• Biomolecules & Therapeutics
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• v.3 no.2
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• pp.143-148
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• 1995

Recently, we reported that GS 389 has vasodilating action without cardiac inotropic action (Chang et al., Can. J. Physiol. Pharmacol. 72, 327-334, 1994). However the mechanism of action of GS 389 has not been thoroughly evaluated. In the present study, we performed functional study of GS 389 in rat trachealis, thoracic aorta, pig coronary artery by isometric tension and in human platelets by aggregation experiments. We also tested if GS 389 influences on $Ca^{2+}$movement and inositol phosphate metabolism. In rat trachealis, GS 389 concentration-dependently relaxed carbachol (0.1 $\mu$M)- and high $K^{+}$(65.4 mM)-induced contraction with p$IC_{50}$/ of 4.43$\pm$ 0.19 and 4.11$\pm$0.12, respectively. In $Ca^{2+}$-free media, GS 389 inhibited carbachol-induced phasic contraction. In rat thoracic aorta, GS 389 inhibited $^{45}$ Ca uptake due to norepinephrine and high $K^{+}$, indicating that GS 389 has direct inhibitory action of $Ca^{2+}$movement. Furthermore, GS 389 competitively inhibited U46619-induced contraction in rat thoracic aorta and pig coronary artery with K, values of 5.23$\pm$0.12 and 5.56$\pm$0.14, respectively, and inhibited U 46619-induced phosphatidylinositide (PI) turnover in rat aorta. GS 389 also concentration-dependently inhibited the human platelet aggregation against U 46619 with p$IC_{50}$/ 5.66$\pm$0.02. These results indicate that GS 389 has thromboxane $A_2$ antagonistic action in vascular and platelets as well as direct action on $Ca^{2+}$ movement, which may account, at least in part, for relaxing action of rat trachealis. trachealis.

• Journal of Physiology & Pathology in Korean Medicine
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• v.18 no.5
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• pp.1494-1504
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• 2004

The present paper reports the effects of Hwaotang an atherosclerosis using a spontaneous experimental model, We have also investigated the pharmacological effect of Hwaotang on collagen- and ADP-induced blood platelet aggregation, thrombin-induced conversion of fibrinogen and fibrinolysis in in vitro experiments, and various effects on stimuli-induced superoxide generation in human neutrophils. Hwao-tang was shown to have inhibitory effect on collagen- and ADP-induced blood platelet aggregation, on thrombin-induced conversion of fibrinogen to fibrin and on the activity of plasminogen or plasmin. Hwao-tang also significantly inhibited fMLP-induced superoxide generation in a concentration-dependent manner, but not that induced by arachidonic acid. Hwao-tang inhibited neutrophil functions, including degranulation, superoxide generation, and leukotriene B4 production, without any effect on 5-lipoxygenase activity. In conclusion, the protection of extracts of Hwao-tang on the ischemic infarction induced artificially might be involved to their inhibition of thrombotic action. The results also indicate that Hwao-tang exerts the effects on superoxide generation related to the inhibition of neutrophil functions.

• Journal of Ginseng Research
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• v.21 no.2
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• pp.132-140
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• 1997

The effects of ginsenosides purified from red ginseng on platelet aggregation were investigated. Preincubation of washed platelets from rats with either ginsenoside Rg3, ginsenosides non-polar fraction (G-NPF), ginsenoside Rg1(Rg1) or ginsenosides polar fraction(G-PF) reduced the plytelet aggrelation induced by collagen in a dose-dependent manner, whereas ginsenoside Rg2 failed to inhibit the aggregation. Their IC50 values of Rg3, G-NPF, Rgl, and G-PF were 8.7$\pm$1.0, 150.3$\pm$0.1, 369.9$\pm$ 1.0, 606.211.3 $\mu\textrm{g}$/ml, respectively. Aggrelation induced by thrombin was also inhibited by Rg3 and G-NPF with IC50 being 5.2$\pm$ 1.1 and 66.5$\pm$0.8 $\mu\textrm{g}$/ml, respectively. The alterations of Intracellular Ca2+ concentration in platelets were monitored using fura-2 as a fluorescent Ca2+ indicator. Both Ca2+ release from internal stores and Ca2+ influx into cytosol were suppressed by Rg3. Rg3 also inhibited granular release of ATP and TXA2 formation induced by thrombin in a dose-dependent manner in the washed platelets. Rg3 also inhibited Aggregation and ATP release from human platelets induced by collagen to a similar extent as were observed in rat platelets. In conclusion, Rg3 is a Potent anti-aggregating component in ginsenosides and may exert its anti-aggrega1ing activity by decreasing TXAa formation and granular secretion in platelets, most likely by inhibiting Ca2+ influx and Ca2+ mobilization from intracellular stores. Thus ginseng may contribute to the prevention and treatment of thrombosis.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.122-127
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• 2023

