Selegiline의 혈관이완반응에 대한 Ginkgo biloba Extract의 영향

김인경,안형수 동덕여자대학교 종합약학연구소 2003 동덕약학연구지 Vol.7 No.-

This research is made to identify the effects of Ginkgo biloba Extract on the vasorelaxation of selegiline which is the MAO_B inhibitor and used in the treatment of ischemic dementia. Investigation was made to find out whether Ginkgo biloba Extract in combined use with selegiline can reduce the orthostatic hypotension caused as side-effect when treated with selegiline alone. And it was tried to identify by what mechanism of action such a vasorelaxation of selegiline was taken place. The isolated rat thoracic aorta was constricted with phenylephrine (10^(-7) M) in organ bath. And it caused the vasorelaxation by injecting graded doses of selegiline (10^(-7)~3×10^(-4) M) to it as controls. The vasorelaxation of disrupted endothelial cell (pD2=4.43±0.13) is more decreased than that of intact endothelial cell (pD2=5.14±0.25). So it meant the endothelium-dependent vasorelaxation. In pretreatment with Nw-Nitro-L-Arginine Methylester·HCl (L-NAME) (10^(-5) M), inhibitor of NO production, the vasorelaxation of selegiline was significantly inhibited compared as that with the control (P<0.05). In pretreatment with indomethacin (10^(-5) M), inhibitor of prostacycline production, there were no effects. And the same result was produced in pretreatment with sulpiride (10^(-5) M), dopamine D₂ antagonist. Accordingly, the vasorelaxation is to be takne place by production and release of NO, not by the increase of dopamine. In pretreatment with Ginkgo biloba Extract (l0^(-5) g/mL), vasorelaxation was significantly inhibited in intact endothelial cell (P<0.01), but no significant inhibition in disrupted endothelial cell. As the experiment of measuring the blood pressure and heart rate of anaesthetized rats, in giving selegiline of 1, 3, 10 mg/kg i.v. as controls, there were temporal decrease of lood pressure and increase of heart rate. In pretreatment with sulpiride (10 mg/kg i.v.), there was significant inhibition compared as that with the control (P<0.05). Pretreatment with Ginkgo biloba Extract (10 mg/kg i.v.) had no significant inhibition. Therefore it shows that the selegiline inhibits the decomposition of dopamine in blood by inhibiting MAO_B only in living body and, as a result, by the increasing dopamine, it causes the relaxation of blood vessel, decrease of blood pressure, and increase of heart rate as the resultant compensatory mechanism. Accordingly, Ginkgo biloba Extract in combined use with selegiline reduces orthostatic hypotension, the virulence of selegiline, by inhibiting vasorelaxation and so it is expected to rise as desirable treatment of ischemic dementia.

Moderate Elevation of Extracellular K<SUP>⁢</SUP> Concentration Induces Vasorelaxation in Isolated Rat, Rabbit and Human Cerebral Arteries Role of Na Pump and Ba-Sensitive Process

Dong Ho Kim,Sung Joon Kim,Sang Jin Lee,Sung Jin Park,Ki Whan Kim 대한생리학회-대한약리학회 1998 The Korean Journal of Physiology & Pharmacology Vol.2 No.6

