• The Korean Journal of Physiology and Pharmacology
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• 제24권4호
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• pp.287-298
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• 2020

Ca²⁺ signaling of endothelial cells plays a critical role in controlling blood flow and pressure in small arteries and arterioles. As the impairment of endothelial function is closely associated with cardiovascular diseases (e.g., atherosclerosis, stroke, and hypertension), endothelial Ca²⁺ signaling mechanisms have received substantial attention. Increases in endothelial intracellular Ca²⁺ concentrations promote the synthesis and release of endothelial-derived hyperpolarizing factors (EDHFs, e.g., nitric oxide, prostacyclin, or K⁺ efflux) or directly result in endothelial-dependent hyperpolarization (EDH). These physiological alterations modulate vascular contractility and cause marked vasodilation in resistance arteries. Transient receptor potential (TRP) channels are nonselective cation channels that are present in the endothelium, vascular smooth muscle cells, or perivascular/sensory nerves. TRP channels are activated by diverse stimuli and are considered key biological apparatuses for the Ca²⁺ influx-dependent regulation of vasomotor reactivity in resistance arteries. Ca²⁺-permeable TRP channels, which are primarily found at spatially restricted microdomains in endothelial cells (e.g., myoendothelial projections), have a large unitary or binary conductance and contribute to EDHFs or EDH-induced vasodilation in concert with the activation of intermediate/small conductance Ca²⁺-sensitive K⁺ channels. It is likely that endothelial TRP channel dysfunction is related to the dysregulation of endothelial Ca²⁺ signaling and in turn gives rise to vascular-related diseases such as hypertension. Thus, investigations on the role of Ca²⁺ dynamics via TRP channels in endothelial cells are required to further comprehend how vascular tone or perfusion pressure are regulated in normal and pathophysiological conditions.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.769-774
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• 1997

Non-neuronal high affinity binding sites for benzodiazepines have been found in many peripheral tissues including cardiac muscle and vascular smooth muscle, and have been designated as 'peripheral benzodiazepine receptor'. Benzodiazepines have been shown to induce relaxation of the ileal, vesical, and uterine smooth muscles. However, it is still unclear about possible involvement of peripheral benzodiazepine receptor on the contractility of trachealis muscle. This study was performed to investigate the role of the peripheral benzodiazepine receptor on the contractility of canine trachealis muscle. Canine trachealis muscle strips of 15 mm long were suspended in an isolated organ bath containing 1 ml of physiological salt solution maintained at $37^{\circ}C$, and aerated with $95%\;O_2/5%\;CO_2$. Isometric myography was performed, and the results of the experiments were as follows: Ro5-4684, FGIN-1-27 and clonazepam reduced a basal tone of isolated canine trachealis muscle strip concentration dependently, relaxant actions of RoS-4684 and FGIN-1-27 were antagonized by PK11195, a peripheral benzodiazepine receptor antagonist. Flumazenil, a central type antagonist, did not antagonize the relaxant action of Peripheral type agonists. Saturation binding assay of [3H]Ro5-4864 showed a high affinity$(Kd=5.33{\pm}1.27nM,\;Bmax=\;867.3{\pm}147.2\;fmol/mg\;protein)$ binding site on the canine trachealis muscle. Ro 5-4684 suppressed the bethanechol-, 5-hydroxyoyptamine- and histamine- induced contractions. Platelet activating factor (PAF) exerted strong and prolonged contraction in trachealis muscle strip. Strong tonic contraction by PAE was attenuated by Ro 5-4684, but not by WEB 2086, a PAF antagonist. Based on these results, it is concluded that the peripheral benzodiazepine receptor mediates the inhibitory regulation of contractilty of canine trachealis muscle.

• Biomolecules & Therapeutics
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• 제13권1호
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• pp.48-58
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• 2005

The present study was conducted to investigate the effects of nicorandil on arterial blood pressure and vascular contractile responses in the normotensive anesthetized rats and to establish the mechanism of action. Nicorandil (30~300 ${\mu}g/kg$) given into a femoral vein of the normotensive anesthetized rat produced a dose-dependent depressor response. These nicorandil-induced hypotensive responses were not affected by pretreatment with atropine (3.0 mg/kg, i.v.) or propranolol (2.0 mg/kg, i.v.), while markedly inhibited in the presence of chlorisondamine (1.0 mg/kg, i.v.) or phentolamine (2.0 mg/kg, i.v.). Futhermore, after the pretreatment with 4-aminopyridine (1.0 mg/kg/30 min, i.v.) or glibenclamide (50.0 ${\mu}g/kg$/30min) into a femoral vein made a significant reproduction in pressor responses induced by intravenous norepinephrine. In he isolated rat aortic strips, both phenylephrine (10$^{-5}$ M)- and high potassium (5.6 ${\times}\;10^{-2}$ M)-inducedcontractile responses were dose-dependently depressed in the presence of nicorandil (25~100 ${\mu}M$). Collectively, these experimental results demonstrate that intravenous nicorandil causes a dose-dependent depressor action in the anesthetized rat at least partly through the blockade of vascular adrenergic ${\alpha}_1$-receptors, in addition to the well-known mechanism of potassium channel opening-induced vasorelaxation.

