• The Korean Journal of Physiology and Pharmacology
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• 제24권4호
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• pp.339-348
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• 2020

We aimed to characterize the participation of rapid non-genomic and delayed non-genomic/genomic or genomic mechanisms in vasoactive effects to triiodothyronine (T3), emphasizing functional analysis of the involvement of these mechanisms in the genesis of nitric oxide (NO) of endothelial or muscular origin. Influences of in vitro and in vivo T3 treatments on contractile and relaxant responsiveness of isolated rat aortas were studied. In vivo T3-treatment was 500 ㎍·kg^-1·d^-1, subcutaneous injection, for 1 (T3_1d) and 3 (T3_3d) days. In experiments with endothelium-intact aortic rings contracted with phenylephrine, increasing concentrations of T3 did not alter contractility. Likewise, in vitro T3 did not modify relaxant responses induced by acetylcholine or sodium nitroprusside (SNP) nor contractile responses elicited by phenylephrine or angiotensin II in endothelium-intact aortas. Concentration-response curves (CRCs) to acetylcholine and SNP in endothelium-intact aortic rings from T3_1d and T3_3d rats were unmodified. T3_3d, but not T3_1d, treatment diminished CRCs to phenylephrine in endothelium-intact aortic rings. CRCs to phenylephrine remained significantly depressed in both endothelium-denuded and endothelium-intact, nitric oxide synthase inhibitor-treated, aortas of T3_3d rats. In endothelium-denuded aortas of T3_3d rats, CRCs to angiotensin II, and high K⁺ contractures, were decreased. Thus, in vitro T3 neither modified phenylephrine-induced active tonus nor CRCs to relaxant and contractile agonists in endothelium-intact aortas, discarding rapid non-genomic actions of this hormone in smooth muscle and endothelial cells. Otherwise, T3_3d-treatment inhibited aortic smooth muscle capacity to contract, but not to relax, in an endothelium- and NO-independent manner. This effect may be mediated by delayed non-genomic/genomic or genomic mechanisms.

• 대한약리학회지
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• 제12권1호
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• pp.23-29
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• 1976

최근(最近) 현저한 심근수축증강작용(心筋收縮增强作用)이 알려져 있는 부자(附子) ${\ulcorner}$부타놀${\lrcorner}$ 분획의 작용기전(作用機轉)을 구명(究明)코저 하는 시도(試圖)의 일환으로 심근수축단백(心筋收縮蛋白)에 대한 직접적인 영향을 관찰하였다. 부자${\ulcorner}$부타놀${\lrcorner}$ 분획은 actomyosin ATPase 활성(活性)에 대하며 별(別) 영향을 미치지 않았으며 actin-myosin 상호결합(相互結合)에서 $Ca^{++}$과 유사한 역활을 나타내지도 못했다. 단 actomyosin의 superprecipitation에 대하여는 약간 촉진적(促進的)이었으나 이러한 작용은 actomyosin ATPase 활성(活性)의 증가를 동반치 못했다. 그러나 microsmal $Na^+-K^+$-activated ATPase 활성(活性)은 현저히 억제하였으며 이러한 현상은 부자(附子)${\ulcorner}$부타놀${\lrcorner}$ 분획이 $Ca^{++}$의 membrane transport에 영향을 미칠것으로 인정되는 사실로서 부자(附子)${\ulcorner}$부타놀${\lrcorner}$ 분획의 심근수축증강작용기전(心筋收縮增强作用機轉)의 일부는 근수축단백(筋收縮蛋白)에 대한 직접작용보다는 extracellular 또는 intracellular membrane에서의 $Ca^{++}$ 이동에 영향을 미쳐 세포내 유리 $Ca^{++}$농도를 증가시키는것이 간접적으로 심근수축(心筋收縮)을 촉진(促進)시킬 것으로 사료되었다.

