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Thomas N Wight - One of the best experts on this subject based on the ideXlab platform.

  • expression of v3 versican by rat Arterial Smooth Muscle cells promotes differentiated and anti inflammatory phenotypes
    Journal of Biological Chemistry, 2015
    Co-Authors: Inkyung Kang, Jeremy L Barth, Erin P Sproul, Dong Won Yoon, Gail Workman, Kathleen R Braun, Scott W Argraves, Thomas N Wight
    Abstract:

    Arterial Smooth Muscle cells (ASMCs) undergo phenotypic changes during development and pathological processes in vivo and during cell culture in vitro. Our previous studies demonstrated that retrovirally mediated expression of the versican V3 splice variant (V3) by ASMCs retards cell proliferation and migration in vitro and reduces neointimal thickening and macrophage and lipid accumulation in animal models of vascular injury and atherosclerosis. However, the molecular pathways induced by V3 expression that are responsible for these changes are not yet clear. In this study, we employed a microarray approach to examine how expression of V3 induced changes in gene expression and the molecular pathways in rat ASMCs. We found that forced expression of V3 by ASMCs affected expression of 521 genes by more than 1.5-fold. Gene ontology analysis showed that components of the extracellular matrix were the most significantly affected by V3 expression. In addition, genes regulating the formation of the cytoskeleton, which also serve as markers of contractile Smooth Muscle cells (SMCs), were significantly up-regulated. In contrast, components of the complement system, chemokines, chemokine receptors, and transcription factors crucial for regulating inflammatory processes were among the genes most down-regulated. Consistently, we found that the level of myocardin, a key transcription factor promoting contractile SMC phenotype, was greatly increased, and the proinflammatory transcription factors NFκB1 and CCAAT/enhancer-binding protein β were significantly attenuated in V3-expressing SMCs. Overall, these findings demonstrate that V3 expression reprograms ASMCs promoting differentiated and anti-inflammatory phenotypes.

  • intracellular hyaluronan in Arterial Smooth Muscle cells association with microtubules rhamm and the mitotic spindle
    Journal of Histochemistry and Cytochemistry, 2004
    Co-Authors: Stephen P Evanko, Tony W Parks, Thomas N Wight
    Abstract:

    Although considered a pericellular matrix component, hyaluronan was recently localized in the cytoplasm and nucleus of proliferating cells, supporting earlier reports that hyaluronan was present in locations such as the nucleus, rough endoplasmic reticulum, and caveolae. This suggests that it can play roles both inside and outside the cell. Hyaluronan metabolism is coupled to mitosis and cell motility, but it is not clear if intracellular hyaluronan associates with cytoskeletal elements or plays a structural role. Here we report the distribution of intracellular hyaluronan, microtubules, and RHAMM in Arterial Smooth Muscle cells in vitro. The general distribution of intracellular hyaluronan more closely resembled microtubule staining rather than actin filaments. Hyaluronan was abundant in the perinuclear microtubule-rich areas and was present in lysosomes, other vesicular structures, and the nucleolus. Partially fragmented fluorescein-hyaluronan was preferentially translocated to the perinuclear area comp...

  • retrovirally mediated overexpression of versican v3 by Arterial Smooth Muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury
    Circulation Research, 2002
    Co-Authors: Mervyn J Merrilees, Kathleen R Braun, Joan M Lemire, Jens W Fischer, Michael G Kinsella, Alexander W Clowes, Thomas N Wight
    Abstract:

    Versican is an extracellular matrix (ECM) proteoglycan that is synthesized as multiple splice variants. In a recent study, we demonstrated that retroviral-mediated overexpression of the variant V3, which lacks chondroitin sulfate (CS) chains, altered Arterial Smooth Muscle cell (ASMC) phenotype in short-term cell culture. We now report that V3-overexpressing ASMCs exhibit significantly increased expression of tropoelastin and increased formation of elastic fibers in long-term cell cultures. In addition, V3-overexpressing ASMCs seeded into ballooned rat carotid arteries continued to overexpress V3 and, at 4 weeks after seeding, produced a highly structured neointima significantly enriched in elastic fiber lamellae. In contrast to the hydrated, myxoid neointima produced by rounded or stellate vector-alone–transduced cells, V3-expressing cells produced a compact and highly ordered neointima, which contained elongated ASMCs that were arranged in parallel arrays and separated by densely packed collagen bundles...