• 약학회지
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• 제51권5호
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• pp.301-306
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• 2007

Rosiglitazone ($Avandia^{(R)}$) represents a new class of antidiabetic drugs which are $PPAR{\gamma}$ agonists. The present study was undertaken to determine whether the new antidiabetic rosiglitazone influences on the agonist-induced regulation of vascular smooth muscle contraction as an antihypertensive and, if so, to investigate the related mechanism. Endothelium-denuded arterial rings from male Sprague-Dawley rats were used and isometric contractions were recorded using a computerized data acquisition system. Rosiglitazone decreased Rho-kinase activating agonist (NaF or thromboxane $A_2$ mimetic)-induced contraction but not depolarization- or phorbol ester-induced contraction. Surprisingly, it slightly potentiated the latter contraction possibly opening a voltage-dependent calcium channel by its chemical structure on 50 mM KCI- or $1{\mu}M$ phorbol 12,13-dibutyrate-induced vasoconstriction. In conclusion, this study provides the evidence and possible related mechanism concerning the biphasic effect of an antidiabetic rosiglitazone as a possible antihypertensive on the agonistinduced contraction in rat aortic rings regardless of endothelial function.

• 약학회지
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• 제53권3호
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• pp.156-160
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• 2009

The present study was undertaken to determine whether transgelin participates in the regulation of vascular smooth muscle contraction and, if so, to investigate the mechanism. By PCR homology cloning, the cDNA sequence of ferret transgelin was determined and phosphorothioate antisense and random oligonucleotides were synthesized and introduced into strips of ferret aorta by a chemical loading procedure. Treatment of ferret aorta with transgelin antisense oligonucleotides resulted in a significant decrease in protein levels of transgelin to sham- or random sequence-loaded muscles, but no change in the protein levels of actin. Contraction in response to a phorbol ester was significantly decreased in antisense-treated muscles compared to sham- or random sequence-loaded controls. Neither basal intrinsic tone nor the contraction in response to phenylephrine was significantly affected by the antisense treatment. The data indicate that transgelin plays a significant role in the regulation of contraction and suggest that in a tonically active smooth muscle transgelin may function as a signalling protein to facilitate PKC or ERK-dependent signalling rather than thick filament regulation including $Ca^{2+}$ or calmodulin dependent regulation of myosin light chain kinase.

• Molecules and Cells
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• 제27권2호
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• pp.191-198
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• 2009

The present study was undertaken to determine whether treatment with genistein, the plant-derived estrogen-like compound influences agonist-induced vascular smooth muscle contraction and, if so, to investigate related mechanisms. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Genistein completely inhibited KCl-, phorbol ester-, phenylephrine-, fluoride- and thromboxane $A_2$-induced contractions. An inactive analogue, daidzein, completely inhibited only fluoride-induced contraction regardless of endothelial function, suggesting some difference between the mechanisms of RhoA/Rho-kinase activators such as fluoride and thromboxane $A_2$. Furthermore, genistein and daidzein each significantly decreased phosphorylation of MYPT1 at Thr855 had been induced by a thromboxane $A_2$ mimetic. Interestingly, iberiotoxin, a blocker of large-conductance calcium-activated potassium channels, did not inhibit the relaxation response to genistein or daidzein in denuded aortic rings precontracted with fluoride. In conclusion, genistein or daidzein elicit similar relaxing responses in fluoride-induced contractions, regardless of tyrosine kinase inhibition or endothelial function, and the relaxation caused by genistein or daidzein was not antagonized by large conductance $K_{Ca}$-channel inhibitors in the denuded muscle. This suggests that the RhoA/Rho-kinase pathway rather than $K^+$- channels are involved in the genistein-induced vasodilation. In addition, based on molecular and physiological results, only one vasoconstrictor fluoride seems to be a full RhoA/Rho-kinase activator; the others are partial activators.