• BMB Reports
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• 제46권5호
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• pp.237-243
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• 2013

Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired $Ca^{2+}$ cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/endoplasmic reticulum $Ca^{2+}$ ATPase 2a (SERCA2a) mediates $Ca^{2+}$ reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR $Ca^{2+}$ uptake, are significantly reduced in failing hearts. Normalization of the SERCA2a expression level by gene delivery has been shown to restore hampered cardiac functions and ameliorate associated symptoms in pre-clinical as well as clinical studies. SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and $PKC{\alpha}$. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation. In this review, we will highlight the molecular mechanisms underlying the regulation of SERCA2a activity and the potential therapeutic modalities for the treatment of heart failure.

• Journal of Pharmaceutical Investigation
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• 제12권3호
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• pp.93-99
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• 1982

The effects of erythrosine on motility of frog heart, rabbit duodenum and uterus isolated, and on mice intestinal motility and voluntary activity were investigated. The effect of erythrosine $2.3{\times}10^{-5}M$ on isolated frog heart showed a slight decrease of the amplitude of motility, and the heart motility stopped in $3.5{\times}10^{-4}M$. With the administration of erythrosine $3.4{\times}10^{-4}M$, the isolated rabbit duodenum showed a remarkable contraction and this effect was inhibited by atropine $1.4{\times}10^{-7}M$. The administration of erythrosine $2.3{\times}10^{-3}M$, produced a contractile effect on the isolated rabbit uterus, and the motility of $6.9{\times}10^{-3}M$ started to increase in contractions at first and finally stopped, keeping in continuous contractions. The effects of erythrosine 0.5, 1.0, 10, and 20mg/kg on mice intestinal motility were not significantly different from this of the normal control. With 20 and 40mg/kg of erythrosine, the effects on voluntary activity showed the decrease of 21 and 58% respectively, and voluntary activity of the mice pretreated with erythrosine 20 and 40mg/kg, induced by C. N. B. 30mg/kg showed the decrease of 57 and 78% respectively in contrast with the normal control group.

• The Korean Journal of Physiology and Pharmacology
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• 제16권1호
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• pp.37-42
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• 2012

The aim of the present study was to elucidate the direct effects of melatonin on bladder activity and to determine the mechanisms responsible for the detrusor activity of melatonin in the isolated rat bladder. We evaluated the effects of melatonin on the contractions induced by phenylephrine (PE), acetylcholine (ACh), bethanechol (BCh), KCl, and electrical field stimulation (EFS) in 20 detrusor smooth muscle samples from Sprague-Dawley rats. To determine the mechanisms underlying the inhibitory responses to melatonin, melatonin-pretreated muscle strips were exposed to a calcium channel antagonist (verapamil), three potassium channel blockers [tetraethyl ammonium (TEA), 4-aminopyridine (4-AP), and glibenclamide], a direct voltage-dependent calcium channel opener (Bay K 8644), and a specific calcium/calmodulin-dependent kinase II (CaMKII) inhibitor (KN-93). Melatonin pretreatment ($10^{-8}{\sim}10^{-6}M$) decreased the contractile responses induced by PE ($10^{-9}{\sim}10^{-4}M$) and Ach ($10^{-9}{\sim}10^{-4}M$) in a dose-dependent manner. Melatonin ($10^{-7}M$) also blocked contraction induced by high KCl ($[KCl]_{ECF}$; 35 mM, 70 mM, 105 mM, and 140 mM) and EFS. Melatonin ($10^{-7}M$) potentiated the relaxation response of the strips by verapamil, but other potassium channel blockers did not change melatonin activity. Melatonin pretreatment significantly decreased contractile responses induced by Bay K 8644 ($10^{-11}{\sim}10^{-7}M$). KN-93 enhanced melatonin-induced relaxation. The present results suggest that melatonin can inhibit bladder smooth muscle contraction through a voltage-dependent, calcium-antagonistic mechanism and through the inhibition of the calmodulin/CaMKII system.