<P> Cerebral blood vessels relax when extracellular K<SUP>⁢ </SUP>concentrations ([K<SUP>⁢</SUP>])<SUB>e</SUB> are elevated moderately (2∼15 mM, K<SUP>⁢</SUP>-induced vasorelaxation). We have therefore studied the underlying mechanism for this K<SUP>⁢</SUP>- induced vasorelaxation in the isolated middle cerebral arteries (MCAs). The effects of ouabain and Ba<SUP>2⁢ </SUP>on K<SUP>⁢</SUP>-induced vasorelaxation were examined to determine the role of sodium pump and/or Ba-sensitive process (possibly, inward rectifier K current) in the mechanism. Mulvany myograph was used to study 24 rats, 18 rabbits, and 10 humans MCAs (216⁑3 ㄍm, 347⁑7 ㄍm, and 597⁑39 ㄍm in diameter when stretched to a tension equivalent to 55 mmHg). High K<SUP>⁢</SUP> (125 mM) and PGF<SUB>2α</SUB> (1∼10 ㄍM) induced concentration-dependent contractions in all 3 species, while histamine (10∼50 ㄍM) evoked contraction only in the rabbits and induced relaxation in the rats and humans. Addition of K<SUP>⁢ </SUP>(2∼10 mM) to the control solution induced vasorelaxations. These effects were inhibited by the pretreatment with both ouabain (10 ㄍM) and Ba<SUP>2⁢</SUP> (0.1∼0.3 mM) in the rat, but only with ouabain (10 ㄍM) in the rabbit and human. These results suggest that K<SUP>⁢</SUP>-induced vasorelaxation occurs via the stimulation of electrogenic Na pump in the rabbit and human MCAs, while in the rat MCAs via the activation of both Na pump and Ba-sensitive process.

Linalool elicits vasorelaxation of mouse aortae through activation of guanylyl cyclase and K(+) channels.

Kang, Purum,Seol, Geun Hee Pharmaceutical Society of Great Britain 2015 Journal of pharmacy and pharmacology Vol.67 No.5

<P>ObjectivesThe aim of this study was to investigate the cardiovascular relaxing properties of monoterpene alcohol (-)-linalool (LIN), a principal component of several aromatic plants. MethodsWe assessed the effects of LIN on vascular contractility in mouse aortae and evaluated its underlying mechanisms of action. Key findingsWe found that LIN dose-dependently relaxed the vascular tonus of mouse thoracic aortae induced by prostaglandin F-2 alpha (PGF(2), 3m). This effect, however, was reduced by pretreatment with the nitric oxide synthase inhibitor L-NAME (30m). Treatment with the inhibitor of soluble guanylyl cyclase ODQ (2m) or the K+ channel blocker TEA (10mM) partially blocked LIN-induced vasorelaxation. Moreover, addition of TEA after incubation of the rings with L-NAME and ODQ partially blocked LIN-induced vasorelaxation. Furthermore, LIN was able to partially antagonize CaCl2-induced contractions in high potassium (80mM) Krebs' solution, whereas LIN did not affect Ca2+ release from endoplasmic reticulum Ca2+ stores. ConclusionOur findings indicate that LIN may induce endothelium-dependent vasorelaxation in mouse thoracic aortae by activating soluble guanylyl cyclase and K+ channels.</P>

Pharmacological effects of novel quinone compounds, 6-(fluorinated-phenyl)amino-5,8-quinolinediones, on inhibition of drug-induced relaxation of rat aorta and their putative action mechanism

Lee, Jung-Ah,Jung, Sung-Hee,Bae, Mee Kyung,Ryu, Chung-Kyu,Lee, Joo-Young,Chung, Jin-Ho,Kim, Hwa-Jung 梨花女子大學校 藥學硏究所 2000 藥學硏究論文集 Vol.- No.9