• Biomolecules & Therapeutics
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• 제31권2호
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• pp.193-199
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• 2023

In this investigation, we made a study of the efficacy of luteolin (a flavonoid found in plants such as vegetables, herbs and fruits) on vascular contractibility and to elucidate the mechanism underlying the relaxation. Isometric contractions of denuded muscles were stored and combined with western blot analysis which was conducted to assess the phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and phosphorylation-dependent inhibitory protein for myosin phosphatase (CPI-17) and to examine the effect of luteolin on the RhoA/ROCK/CPI-17 pathway. Luteolin significantly alleviated phorbol ester-, fluoride- and thromboxane mimetic-elicited contractions regardless of endothelial nitric oxide synthesis, implying its direct effect on smooth muscle. It also significantly alleviated the fluoride-elicited elevation in pCPI-17 and pMYPT1 levels and phorbol 12,13-dibutyrate-elicited increase in pERK1/2 level, suggesting depression of ROCK and PKC/MEK activity and ensuing phosphorylation of MYPT1, CPI-17 and ERK1/2. Taken together, these results suggest that luteolin-elicited relaxation includes myosin phosphatase reactivation and calcium desensitization, which seems to be arbitrated by CPI-17 dephosphorylation via ROCK/PKC inhibition.

• Biomolecules & Therapeutics
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• 제32권3호
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• pp.361-367
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• 2024

In this study, we investigated the efficacy of kaempferol (a flavonoid found in plants and plant-derived foods such as kale, beans, tea, spinach and broccoli) on vascular contractibility and aimed to clarify the detailed mechanism underlying the relaxation. Isometric contractions of divested muscles were stored and linked with western blot analysis which was carried out to estimate the phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and phosphorylation-dependent inhibitory protein for myosin phosphatase (CPI-17) and to estimate the effect of kaempferol on the RhoA/ROCK/CPI-17 pathway. Kaempferol conspicuously impeded phorbol ester-, fluoride- and a thromboxane mimetic-derived contractions regardless of endothelial nitric oxide synthesis, indicating its direct effect on smooth muscles. It also conspicuously impeded the fluoride-derived elevation in phospho-MYPT1 rather than phospho-CPI-17 levels and phorbol 12,13-dibutyrate-derived increase in phospho-CPI-17 and phospho-ERK1/2 levels, suggesting the depression of PKC and MEK activities and subsequent phosphorylation of CPI-17 and ERK1/2. Taken together, these outcomes suggest that kaempferol-derived relaxation incorporates myosin phosphatase retrieval and calcium desensitization, which appear to be modulated by CPI-17 dephosphorylation mainly through PKC inactivation.

• 유체기계공업학회:학술대회논문집
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• 유체기계공업학회 2006년 제4회 한국유체공학학술대회 논문집
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• pp.501-504
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• 2006

The estimation of the work of heart can be treated as one of the most important parameters for determining the amount of circulating blood needed for harmonious metabolism in the human body. By monitoring the work of heart, one can detect increased work load of heart and start the treatment at the early stage of CHF. Thus it is necessary to estimate the work of heart. The contractility of the left ventricle, the second important parameter for representing the motion of heart, can be estimated through information on the work of heart. In this study, the modified Windkessel model, which has been used for a measure of vascular hemodynamic impedance parameters, was adapted to estimate the work of heart.

• Natural Product Sciences
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• 제20권3호
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• pp.216-225
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• 2014

The present study was designed to investigate whether ethylacetate (EtOAc) fraction extracted from Rubus coreanum affect the contractility of the isolated thoracic aortic strips and blood pressure of normotensive rats. The EtOAc fraction ($400{\mu}g/mL$) significantly depressed both phenylephrine (PE, $10{\mu}M$)- and high $K^+$ (56 mM)-induced contractile responses of the isolated thoracic aortic strips in a concentration-dependent fashion. In the simultaneous presence of L-NAME (an inhibitor of NO synthase, $300{\mu}M$) and EtOAc ($400{\mu}g/mL$), both PE- and high $K^+$-induced contractile responses were recovered to the corresponding control level in comparison with inhibition of EtOAc-treatment alone. Moreover, in the simultaneous presence of EtOAc after pretreatment with 0.4% CHAPS, both PE- and high $K^+$-induced contractile responses were recovered to the corresponding control level compared to the inhibitory response of EtOAc-treatment alone. Also, in anesthetized rats, EtOAc fraction (0.3~3.0 mg/kg) injected into a femoral vein dose-dependently produced depressor responses. This hypotensive action of EtOAc fraction was greatly inhibited after treatment with phentolamine (1 mg/kg), chlorisondamine (1 mg/kg), L-NAME (3 mg/kg/30 min) or sodium nitroprusside ($30{\mu}g/kg/30 min$). Intravenous infusion of EtOAc fraction (1.0~10.0 mg/kg/30 min) markedly inhibited norepinehrine-induced pressor responses. Taken together, these results demostrate that EtOAc causes vascular relaxation in the isolated rat thoracic aortic strips as well as hypotensive action in anesthetized rats. These vasorelaxation and hypotension of EtOAc seem to be mediated at least by the increased NO production through the activation of NO synthase of vascular endothelium, and the inhibitory adrenergic modulation.