  • proteoglycans synthesized by Arterial Smooth Muscle cells in the presence of transforming growth factor β1 exhibit increased binding to ldls
    Arteriosclerosis Thrombosis and Vascular Biology, 2002
    Co-Authors: Peter J Little, Alan Chait, Lisa R Tannock, Katherine L Olin, Thomas N Wight
    Abstract:

    The "response-to-retention" hypothesis of atherogenesis states that atherogenic lipoproteins, such as low density lipoprotein (LDL), are retained in vessels by proteoglycans and undergo proatherosclerotic modifications. Transforming growth factor (TGF)-1 has been identified in atherosclerotic vessels and has been shown to stimulate the synthesis of chondroitin sulfate- and dermatan sulfate- containing proteoglycans by Arterial Smooth Muscle cells (ASMCs), but whether it promotes lipid retention has not been addressed. We investigated whether TGF-1 modulates the biosynthesis of proteoglycans by ASMCs in a manner that promotes binding to LDL. Proteoglycans isolated from TGF-1-treated ASMCs exhibited enhanced binding to native LDL compared with the binding of proteoglycans isolated from control cultures (Kd 18 g/mL LDL versus 81 g/mL LDL, respectively). The increase in proteoglycan-LDL binding caused by TGF-1 could be attributed primarily to the glycosaminoglycan portion of the proteoglycans, since the glycosaminoglycan chains liberated from the core proteins of these proteoglycans synthesized in the presence of TGF-1 exhibited increased LDL binding as well. Furthermore, glycosaminoglycan chains initiated on xyloside (an initiator of glycosaminoglycan synthesis) in the presence of TGF-1 were longer and displayed enhanced binding to LDL compared with the LDL binding of xyloside-initiated glycosaminoglycan chains from control cultures. These results indicate that TGF-1 promotes LDL-proteoglycan interaction primarily by its effects on the glycosaminoglycan synthetic machinery of the ASMCs. Therefore, this study supports a proatherogenic role for TGF-1. (Arterioscler Thromb Vasc Biol. 2002;22:55-60.)

  • overexpression of the v3 variant of versican alters Arterial Smooth Muscle cell adhesion migration and proliferation in vitro
    Journal of Cellular Physiology, 2002
    Co-Authors: Joan M Lemire, Mervyn J Merrilees, Kathleen R Braun, Thomas N Wight
    Abstract:

    Versican is an extracellular matrix proteoglycan produced by many cells. Although versican is generally known as a large chondroitin sulfate proteoglycan (CSPG), the smallest splice variant, V3, consists only of the amino- and carboxy-terminal globular domains and is therefore predicted to be a small glycoprotein, lacking CS chains. The large size, negative charge, and ability of versican variants to form pericellular coats with hyaluronan are responsible for many of its effects. V3, lacking the large size and high charge density, but retaining the hyaluronan-binding domain of the larger isoforms, may have different effects on cell phenotype. To determine whether V3 alters cell phenotype, Fisher rat Arterial Smooth Muscle cells (ASMCs), which express the larger CSPG versican splice forms (V0 and V1) were retrovirally transduced with the rat V3 cDNA. Northern analysis for versican RNAs confirmed that cells transduced with V3 retrovirus, but not cells tranduced with the empty vector, expressed RNA of the size expected for V3/neo(r) bicistronic RNA. V3 overexpressing cells were more spread on tissue culture plastic, had a smaller length-to-breadth ratio and were more resistant to release from the culture dish by trypsin. Interference reflection microscopy of sparsely plated cells showed larger areas of close contact between the V3 expressing cells and the coverslip, in comparison to control cells. Focal contacts in the periphery of V3 expressing cells were larger. Growth and migration studies revealed that V3 transduced cells grow slower and migrate a shorter distance in a scratch wound assay. The increased adhesion and the inhibition of migration and proliferation resulting from V3 overexpression are the opposites of the known and predicted effects of the other variants of versican. V3 may exert these effects through changes in pericellular coat formation, either by competing with larger isoforms for hyaluronan-binding, or by altering other components of the pericellular matrix.