• 대한약리학회지
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• 제26권2호
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• pp.121-126
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• 1990

Lidocaine의 심근 수축력 억제작용의 기전을 규명하기 위한 일환으로 정상 Krebs-Ringer bicarbonate glucose용액에서 각종 대사기질이 lidocaine 억제심방과 정상심방의 수축력에 미치는 영향, 그리고 glucose 제거용액에서 lidocaine의 심방 수축력에 대한 영향을 검토하여 다음과 같은 결과를 얻었다. 1. Pyruvate(5mM), acetate(5mM), fructose(30mM)는 lidocaine에 의해 감소된 심방 수축력을 현저히 증가시켰으나, 정상심장에는 별 영향이 없었다. 2. Glucose(20mM)는 lidocaine억제심방의 수축력을 증가시키지 못하였으나 정상심방의 수축력을 현저히 증가시켰다. 3. Glucose 제거용액에서 lidocaine은 정상용액에서보다 심방 수축력을 현저히 더 감소시켰다. 이상의 결과로 보아 lidocaine은 적출심장에서 외인성 glucose를 제거시, 심장 glycogen의 이용을 glucose phosphate isomerase 단계 혹은 glycogen이 glucose-6-phosphates로 전환되는 단계를 억제한다는 것을 시사하고 있다.

• 한국식품위생안전성학회지
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• 제9권3호
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• pp.163-168
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• 1994

In the present study we investigated the peripheral function of capsaicin and KR-25018, a newly synthesized capsaicin derivative, which was demonstrated to have a potent analgesic activity through different mechanism from morphine and nonsteroidal antiinflammatory drugs. Capsaicin (10-8~10-5 M) and KR-25018 (10-8~10-5 M) produced concentration-dependent contractions of the isolated guinea pig bronchi. There were no significant differences in the maximum response and the EC50 values (EC50: 0.137$\pm$0.025 $\mu$M and 0.097$\pm$0.031 $\mu$M for capsaicin and KR-25018, respectively, P>0.05). Phosphoramidon (10 $\mu$M) and indomethacin (10 $\mu$M) had no significant effect on contractile response to the submaximal concentration range of capsaicin and KR-25018 (3$\times$10-9~3$\times$10-7 M). The response to KR-25018, like that to capsaicin, was significantly inhibited by ruthenium red with reduction in the maximum response, which is indicative of non-competitive antagonism. A further common feature of the responses to capsaicin and KR-25018 in the guinea pig bronchi was their sensitivity to capsazepine. Capsazepine caused a rightward parallel shift in concentration-response curves obtained by capsaicin and KR-25018. the pA2 values of capsazepine were 5.90 and 5.99 against capsaicin and KR-25018 response, respectively. In conclusion, KR-25018 and capsaicin exert their contractile effects in the isolated guinea pig bronchial muscle by common mechanisms, probably via the activation of a specific receptor.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.301-301
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• 1994

〔$^3$H〕Ouabain binding parameters(K$\_$D/ and B$\_$max/,) in homogenates prepared fpom control rat ventricular strip and Langendorff preparations which were not previously exposed to ouabain were compared to those in homogenates from ventricular strip and Langendorff preparations that had been first exposed to a complete ouabain dose-response curve(10$\^$-7/M to 10$\^$-4/ M). In rat ventricular strips and Langendorff perfused rat heart preparations, cumulative dose-response cruves of ouabain revealed biphasic positive inotropic effects, a "low-dose" and a "high-dose" effect with ED$\_$50/ values of 0.5${\mu}$M and 35${\mu}$M ouabain, respectively- The "low-dose" effect in rat ventricular strips disappeared or was diminished significantly when the ouabain dose-response curve wag repeated after the washout of the effects of the first curve, whereas the maximal "high-dose" effect was identical in both exposures to oubain. However, there was no change in the "low-dose" effects in both sets of the Langendorff perfused hearts. The contractile activity of the pre-exposed strips did not indicate the presence of residual ouabain since their basal contractile force was decreased 10% compared to initial control. 〔$^3$H〕Ouabain binding parameters, K$\_$D/ and B$\_$max/, were not changed comparing homogenate of control ventricular strips with that of strips pre-exposed to ouabain. These results suggest that digitalis receptor desensitization in the rat ventricular strip may due to the change of post-receptor events induced by ouabain binding to a high affinity site(${\alpha}$$_2$ isoform).