Cardiovascular disease (CVD) is increasingly increasing as the main cause of death worldwide, and activation of platelet in vascular damage is one of the important causes of CVD. In recent, there is a growing interest in anti-thrombotic materials through platelet suppression, and efforts are being made to reduce side effects by using natural bioactive compounds. Known as one of the Flavonoids, hydroxygenkwanin (HGK) is a purified substance in Daphne Genkwa, which is known to have antibacterial, anti-inflammatory and anti-cancer effects, and has been reported to serve as an inhibitor of tissue factor that prevents thrombosis, but its anti-platelet effects and the action mechanisms is not known. In this study, we confirmed that the effects of HGK on the collagen-induced human platelets activation. HGK suppressed phosphorylation of PI3K/AKT and mitogen-activated protein kinases during platelet signaling, and reduced granule secretion in platelets such as ATP and serotonin. In addition, HGK inhibited the phosphorylation of cPLA₂ and strongly undermined the production of TXA₂, which is a powerful aggregation amplifier. As a result, the platelet aggregation derived by Collagen, a cohesive induced substance, was strongly suppressed by HGK to an IC₅₀ of 86.36 µM. Therefore, HGK might be worth the antithrombotic substance that inhibits the activation and aggregation of human platelets that occur through blood vessel damage.

• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.2
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• pp.380-388
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• 2002

The inhibitory effects of the traditional herbal medicine Hwao-tang on the progression of the atherosclerotic lesions were studied using the spontaneous familial hypercholesterolemia (FH) model, Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Hwao-tang is activate blood circulation, vital energy and regulate menstruation, etc. Nowadays, Hwao-tang is mainly used for the treatment of inflammation, hyperlipemia and arteriosclerosis. However, pharmacological mechanisms of Hwao-tang on lipid metabolism and atherosclerosis formation are poorly understood. We have investigated the pharmacological effects of Hwao-tang on hypercholesterolemia and atherosclerosis using a spontaneous experimental model. In conclusion, the protection of extracts of HOT and its herbs on the ischemic infarction induced artificially might be related to their inhibitory effects on DIC, platelet coagulation and thrombic action. These suggest that Hwao-tang has inhibitory effects on the development of atheromatous plaque formation in spontaneous FH model rabbits. It is possible that the anti oxidative effects of Hwao-tang on LDL led to the beneficial effects observed in this study.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.203-203
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• 1996

It has been known that pinusolide isolated from Biota orientalis inhibits specifically [$^3$H] PAF binding to and PAF-induced aggregation of rabbit platelets in vitro. The present study was undertaken to evaluate the effects of pinusolide on hypotension and bronchoconstriction due to PAF. PAF(i.v.) in doses of 0.01 to 0.3 $\mu\textrm{g}$/kg induced a dose-dependent hypotension without tachyphylaxis in rat. Pinusolide(5～20 mg/kg, i.v.) inhibited PAF(0.03 $\mu\textrm{g}$/kg, i.v.)-induced hypotension dose-dependently, while it failed to block the hypotensive action of histamine, serotonin and acetylcholine. It inhibited bronchoconstriction and cutaneous vascular permeability induced by PAF in anesthetized guinea-pigs and rats, respectively, but it showed no inhibitory effect on the increase in bronchial resistance by histamine and acetylcholine. These results strongly suggest that in vivo pinusolide acts as a selective antagonist of PAF.

• The Korean Journal of Pharmacology
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• v.18 no.2
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• pp.15-25
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• 1982

It was undertake to investigate the factors involved in the micro thrombus formation in the plasma from the patients with cerebrovascular disease(CVD) and the in vitro actions of sodium nitroprusside on the platelet aggregate formation. 1) The microthrombus formation in the plasma from CVD was significantly enhanced, in comparison with that from the healthy volunteers. 2) Both lipid peroxide and cathepsin D in the plasma from CVD were higher than those levels from the healthy volunteers. 3) Whereas the platelets from healthy individuals showed less aggregation activity in response to ADP in the second phase those from CVD revealed the enhanced aggregating response to ADP. 4) When the bovine basilar artery, rabbit aorta and human umbilical artery were pretreated with $K^+-free$ PSS, ouabain, 13-hydroperoxylinoleic acid(13-HPLA) and cadmium they markedly enhanced the platelet aggregability respectively. 5) Platelet aggregation induced by $K^+-free$ PSS-treated bovine basilar artery was decreased by sodium nitroprusside in a dose-dependent manner, but not by either hydralazine. 6) Both dibutyryl cyclic AMP and 8-bromo cyclic GMP had the inhibitory action on the platelet aggregation. However, the latter had more prominent action than former. The antiaggregating effect by sodium nitroprusside was antagonized by pretreatment with methylene blue, but not by hemoglobin. These results provide the evidences for the therapeutic use of sodium nitroprusside in the emergency of cerebrovascular disease and in remains the further study of the clinical therapy with it.