Two 6-(fluorinated-phenyl)amino-5,8-quinolinedione derivatives, OQ21 and OQ1, were newly synthesized as potent inhibitors of endothelial-dependent vasorelaxation. The purpose of the present study was to investigate the effects of OQ21 and OQ1 on different types of vasorelaxation and to pursue their action mechanisms. For acetylcholine both compounds, at a low concentration (0.1 μM), reduced the maximal response with increase of EC_50 values. OQ21 is a novel quinone compound and showed a more potent and efficacious inhibitory effect on acetylcholine-induced relaxation of rat aorta than that of LY83583 (6-anilino-5,8-quinolinedione). Relatively high concentrations (1 μM) of OQ21 and OQ1 inhibited the sodium nitroprusside-induced relaxation of endothelium-denuded ring, producing rightward shifts of the curve for sodium nitroprusside without altering the maximal response. They also prevented acetylcholine and sodium nitroprusside-induced elevations of cyclic GMP. In addition, OQ21 and OQ1 (1 μM) significantly decreased (52-72%) the sensitivity of L-arginine-induced relaxation of precontracted endothelium-denuded aortic rings from lipopolysaccaride-treated (20 ㎎/㎏, i.p.) rats. The inhibitory effect of OQ21 on endothelium-dependent vasodilation was enhanced by N^G-nitro-L-arginine, which inhibits nitric oxide synthase (NOS) by binding the oxygenase domain of the enzyme, but not by diphenylendiodonium, which inhibits NOS by binding to the reductase domain of the enzyme. Treatment of blood vessels with OQ21 or OQ1 showed a significant increase in chemiluminescence output, which was prevented by adding superoxide dismutase, suggesting that superoxide generation is involved in the action mechanism for OQ21. Present results indicate that a novel naphthoquinone compound, OQ21, potently inhibits endothelial NOS, possibly by interacting with the reductase domain of the enzyme, which leads to induce superoxide formation. The new benzoquinone compounds, OQ21 and OQ1, inhibit not only endothelium-dependent vasorelaxation but also endothelium-independent relaxation induced by exogenous NO generated from a nitrovasodilator via the reduction of cyclic GMP. They also reduced L-arginine-induced vasorelaxation in endotoxin-treated rats, indicating their possession of inhibitory effect on inducible NOS.

Protein Kinase-C의 활성화가 퓨린수용체에 의한 혈관이완작용에 미치는 영향

김은기,박규상,공인덕,이중우 연세대학교 원주의과대학 1995 원주의대논문집 Vol.8 No.1

6-Arylamino-5,8-quinazolinediones as potent inhibitors of endothelium-dependent vasorelaxation

Ryu, Chung-Kyu,Shin, Keun-Hwa,Seo, Ji-Hui,Kim, Hwa-Jung 梨花女子大學校 藥學硏究所 2002 藥學硏究論文集 Vol.- No.11

6-(Substituted-phenyl)amino-5,8-quinazolinediones (3) were synthesised by regioselective substitution of 5,8-quinaaolinedione(5) with appropriate aflamines in the presence of Ce(Ⅲ) ions. All synthesised 5,8-quinazolinediones 3 showed a potent andefficacious inhibitory effect on the acetylcholine (ACh)-induced vasorelaxation of rat aorta with the endothelium. The quinones3, at a low concentration of 0.1 μM, reduced the maximal response with increase of EC_50 values for ACh. The results indicatethat quinones 3 are potent inhibitors of endofhelium-dependent vasorelaxation.

Relaxant Effect of 4-Aminopyridine on the Mesenteric Artery of Rat

Se-Hoon Kim,Tae-Im Lee 대한생리학회-대한약리학회 2000 The Korean Journal of Physiology & Pharmacology Vol.4 No.6

<P> It has been well known that 4-aminopyridine (4-AP) has an excitatory effect on vascular smooth muscle due to causing membrane depolarization by blocking K<SUP>⁢</SUP>-channel. However, we observed that 4-AP had an inhibitory effect on the mesenteric artery of rat. Therefore, we investigated the mechanism of 4-AP-induced vasorelaxation. The mesenteric arcuate artery and its branches were isolated and cut into ring. The ring segment was immersed in HEPES-buffered solution and its isometric tension was measured. 4-AP (0.1∼10 mM) induced a concentration-dependent relaxation, which was unaffected by NO synthase inhibitor, N<SUP>G</SUP>-nitro-L-arginine methylester (100μM) or soluble guanylate cyclase inhibitor, methylene blue (10μM). Glibenclamide (10μM), ATP-sensitive K<SUP>⁢</SUP> channel blocker, did not exert any effect on the 4-AP-induced vasorelaxation. 4-AP relaxed the sustained contraction induced by 100 mM K<SUP>⁢</SUP> or Ca<SUP>2⁢</SUP> ionophore, A23187 (10μM) in a dose-dependent manner. In addition, 4-AP significantly decreased the phasic contractile response to norepinephrine in the absence of extracellular Ca<SUP>2⁢</SUP>. However, 4-AP did not block the <SUP>45</SUP>Ca influx of rat aorta. From the above results, we suggest that 4-AP may not block the Ca<SUP>2⁢</SUP> influx through Ca<SUP>2⁢</SUP>-channel, but act as a nonspecific vasorelaxant in arterial smooth muscle.

