\circ}$ for non-dominant shoulders. Humeral head retroversion measured $47.6{\pm}6.1^{\circ}$ in dominant and $37.8{\pm}5.3^{\circ}$ in non-dominant extremities. The mean internal rotator concentric contraction (IR-Con) showed a significant difference compared to $31.5{\pm}5.1$ (Nm) in dominant and $38.7{\pm}5.2$ (Nm) in non-dominant shoulders at $180^{\circ}/s$ (p<0.05). The mean external rotator eccentric contraction (ER-Ecc) showed a significant difference compared to $20.3{\pm}4.7$ (Nm) in dominant and $25.1{\pm}3.7$ (Nm) in non-dominant shoulders at $90^{\circ}/s$ (p<0.05). There is a pattern of increased external rotation and decreased internal rotation in the dominant extremity that significantly correlates with an increase in humeral retroversion.

• The Korean Journal of Pharmacology
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• v.25 no.1
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• pp.43-51
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• 1989

Responsiveness of muscarinic and alpha adrenoceptor activation on endothelial cells was studied in isolated canine renal artery rings. Ach (10-100 nM), dose dependently, relaxes endothelial intact rings precontracted with phenylephrine ($IC_{50}$ of Ach was 34.5 nM). Selective mechanical destruction of the endothelium transformed the activity of this substance from vasodilatation to vasoconstriction. Acetylcholine induced relaxations could be selectively inhibited competitively by atropine, but could not be inhibited by cyclooxygenase inhibitor. Methylene blue, however, an inhibitor of soluble guanylate cyclase activity, inhibited Ach as well as sodium nitroprusside (SNP) induced relaxation. Relaxation produced by prostacyclin was not modified by methylene blue. On the other hand, alpha adrenoceptor agonist did not relax but contract canine renal artery rings possessing an intact intima precontracted with U-46619. Clonidine, however, selective alpha-2 adrenergic agonist, is more susceptible than phenylepherine, selective alpha-1 adrenergic agonist, to the inhibitory effect of contraction. These results suggest that in canine renal artery rings, 1) muscarinic receptor is responsible for releasing endothelium dependent relaxation factor (EDRF). 2) alpha-1 and alpha-2 adrenergic receptors are present in canine renal artery. 3) relaxation via EDRF is antagonized by methylene blue, providing further evidence that EDRF acts through a cGMP mechanism.

• Korean Journal of Veterinary Research
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• v.43 no.3
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• pp.361-371
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• 2003

The vasorelaxant actions and blood pressure lowering of the ${\alpha}_2$-adrenoceptor agonists (${\alpha}_2$-AAs) clonidine and xylazine were investigated in rat isolated aortic rings and anesthesized rats. Both clonidine and xylazine produced a concentration-dependent inhibition of the sustained contraction induced by norepinephrine (NE), but not by KCl. NE-induced contractions were attenuated partly by nifedipine or verapamil, voltage dependent $Ca^{2+}$ channel blockers. These $Ca^{2+}$ channel blockers-resistant contractions were abolished by clonidine or xylazine. Inhibitory effects of a ${\alpha}_2$-AAs on contractions could be reversed by ryanodine, an intracellular $Ca^{2+}$, transport blocker, and tetrabutylammonium (TBA), a $Ca^{2+}$ activated $K^+$ channel blocker, but not by nifedipine, glibenclamide or removal of extracellular $Ca^{2+}$ and endothelium. Moreover, ${\alpha}_2$-AAs produced relaxation in NE-precontracted isolated intact aortic rings in a concentration-dependent manner, but not in KCl-precontracted rings. The relaxant effects of ${\alpha}_2$-AAs were inhibited by ryanodine and TBA, but not by nifedipine, glibenclamide, N (G)-nitro-L-arginine (L-NNA), N(omega)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG), 2-nitro-4-carboxyphenyl N,N-diphenylcarhurnte (NCDC), lithium sulfate, staurosporine or removal of extracellular $Ca^{2+}$ and endothelium. In vivo, infusion of xylazine elicited significant decrease in anerial blood pressure. This xylazinelowered blood pressure was completely inhibited by the intravenous injection of TBA, but not by the intravenous injection of glibenclamide, L-NNA, L-NAME, AG, nifedipine, lithium sulfate or saponin.. These findings showed that the receptor-mediated and ${\alpha}_2$-adrenoceptor A-stimulated endothelium-independent vasorelaxant effect may be explained by decreasing intracellular $Ca^{2+}$ release and activation of $Ca^{2+}$-activated $K^+$ channels, which may contribute to the hypotensive effects of ${\alpha}_2$-AAs in rats.

• Journal of Yeungnam Medical Science
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• v.8 no.2
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• pp.95-105
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• 1991

This study was designed to investigate the effect of GABA and related substances on the spontaneous contraction of rat small intestine. The rats(Sprague-Dawley), weighing 200-250g, were sacrificed by cervical dislocation, and the small intestine was isolated. Longitudinal muscle strips from duodenum, jejunum and ileum were suspended in Biancani's isolated muscle chambers and myographied isometrically. GABA and muscimol, a GABA A receptor agonist relaxed the duodenum and jejunum significantly, but baclofen-induced relaxation in those muscle strips was negligible. The effectiveness of GABA and muscimol in various regions were the greatest on duodenum, and greater on jejunum than on ileum The effect of GABA and muscimol was antagonized by bicuculline, a compeptitive GABA A receptor antagonist and picrotoxin, a noncomptitive GABA A receptor antagonist. Duodenal relaxation induced by GABA and muscimol was unaffected by hexamethonium, but was prevented by tetrodotoxin. These results suggest that GABA inhibit the contractility of smooth muscle with distinct regional difference of efficacy, and the site of inhibitory action is the GABA A receptor existing at the presynaptic membrane of postganglionic excitatory nerves.