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.252-252
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• 1996

We Investigated the peripheral excitatory effect of capsaicin and KR-25018, a newly synthesized capsaicin derivative which was demonstrated to have a potent analgesic activity. KR-25018 and capsaicin were found to be both potent efficacious contractors of isolated guinea pig bronchial smooth muscle. KR-25018 was equipotent with capsaicin and [Sar$\^$9/,Met(O$_2$)$\^$11/]-substance P, 10-fold more potent than histamine and 10-fold less potent than (${\beta}$ -Ala$\^$8/)-neurokinin A(4-10), and their -log(M)EC$\_$50/ values were 6.94${\pm}$0.08, 6.86${\pm}$0.05, 6.96${\pm}$0.07, 5.64${\pm}$0.04, 7.96${\pm}$0.02, respectively. Contractile responses to KR-25018 and capsaicin were potentiated by phosphoramidon (1 ${\mu}$M), an inhibitor of neuropeptide-inactivating endopeptidase, but completely abolished in a calcium-free medium. These responses to KR-25018 and capsaicin were unaffected by the NK-1 antagonist CP96345 (1${\mu}$M), partially inhibited by the NK-2 antagonist SR48968 (1 ${\mu}$M) but almost completely abolished by a combination of the antagonists. A vanilloid receptor antagonist capsazepine competitively antagonized the responses to both KR-25018 and capsaicin (pA$_2$: aganst KR-25018, 5.98${\pm}$0.47; against capsaicin, 5.80${\pm}$0.31), and a capsaicin-sensitive cation channel antagonist ruthenium red caused significant reduction in the maximum responses to KR-25018 and capsaicin (pD'$_2$: against KR-25018, 4.61${\pm}$0.33; against capsaicin 4.96${\pm}$0.21). In conclusion, the present results suggest that KR-25018 and cpasaicin act on the same vanilloid receptor inducing the influx of calcium through ruthenium red-sensitive cation channel and produce contractile responses via the release of tachykinins that act on both NK-1 and NK-2 receptor subtypes.

• 대한약리학회지
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• 제8권2호
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• pp.55-61
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• 1972

Superprecipitation of actomyosin has been considered to be an in vitro model of the muscle contraction. The superprecipitation and ATPase activity (which supplies the energy for contraction) are influenced by several factors which are the large amount of changes in ionic strength, Mg and ATP concentrations. But those behaviors are found to be promptly influenced by the change in a small range of calcium concentration which can be controlled by the cellular function of muscle physiologically only in the presence of the modullatory proteins, tropomyosin and troponin. In order to elucidate the precise roles of calcium in the muscle contraction and relaxation, the effects of calcium on the actin- myosin interaction was observed in the presence of tropomyosin and troponin using the superprecipitation system. The results are summarized as follows: 1. EGTA (glycol ether diaminetetraacetic acid)prolonged the initiation of the superprecipitation of natural actomyosin. 2. Superprecipitation curve was declined by adding EGTA at the time when tile curve reached the half- maximum. The degree of declining was proportional to the amount of EGTA added. Especially, upon adding 0.25 mM EGTA the curve was lowered to the level before the protein superprecipitated. But addition of EGTA did not affect the curve after attaining the maximum. 3. Superprecipitation of Perry myosin B was not affected by EGTA added both before and during the course of the reaction. 4. Tropomyosin did not change the response of Perry myosin B to EGTA added at any time of the reaction. 5. Troponin also did not change the response of Perry myosin B to EGTA. 6. Both tropomyosin and troponin together rendered the Perry myosin B to obtain the same response as natural actomyosin to EGTA. 7. It was concluded that actin-myosin interaction was influenced by the minute change of calcium concentration only in the presence of both tropomyosin and troponin. We could reproduce the contraction and relaxation of the muscle in vitro under the presence of ATP by changing the calcium concentration.