쇄양(鎖陽)의 내피세포 의존성 혈관이완효과

박선영 ( Sun Young Park ) 대한본초학회 2015 大韓本草學會誌 Vol.30 No.6

Objectives : The purpose of this study was to investigate the endothelium-dependent vasorelaxation effect of Cynomorii Herba(CH) extract on contracted rabbit carotid artery. Methods : To clarify the vasorelaxation effect of CH extract, arterial strips with intact was used, to endothelium -dependent vasorelaxation effect of CH extract, arterial strips damaged endothelium was used for experiment using organ bath. Arterial strips was contracted with phenylephrine(PE) before treated with CH extract(0.01, 0.03 and 0.1 ㎎/㎖). To study mechanisms of CH-induced vasorelaxation effect, CH extract infused into arterial rings after treatment by indomethacin(IM), tetraethylammonium chloride(TEA), Nω-nitro-L-arginine (L-NNA), methylene blue(MB) for comparing with non-treated. And calcium chloride(Ca2+) 1 mM was treated into precontracted arterial ring induced by PE after treatment of CH extract in Ca2+-free krebs solution. Cytotoxic activity of CH extract on human umbilical vein endothelial cell(HUVEC) was measured by MTT assay, and nitric oxide(NO) concentration was measured by Griess reagent. Results : PE-induced arterial strips was significantly relaxed, but the damaged endothelium arterial ring wasn``t relaxed by CH extract. Pretreatment of IM, TEA didn``t inhibit the vasorelaxation of CH extract, but pretreatment of L-NNA, MB inhibited the vasorelaxation of CH extract. Pretreatment of CH extract reduced the increase of contraction by influx of extracellular Ca2+ in contracted arterial ring induced by PE, CH extract increased nitric oxide concentration on HUVEC significantly. Conclusions : This study shows that CH extract have the vasorelaxation effect by blocking the influx of extracellular Ca2+ through the activating NO-cGMP system.

Effects and Mechanism of Turmeric Vasorelaxation of the Thoracic Aorta in Hypercholesterolemic Rats

Tsz-Shan Kam,Cho-Yee Wong,Pui-Long Kwan,Wing Fat-Yiu,Sin-Ming Chiu,Shun-Wan Chan,Kit-San Yuen,Robbie Chan 한국식품영양과학회 2012 Journal of medicinal food Vol.15 No.2

An extract of Curcuma longa was tested in hypercholesterolemic rats to investigate its potential therapeutic effect on vascular conditions. Four experimental groups were used: normal diet (ND) control group, high cholesterol diet (HCD) group, and HCD subgroups supplemented with turmeric extract at 100 or 300 mg/kg of body weight (HCD100Tur and HCD300Tur groups, respectively). Turmeric extract was fed orally to animals, and dietary treatments lasted for 28 days. Hypercholesterolemia developed in the HCD, HCD100Tur, and HCD300Tur rats. Segments of the thoracic aorta were isolated, and an organ bath experiment was used to assess the vasorelaxation capability among all rats. Rats fed only HCD showed a marked decrease in acetylcholine-induced vasorelaxation compared with ND control rats. The HCD100Tur and HCD300Tur rats showed significant improvement in vasorelaxation compared with HCD rats. When vasorelaxation was induced by high concentrations of sodium nitroprusside, no differences in vasorelaxation were observed among the four groups of rats. A mechanistic study showed that HCD100Tur and HCD300Tur rats had significantly higher levels of the antioxidant enzymes superoxide dismutase and glutathione peroxidase than HCD rats. The transcript levels of heat shock protein 70 (hsp70), bcl2, bax-a, caspase (casp3), and glyceraldehyde 3-phosphate dehydrogenase in aortic tissues indicated that hypercholesterolemia significantly increased the expression of bax-a and casp3 but down-regulated bcl2 expression compared with the control group. Turmeric increased the expression of hsp70 and bcl2 but greatly reduced casp3 expression,indicating that turmeric improves vasorelaxation of the aorta in hypercholesterolemic rats by increasing antioxidant enzyme activities and likely suppressing apoptosis.

