• Journal of Ginseng Research
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• 제32권2호
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• pp.89-98
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• 2008

There are increasing evidences in the literatures on the potential role of ginsenosides in treating cardiovascular diseases. In this article, current information about ginsenosides-mediated vascular relaxation are reviewed. From the published studies using isolated organs, cell culture systems and animal models, ginsenosides are shown to relax blood vessels and improve blood flow through diverse mechanisms, including nitric oxide release by activating eNOS phosphorylation via PI3K/Akt and/or ERK1/2 pathways in endothelial cells, induction of inducible nitric oxide synthase through activation of NF-${\kappa}$B, reducing the intracelluar Ca$^{2+}$ levels by activating Ca$^{2+}$-activated K$^{+}$ channels in vascular smooth muscle cells and reducing platelet aggregation by decreasing thromboxane A$_2$ formation and intracelluar Ca$^{2+}$in platelets. In addition, the relevant clinical trials regarding the effects of ginsenosides on the cardiovascular disease are summarized, particulary focusing on managing hypertension and improving thrombotic disorders. Finally, antagonistic effects of ginsenosides on the prostaglandin H$_2$ receptor and scavenging effects on the generation of oxygen-derived free radicals in spontaneously hypertensive rats (SHR) are discussed.

• The Korean Journal of Physiology and Pharmacology
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• 제23권6호
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• pp.427-448
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• 2019

Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying $K^+$ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.

• 대한수의학회지
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• 제41권4호
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• pp.485-495
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• 2001

It was investigated whether $Ca^{2+}$ and $K^+$ channels were involved in the inhibitory action of nitric oxide (NO) on the contractile and slow wave activity of guinea pig gastric antral circular muscle. The gastric antral circular muscle showed spontaneous phasic contraction and slow wave. NO donors, 3-morpholinosydnonimine hydrochloride (SIN-1, $0.01{\sim}100{\mu}M$) and S-nitroso-L-cysteine (CysNO, $0.001{\sim}10{\mu}M$), reduced not only the amplitude of phasic contraction but also that of slow wave in a concentration-dependent manner. Both the perfusion of $Ca^{2+}$-free solution and the administration of $Ni^{2+}$, a nonselective $Ca^{2+}$ channel blocker, reduced the phasic contraction as well as the amplitude and frequency of the slow wave. The effects of these treatments were similar to those of NO donors. Nifedipine ($10{\mu}M$), a specific L-type $Ca^{2+}$ channel blocker, abolished the phasic contraction and remarkably reduced the plateau of slow wave but had no profound effect on the upstroke of slow wave. In the whole-cell patch clamp mode, CysNO shifted the steady-state activation curve for L-type $Ca^{2+}$ current to the right and the steady-state inactivation curve to the left. Pretreatment of various $K^+$ channel blockers such as tetraethylammonium (1 mM), 4-aminopyridine (0.5 mM), glibenclamide (10 mM), apamin ($0.1{\mu}M$), and iberiotoxin ($0.1{\mu}M$) did not affect the inhibitory action of SIN-1. These results suggest that NO donors suppress mechanical and electrical activity of guinea pig gastric antral circular muscle by inhibition of L-type $Ca^{2+}$ channel rather than by activation of $K^+$ channels.

• 대한수의학회지
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• 제36권1호
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• pp.83-91
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• 1996

Activation of $K^+$ channels induces relaxation of smooth muscles by reducing electrical excitability and cytosolic free $Ca^{2+}$ level. ${\beta}$-adrenergic agonist isoproterenol is known to induce relaxation of the uterine smooth muscle by membrane hyperpolarization and $K^+$ efflux. Recently it is suggested that the activity of $Ca^{2+}$-activated $K^+$ channel was increased by isoproterenol in the uterine myocytes isolated from myometrium of the pregnant rat. However, the type of $K^+$ channel mediating the relaxant effect of isopreterenol in the tissue level has not yet studied. In this work, we investigated the type of $K^+$ channels involved in the isoproterenol-induced relaxation of uterine smooth muscle by measuring the integrated insometric tension of the estrogen-treated isolated nonpregnant rat uterus. Contraction of uterine tissue was induced by oxytocin (0.2nM, 2~3 contractions/min) or high KCl(20~80mM). The result are as follows : 1. Isoproterenol($10^{-10}{\sim}10^{-4}M$) inhibited oxytocin-induced contraction of isolated rat uterus($EC_{50}=1.17{\times}10^{-10}M$). 2. Isoproterenol($10^{-10}{\sim}10^{-4}M$) effectively inhibited uterine contraction induced by low KCl(20~40mM) but little those induced by high KCl(60~80mM). 3. Relaxant effect of isoproterenol($10^{-10}{\sim}10^{-4}M$) on 0.2nM oxytocin-induced contraction was effectively reduced by 4-aminopyridine(3, 10mM) but little by TEA(10~30mM), $Ba^{2+}$($1{\sim}30{\mu}M$) and glibenclamide($100{\mu}M$). Our data suggest that the relaxant effect of isoproterenol is mediated by the $K^+$ channel(s) which can be blocked by 4-aminopyridine.