Jingjin Liu - One of the best experts on this subject based on the ideXlab platform.

  • Arterial wall stress induces phenotypic switching of Arterial Smooth Muscle cells in vascular remodeling by activating the yap taz signaling pathway
    Cellular Physiology and Biochemistry, 2018
    Co-Authors: Wei Cao, Jinjin Cui, Jingjin Liu, Yongshun Wang, Yubo Zhao, Jian Shi, Zhengyuan Xia
    Abstract:

    Background/aims Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical Arterial Smooth Muscle cells (HUASMCs) to a proliferative phenotype were examined. Methods HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. Results We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. Conclusion Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis.

  • Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway
    Karger Publishers, 2018
    Co-Authors: Yongshun Wang, Wei Cao, Jinjin Cui, Yubo Zhao, Jian Shi, Zhengyuan Xia, Jingjin Liu
    Abstract:

    Background/Aims: Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical Arterial Smooth Muscle cells (HUASMCs) to a proliferative phenotype were examined. Methods: HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. Results: We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. Conclusion: Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis

  • biomechanical stretch induces inflammation proliferation and migration by activating nfat5 in Arterial Smooth Muscle cells
    Inflammation, 2017
    Co-Authors: Wei Cao, Donghui Zhang, Yue Liu, Shenhong Jing, Jinjin Cui, Jingjin Liu
    Abstract:

    The increasing wall stress as is elicited by Arterial hypertension promotes their reorganization in the vessel wall which may lead to Arterial stiffening and contractile dysfunction. The nuclear factor of activated T cells 5 (NFAT5) pathway plays a role in regulating growth and differentiation in various cell types. We investigated whether the NFAT5 pathway was involved in the regulation of biomechanical stretch-induced human Arterial Smooth Muscle cell (HUASMC) proliferation, inflammation, and migration. Herein, we showed that stretch promoted the expression of NFAT5 in human Arterial Smooth Muscle cells and regulated through activation of c-Jun N-terminal kinase under these conditions. This may contribute to an improved activity of HUASMCs and thus promote reorganization in vascular remodeling processes such as hypertension-induced Arterial stiffening and contractile dysfunction.

Jian Wang - One of the best experts on this subject based on the ideXlab platform.

Amy L. Firth - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of the voltage dependent k current by the tricyclic antidepressant desipramine in rabbit coronary Arterial Smooth Muscle cells
    Cardiovascular Toxicology, 2018
    Co-Authors: Sung Eun Shin, Ilwhan Choi, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Won-kyo Jung, Won Sun Park
    Abstract:

    We describe the effect of a tricyclic antidepressant drug desipramine on voltage-dependent K+ (Kv) currents in freshly isolated rabbit coronary Arterial Smooth Muscle cells using a conventional whole-cell patch clamp technique. Application of desipramine rapidly decreased the Kv current amplitude in a concentration-dependent manner, with an IC50 value of 5.91 ± 0.18 μM and a Hill coefficient of 0.61 ± 0.09. The steady-state inactivation curves of the Kv channels were not affected by desipramine. However, desipramine shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses (1 or 2 Hz) slightly reduced the Kv current amplitude. Such reduction in the Kv current amplitude by train pulses increased in the presence of desipramine. Furthermore, the inactivation recovery time constant was also increased in the presence of desipramine, suggesting that desipramine-induced inhibition of the Kv current was use-dependent. Application of a Kv1.5 inhibitor (DPO-1) and/or a Kv2.1 inhibitor (guangxitoxin) did not change the inhibitory effect of desipramine on Kv currents. Based on these results, we concluded that desipramine directly inhibited the Kv channels in a dose- and state-dependent manner, but the effect was independent of norepinephrine/serotonin reuptake inhibition.