• The Journal of Korean Medicine
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• v.16 no.2 s.30
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• pp.365-385
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• 1995

In order to prove the antitumor effect of Wekyungtang(WKT) that was originated in Bigeubchunkeumyobang(備急千金要方), Wekyungtang with Houttuyniae Herba(WKT-I) and Wekyungtang with Oldenlandiae diffusae Herba(WKT-II) experimentally, the studies were done, We evaluated the cytotoxic activity against B16- Fo as well as the synergistic effects with anticancer drugs such as cyclophophamide (CPM), cisplatin(CPT) and 5-fluorouracil (5-FU) in vitro and measured body weight, survival time, hematological changes, changes of tissues in G57BL／6 implanted with B16-Fo. The results were obtained as follows: 1. In vitro cytotoxic effect against B16-Fo was shown in all groups as compared with control group, but the concentrations showing inhibitory growth rate below 55% of control was recognized in all concentrations of Wekyungtang(WKT) against B16-Fo and also concentration of $10^4$g／ml above in all group with cyclophophamide (CPM), concentration of $10^3$g／ml in Wekyungtang(WKT-l) with cisplatin(CPT) in synergistic effect, 2. In vivo body and tumor weight were significantly suppressed in all groups as compared with control group 3. The number of platelet, WBC, RBC were significantly increased in all groups, platelet aggregation was significantly increased in WKT-I and WKT-II as compared with control group. 4. In changes of tissues heavy infiltration oh cancer was shown in portal vein, pulmonary tissue, vein, peribronchiole, aveoli, while WKT-I was effective in antihepatic metastasis and WKT-II in pulmonary matastasis. From above results it was concluded that wekyungtang(WKT), wekyungtang with Houttuyniae Herba(WKT-I) and wekyungtang with Oldenlandiae diffusae Herba(WKT -II) had antitumor effect, and also wekyungtang combined with Houttuyniae Herba or Oldenlandiae diffusae Herba were more effective than wekyungtang only and also cyclophophamide (CPM), cisplatin(CPT) showed the more synergistic effect which suggests the necessity of continuous study on the mechanism of antitumor action of Houttuyniae Herba or Oldenlandiae diffusae Herba.

• Journal of Applied Biological Chemistry
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• v.65 no.4
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• pp.239-245
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• 2022

Although normal activation of platelets is important in the process of hemostasis, excessive or abnormal activation of platelets can lead to cardiovascular diseases. Therefore, the discovery of novel substances capable of regulating or inhibiting platelet activation may be helpful in the prevention and treatment of cardiovascular diseases. Artemether is a derivative of artemisinin, known as an active ingredient of Artemisia annua, which has been reported to be effective in treating malaria, and is known to function through antioxidant and metabolic enzyme inhibition. However, the role of artemether in platelet activation and aggregation and the mechanism of action of artemether in collagen-induced human platelets are not known until now. This study investigated the effects of artemether on platelet activation and thrombus formation induced by collagen. As a result, cAMP level was significantly increased by artemether, and VASP and IP3R, substrates of cAMP-dependent kinase, were phosphorylated. IP3R phosphorylation by Artemether inhibited Ca²⁺ recruitment into the cytoplasm, and phosphorylated VASP inhibited fibrinogen binding by inactivating αIIb/β3 located on the platelet membrane. Consequently, artemether inhibited thrombin-induced fibrin clot formation. Therefore, we propose that artemether can act as an effective prophylactic and therapeutic agent for cardiovascular diseases caused by excessive platelet activation and thrombus formation.

• Biomolecules & Therapeutics
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• v.11 no.1
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• pp.41-50
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• 2003

General pharmacological properties of DA-8159, a new pyrazolopyrimidinone derivative were examined in laboratory animals to investigate its safety profile. The oral administration of DA-8159 (1, 5 or 30 mg/kg) in mice and rats had no effect on general behaviors and central nervous system of the animals in test systems, such as hexobarbital-induced sleeping time, motor coordination, normal body temperature, writhing syndromes induced by 0.75% acetic acid solution, chemo-shock produced by pentetrazole solution and rotar rod test. Anesthetized cats treated intravenously with DA-8159 (0.1, 0.3, 1, 3 or 10 mg/kg) showed transient and mild decrease in blood pressure. However, heart rate, respiration rate and tidal volume were not changed by intravenous DA-8159. In the isolated organs including ileum, heart (sinus rate of atria and contractility of papillary muscle), trachea of guinea pigs and phrenic nerve of rats, DA-8159 ($10^{-8}$ ∼$10^{-5}$ mg/L) did not elicit any effect or inhibitory action on the chemically or electrically stimulated contraction. DA-8159 did not influence gastric secretion, pH and total acid output in rats and intestinal propulsion in mice. The administration of DA-8159 in rats had no effect on the platelet aggregation induced by ADP in rabbit plasma, urinary volume and electrolyte ion ($Na^{+}$, $K^{+}$, $Cl^{-}$) excretion in rats. Prothrombin time (PT) of the rats showed a mild but significant increase after administration of DA-8159. Activated partial thromboplastin time (APTT), however, was not affected by DA-8159. These results indicate that DA-8159 does not exert any of serious pharmacological effects.