• Journal of Ginseng Research
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• 제24권4호
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• pp.168-175
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• 2000

Xenopus oocytes를 이용하여 인삼의 유효 성분으로 알려진 Ginseng total saponin(GTS)의 신호 전달 기작을 two electrode voltage clamp 방법을 이용하여 연구하였다. GTS는 세포 바깥에 처리했을 때 -2OmV보다 더 positive한 voltage에서 커다란 outward current를 유도하였다. 그러나, 세포 안쪽에 GTS를 injection할 경우 아무런 효과가 없는 것으로 나타났다. GTS처리에 의한 outward current유발 효과는 GTS 투여 용량에 의존적인 것으로 나타났다(EC$_{50}$ : 4.4 $\mu\textrm{g}$/ml). GTS의 작용은 $Ca^{2+}$-activated Cl- channel blocker인 niflumic acid에 의하여 차단되었다. 칼슘 chelator인 BAPIA와 IP$_3$ 수용체 길항제인 heparin을 세포내 injection에 의하여 차단되었다. 또한 active phospholipase C inhibitor(PLC)인U-73122를 세포 바깥에 전처리할 경우에도 GTS의 작용이 부분적으로 억제되는 것으로 나타났다. 백일해 독소를 전처리할 경우GTS의 작용은 억제되지 않은 것으로 나타났으나, GTP analog인 GTP${\gamma}$S를 세포내 injection할 경우 GTS의 작용은 억제되는 것으로 나타났다. 이러한 연구 결과는 GTS가 oocytes세포막 성분과 상호 작용에 의하여 $Ca^{2+}$-activated Cl- channel이 열리도록 하고, 이 과정에 PLC활성 및 백일해 독소에 민감하지 않은 G단백질활성 및 IP3에 민감한 세포내 $Ca^{2+}$-activated로부터 칼슘 방출을 유도하는 것으로 나타났다났다

• The Korean Journal of Physiology and Pharmacology
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• 제5권2호
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• pp.189-197
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• 2001

To investigate propofol's effects on ionic currents induced by ${\gamma}-aminobutyric$ acid (GABA) and glycine as well as on those produced by the nicotinic acetylcholine- and glutamate-responsive channels, rat dorsal raphe neurons were acutely dissociated and the nystatin-perforated patch-clamp technique under voltage-clamp conditions was used to observe their responses to the administration of propofol. Propofol evoked ion currents in a dose-dependent manner, and propofol $(10^{-4}\;M)$ was used to elicit ion currents through the activation of $GABA_A,$ glycine, nicotinic acetylcholine and glutamate receptors. Propofol at a clinically relevant concentration $(10^{-5}\;M)$ potentiated $GABA_A-,$ glycine- and NMDA receptor-mediated currents. The potentiating action of propofol on $GABA_A-,$ glycine- and NMDA receptor-mediated responses involved neither opioid receptors nor G-proteins. Apparently, propofol modulates inhibitory and excitatory neurotransmitter-activated ion channels either by acting directly on the receptors or by potentiating the effects of the neurotransmitters, and this modulation appears to be responsible for the majority of the anaesthetic and/or adverse effects.

• The Korean Journal of Physiology and Pharmacology
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• 제5권5호
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• pp.413-421
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• 2001

An impaired smooth muscle cell (SMC) relaxation of coronary artery by alteration of $K^+$ channels would be the most potential explanation for reduced coronary reserve in left ventricular hypertrophy (LVH), however, this possibility has not been investigated. We performed morphometrical analysis of the coronary artery under electron microscopy and measured $Ca^{2+}-activated\;K\;(K_{Ca})$ currents and delayed rectifier K $(K_{dr})$ currents by whole-cell and inside-out patch-clamp technique in single coronary arterial SMCs from rabbits subjected to isoprenaline-induced cardiac hypertrophy. Coronary arterial SMCs underwent significant changes in ultrastructure. The unitary current amplitude and the open-state probability of $K_{Ca}$ channel were significantly reduced in hypertrophy without open-time and closed-time kinetic. The concentration-response curve of $K_{Ca}$ channel to $Ca^{2+}$ is shifted to the right in hypertrophy. The reduction in the mean single channel current and increase in the open channel noise of $K_{Ca}$ channel by TEA were more sensitive in hypertrophy. $K_{dr}$ current density is significantly reduced in hypertrophy without activation and inactivation kinetics. The sensitivity of $K_{dr}$ current on 4-AP is significantly increased in hypertrophy. This is the first study to report evidence for alterations of $K_{Ca}$ channels and $K_{dr}$ channels in coronary SMCs with LVH. The findings may provide some insight into mechanism of the reduced coronary reserve in LVH.