  • blockade of voltage dependent k current in rabbit coronary Arterial Smooth Muscle cells by the tricyclic antidepressant clomipramine
    Journal of Pharmacological Sciences, 2018
    Co-Authors: Sung Eun Shin, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Dae Sung Lee, Mijin Yim, Jeong Min Lee, Grace Choi, Ilwhan Choi
    Abstract:

    Abstract We investigated the effect of the tricyclic antidepressant clomipramine on voltage-dependent K+ (Kv) channels in native rabbit coronary Arterial Smooth Muscle cells. Our results showed that clomipramine inhibited vascular Kv channels in a concentration-dependent manner, with an IC50 value of 8.61 ± 4.86 μM and a Hill coefficient (n) of 0.58 ± 0.07. The application of 10 μM clomipramine did not affect the activation curves of the Kv channels; however, the inactivation curves of the Kv channels were shifted toward a more negative potential. The clomipramine-induced inhibition of Kv currents was not changed by the application of train pulses (1 or 2 Hz), which demonstrated that clomipramine inhibited Kv current in a state (use)-independent manner. Pretreatment with the Kv1.5 and Kv2.1 inhibitors, DPO-1 and guangxitoxin, respectively, partially reduced the clomipramine-induced inhibition of Kv currents. Therefore, we concluded that clomipramine inhibited vascular Kv channels in a concentration-dependent, but state (use)-independent manner, regardless of its own function.

  • inhibitory effect of the tricyclic antidepressant amitriptyline on voltage dependent k channels in rabbit coronary Arterial Smooth Muscle cells
    Clinical and Experimental Pharmacology and Physiology, 2018
    Co-Authors: Sung Eun Shin, Ilwhan Choi, Eun-taek Han, Seok-ho Hong, Mi Seon Seo, Dae Sung Lee, Mijin Yim, Jeong Min Lee, In Duk Jung, Amy L. Firth
    Abstract:

    Amitriptyline, a tricyclic antidepressant (TCA) drug, is widely used in treatment of psychiatric disorders. However, the side effects of amitriptyline on vascular K+ channels remain to be determined. Therefore, we investigated the effect of the tricyclic antidepressant and serotonin reuptake inhibitor amitriptyline on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary Arterial Smooth Muscle cells, using the whole-cell patch clamp technique. The Kv current amplitudes were inhibited by amitriptyline in a concentration-dependent manner, with an apparent IC50 value of 2.2 ± 0.14 μmol/L and a Hill coefficient of 0.87 ± 0.03. Amitriptyline shifted the activation curve to a more positive potential, but had no significant effect on the inactivation curve, suggesting that amitriptyline altered the voltage sensitivity of Kv channels. Pretreatment with Kv1.5 and Kv1.2 channel inhibitors did not alter the inhibitory effect of amitriptyline on Kv channels. Additionally, application of train pulses (1 and 2 Hz) did not affect amitriptyline-induced inhibition of Kv currents, which suggested that the action of amitriptyline on Kv channels was not use (state)-dependent. From these results, we concluded that amitriptyline inhibited the channels in a concentration-dependent, but state-independent manner.

  • Blockade of voltage-dependent K+ current in rabbit coronary Arterial Smooth Muscle cells by the tricyclic antidepressant clomipramine
    Elsevier, 2018
    Co-Authors: Sung Eun Shin, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Dae Sung Lee, Mijin Yim
    Abstract:

    We investigated the effect of the tricyclic antidepressant clomipramine on voltage-dependent K+ (Kv) channels in native rabbit coronary Arterial Smooth Muscle cells. Our results showed that clomipramine inhibited vascular Kv channels in a concentration-dependent manner, with an IC50 value of 8.61 ± 4.86 μM and a Hill coefficient (n) of 0.58 ± 0.07. The application of 10 μM clomipramine did not affect the activation curves of the Kv channels; however, the inactivation curves of the Kv channels were shifted toward a more negative potential. The clomipramine-induced inhibition of Kv currents was not changed by the application of train pulses (1 or 2 Hz), which demonstrated that clomipramine inhibited Kv current in a state (use)-independent manner. Pretreatment with the Kv1.5 and Kv2.1 inhibitors, DPO-1 and guangxitoxin, respectively, partially reduced the clomipramine-induced inhibition of Kv currents. Therefore, we concluded that clomipramine inhibited vascular Kv channels in a concentration-dependent, but state (use)-independent manner, regardless of its own function. Keywords: Clomipramine, Voltage-dependent K+ channel, Coronary arter

  • nortriptyline a tricyclic antidepressant inhibits voltage dependent k channels in coronary Arterial Smooth Muscle cells
    The Korean Journal of Physiology and Pharmacology, 2017
    Co-Authors: Sung Eun Shin, Ilwhan Choi, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Han Sol Kim, Hye Won Kim, Young Min Bae, Won Sun Park
    Abstract:

    We demonstrated the effect of nortriptyline, a tricyclic antidepressant drug and serotonin reuptake inhibitor, on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary Arterial Smooth Muscle cells using a whole-cell patch clamp technique. Nortriptyline inhibited Kv currents in a concentration-dependent manner, with an apparent IC50 value of 2.86±0.52 µM and a Hill coefficient of 0.77±0.1. Although application of nortriptyline did not change the activation curve, nortriptyline shifted the inactivation current toward a more negative potential. Application of train pulses (1 or 2 Hz) did not change the nortriptyline-induced Kv channel inhibition, suggesting that the effects of nortiprtyline were not use-dependent. Preincubation with the Kv1.5 and Kv2.1/2.2 inhibitors, DPO-1 and guangxitoxin did not affect nortriptyline inhibition of Kv channels. From these results, we concluded that nortriptyline inhibited Kv channels in a concentration-dependent and state-independent manner independently of serotonin reuptake.

Ilwhan Choi - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of the voltage dependent k current by the tricyclic antidepressant desipramine in rabbit coronary Arterial Smooth Muscle cells
    Cardiovascular Toxicology, 2018
    Co-Authors: Sung Eun Shin, Ilwhan Choi, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Won-kyo Jung, Won Sun Park
    Abstract:

    We describe the effect of a tricyclic antidepressant drug desipramine on voltage-dependent K+ (Kv) currents in freshly isolated rabbit coronary Arterial Smooth Muscle cells using a conventional whole-cell patch clamp technique. Application of desipramine rapidly decreased the Kv current amplitude in a concentration-dependent manner, with an IC50 value of 5.91 ± 0.18 μM and a Hill coefficient of 0.61 ± 0.09. The steady-state inactivation curves of the Kv channels were not affected by desipramine. However, desipramine shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses (1 or 2 Hz) slightly reduced the Kv current amplitude. Such reduction in the Kv current amplitude by train pulses increased in the presence of desipramine. Furthermore, the inactivation recovery time constant was also increased in the presence of desipramine, suggesting that desipramine-induced inhibition of the Kv current was use-dependent. Application of a Kv1.5 inhibitor (DPO-1) and/or a Kv2.1 inhibitor (guangxitoxin) did not change the inhibitory effect of desipramine on Kv currents. Based on these results, we concluded that desipramine directly inhibited the Kv channels in a dose- and state-dependent manner, but the effect was independent of norepinephrine/serotonin reuptake inhibition.

  • blockade of voltage dependent k current in rabbit coronary Arterial Smooth Muscle cells by the tricyclic antidepressant clomipramine
    Journal of Pharmacological Sciences, 2018
    Co-Authors: Sung Eun Shin, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Dae Sung Lee, Mijin Yim, Jeong Min Lee, Grace Choi, Ilwhan Choi
    Abstract:

    Abstract We investigated the effect of the tricyclic antidepressant clomipramine on voltage-dependent K+ (Kv) channels in native rabbit coronary Arterial Smooth Muscle cells. Our results showed that clomipramine inhibited vascular Kv channels in a concentration-dependent manner, with an IC50 value of 8.61 ± 4.86 μM and a Hill coefficient (n) of 0.58 ± 0.07. The application of 10 μM clomipramine did not affect the activation curves of the Kv channels; however, the inactivation curves of the Kv channels were shifted toward a more negative potential. The clomipramine-induced inhibition of Kv currents was not changed by the application of train pulses (1 or 2 Hz), which demonstrated that clomipramine inhibited Kv current in a state (use)-independent manner. Pretreatment with the Kv1.5 and Kv2.1 inhibitors, DPO-1 and guangxitoxin, respectively, partially reduced the clomipramine-induced inhibition of Kv currents. Therefore, we concluded that clomipramine inhibited vascular Kv channels in a concentration-dependent, but state (use)-independent manner, regardless of its own function.