• The Korean Journal of Physiology and Pharmacology
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• 제20권1호
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• pp.75-82
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• 2016

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), has been reported to have an effect on several ion channels including human ether-a-go-go-related gene in a SSRI-independent manner. These results suggest that paroxetine may cause side effects on cardiac system. In this study, we investigated the effect of paroxetine on Kv1.5, which is one of cardiac ion channels. The action of paroxetine on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Paroxetine reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an $IC_{50}$ value and a Hill coefficient of $4.11{\mu}M$ and 0.98, respectively. Paroxetine accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -30 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to 0 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance ${\delta}$ of 0.32. The binding ($k_{+1}$) and unbinding ($k_{-1}$) rate constants for paroxetine-induced block of Kv1.5 were $4.9{\mu}M^{-1}s^{-1}$ and $16.1s^{-1}$, respectively. The theoretical $K_D$ value derived by $k_{-1}/k_{+1}$ yielded $3.3{\mu}M$. Paroxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of paroxetine, were superimposed. Inhibition of Kv1.5 by paroxetine was use-dependent. The present results suggest that paroxetine acts on Kv1.5 currents as an open-channel blocker.

• Biomolecules & Therapeutics
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• 제20권6호
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• pp.550-555
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• 2012

TRPA1 and TRPV1 are members of the TRP superfamily of structurally related, nonselective cation channels. TRPA1 and TRPV1 are often co-expressed in sensory neurons and play an important role in somatosense such as cold, pain, and irritants. The first leaves of Kalopanax pictus Nakai (Araliaceae) have long been used as a culinary ingredient in Korea because of their unique chemesthetic flavor. In this study, we observed the intracellular $Ca^{2+}$ response to cultured cells expressing human TRPA1 (hTRPA1) and human TRPV1 (hTRPV1) by $Ca^{2+}$ imaging analysis to investigate the ability of the first leaves of K. pictus to activate the hTRPA1 and hTRPV1. An 80% ethanol extract of K. pictus (KPEx) increased intracellular $Ca^{2+}$ influx in a response time- and concentration-dependent manner via either hTRPA1 or hTRPV1. KPEx-induced response to hTRPA1 was markedly attenuated by ruthenium red, a general blocker of TRP channels, and HC-030031, a specific antagonist of TRPA1. In addition, the intracellular $Ca^{2+}$ influx attained with KPEx to hTRPV1 was mostly blocked by ruthenium red, and capsazepine, a specific antagonist of TRPV1. These results indicate that KPEx selectively activates both hTRPA1 and hTRPV1, which may provide evidence that the first leaves of K. pictus primarily activate TRPA1 and TRPV1 to induce their unique chemesthetic sense.

• Archives of Pharmacal Research
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• 제24권3호
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• pp.240-248
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• 2001

The present study was attempted to investigate the effect of quinine on secretion of catecholamines (CA) etroked by cholinergic stimulation and membrane depolarization from the isolated perfused rat adrenal gland. The perfusion of quinine (15-150${\mu}$M) into an adrenal vein for 60 min produced dose- and time-dependent inhibition in CA secretion evoked by ACh ($5.32{\times}10^{-3}M$), high $K^{+}5.6{\times}10^{-2}M$, DMPP ($10^{-4}M$ for 2 min), McN-A-343 ($10^{-4}M$ for 2 min), cyclopiazonic acid ($10^{-5}$ for 4 min) and Bay-K-8644 ($10^{-5}$ M for 4 min). Also, under the presence of pinacidil ($10^{-4}$ M), which is also known to be a selective potassium channel activator, CA secretory responses evoked by ACh, high potassium, DMPP McN-A-343, Bay-K-8644 and cyclopiazonic acid were also greatly reduced. When preloaded along with quinine ($5{\times}10^{-5}M$) and glibenclamide ($10^{-6}$ M), a specific blocker of ATP-regulated potassium channels, CA secretory responses evoked by ACh, high potassium, DMPP McN-A-343, Bay-K-8644 and cyclopiazonic acid were recovered as compared to those of quinine-treatment only. taken together, these results demonstrate that quinine inhibits CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization through inhibiting influx of extracellular calcium and release in intracellular calcium in the rat adrenmodullary chromaffin cells. These findings suggest that activation of potassium channels may be involved at least in inhibitory action of quinine on CA secretion from the rat adrenal gland.