  • inhibitory effect of the tricyclic antidepressant amitriptyline on voltage dependent k channels in rabbit coronary Arterial Smooth Muscle cells
    Clinical and Experimental Pharmacology and Physiology, 2018
    Co-Authors: Sung Eun Shin, Ilwhan Choi, Eun-taek Han, Seok-ho Hong, Mi Seon Seo, Dae Sung Lee, Mijin Yim, Jeong Min Lee, In Duk Jung, Amy L. Firth
    Abstract:

    Amitriptyline, a tricyclic antidepressant (TCA) drug, is widely used in treatment of psychiatric disorders. However, the side effects of amitriptyline on vascular K+ channels remain to be determined. Therefore, we investigated the effect of the tricyclic antidepressant and serotonin reuptake inhibitor amitriptyline on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary Arterial Smooth Muscle cells, using the whole-cell patch clamp technique. The Kv current amplitudes were inhibited by amitriptyline in a concentration-dependent manner, with an apparent IC50 value of 2.2 ± 0.14 μmol/L and a Hill coefficient of 0.87 ± 0.03. Amitriptyline shifted the activation curve to a more positive potential, but had no significant effect on the inactivation curve, suggesting that amitriptyline altered the voltage sensitivity of Kv channels. Pretreatment with Kv1.5 and Kv1.2 channel inhibitors did not alter the inhibitory effect of amitriptyline on Kv channels. Additionally, application of train pulses (1 and 2 Hz) did not affect amitriptyline-induced inhibition of Kv currents, which suggested that the action of amitriptyline on Kv channels was not use (state)-dependent. From these results, we concluded that amitriptyline inhibited the channels in a concentration-dependent, but state-independent manner.

  • nortriptyline a tricyclic antidepressant inhibits voltage dependent k channels in coronary Arterial Smooth Muscle cells
    The Korean Journal of Physiology and Pharmacology, 2017
    Co-Authors: Sung Eun Shin, Ilwhan Choi, Eun-taek Han, Seok-ho Hong, Amy L. Firth, Mi Seon Seo, Han Sol Kim, Hye Won Kim, Young Min Bae, Won Sun Park
    Abstract:

    We demonstrated the effect of nortriptyline, a tricyclic antidepressant drug and serotonin reuptake inhibitor, on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary Arterial Smooth Muscle cells using a whole-cell patch clamp technique. Nortriptyline inhibited Kv currents in a concentration-dependent manner, with an apparent IC50 value of 2.86±0.52 µM and a Hill coefficient of 0.77±0.1. Although application of nortriptyline did not change the activation curve, nortriptyline shifted the inactivation current toward a more negative potential. Application of train pulses (1 or 2 Hz) did not change the nortriptyline-induced Kv channel inhibition, suggesting that the effects of nortiprtyline were not use-dependent. Preincubation with the Kv1.5 and Kv2.1/2.2 inhibitors, DPO-1 and guangxitoxin did not affect nortriptyline inhibition of Kv channels. From these results, we concluded that nortriptyline inhibited Kv channels in a concentration-dependent and state-independent manner independently of serotonin reuptake.

  • the ca2 channel inhibitor efonidipine decreases voltage dependent k channel activity in rabbit coronary Arterial Smooth Muscle cells
    Vascular Pharmacology, 2013
    Co-Authors: Mihyeong Park, Da Hye Hong, Ilwhan Choi, Sung Hun Na, Hyoweon Bang, Suhyun Jo, Hongliang Li, Won Sun Park
    Abstract:

    Abstract The effect of efonidipine, a commercially available antihypertensive drug and Ca 2 + channel inhibitor, on voltage-dependent K + (Kv) channels was studied in freshly isolated rabbit coronary Arterial Smooth Muscle cells using the whole-cell patch clamp technique. The amplitude of Kv current was decreased by application of efonidipine in a dose-dependent manner, with IC 50 of 0.26 μM and a Hill coefficient of 0.91, which suggests 1:1 binding stoichiometry. Efonidipine did not affect voltage-dependent activation of the Kv channel, but shifted the inactivation curve by − 8.87 mV. The inhibitory effect of efonidipine was not significantly changed by depletion of extracellular Ca 2 + or intracellular ATP, which indicated no involvement of the Ca 2 + channel or intracellular protein kinase-dependent cascades. We conclude that efonidipine dose-dependently inhibits Kv current in a phosphorylation- and Ca 2 + channel-independent manner.