난포 호르몬에 의한 인체 자궁동맥 이완반응과 연령사이의 상관관계에 관한 연구

김연희(Y . H . Kim),박형무(H . M . Park),허민(M . Hur),이무열(M . Y . Lee) 대한산부인과학회 2000 Obstetrics & Gynecology Science Vol.43 No.10

목적 : 본 연구는 난포 호르몬에 대한 혈관반응도를 연구함으로서 난포 호르몬의 혈관에 대한 칼슘 길항작용을 증명하고 연령에 따른 난포 호르몬에 대한 혈관이완반응도의 차이를 비교하고자하였다. 방법 : 본 연구는 자궁 적출술 환자에서 내경 3mm 이상의 자궁동맥을 적출하여 혈관내피를 제거한후 생리적 용액내에서 길이 10mm, 폭 2mm정도의 직사각형 모양의 혈관 평활근 절편을 만들고 용량 30ml의 실혐용기에 옮긴 후 등장성 장력변환기에 연결하여 다양한 실험 조건하에서 수축력을 측정함으로서 에스트로겐이 혈관수축에 미치는 영향을 관찰하였다. 결과 : 1) 노에피네프린에 의해 유발된 혈관경축과 고농도의 포타슘용액에 의해 유발된 혈관경축에 대하여 난포 호르몬은 농도 의존성 이완 효과를 보였고, 이는 난포 호르몬이 혈관 평활근 수용체 작동성 칼슘통로와 전압작동성 칼슘통로를 통해 칼슘 길항작용을 나타내며 이 작용은 농도 의존성 현상임을 추측케 한다. 2) 난포 호르몬의 투여는 수용체의존성 및 전압의존성 칼슘통로를 통한 혈관평활근수축에 대한 이완반응이 연령이 증가함에 따라 유의하게 감소함이 관찰되었다. 결론 : 난포 호르몬은 인간자궁동맥 평활근 세포에서 칼슘 길항작용을 가지며, 그 기전은 수용체 및 전압의존성 칼슘 이온통로를 통해서 나타나고 이로 인한 혈관이완 효과는 에스트로겐의 심혈관보호 효과에 기여할 것으로 생각되며, 연령의 증가에 따른 난포 호르몬에 대한 혈관 이완반응성의 감소는 연령에 따라 심혈관질환이 증가하는 것과 연관성이 있음을 시사한다. Objective : This study was performed to investigate whether 1) estrogen induces the vasorelaxation mediated by calcium channel in smooth muscle of endothelium-denuded human uterine artery, and 2) the degrees of vasorelaxation have some difference according to age. Methods : The uterine arteries from 18 premenopausal women were obtained at the time of hysterectomy due to various indications and endothelium was denuded. Vascular reactivity was monitored by using Isometric force transducer and recorded by physiograph. Endothelial integrity was assessed by sequential administration of 1 μM norepinephrine(α-adrenergic stimulant) and 10 μM acetylcholine (endotelium -dependent vasorelaxant). Integrity of smooth muscle was measured by administration of 10 μM sodium nitroprusside (endotelium - independent vasorelaxant). A dose-dependent action of estrogen was measured on denuded uterine arteries, pretreated with norepinephrine and potassium chloride. Statistical tests were performed at the 5% level of significance using the SPSS PC+ package. Results : Acethylcholine have little effect but sodium nitroprusside showed marked relaxation, which suggested loss of endothelial function and adequacy of smooth muscle function. The contraction by norephinephrine(1 M) revealed estrogen induced relaxation which was concentration-dependent from 10pg/ml to 10ng/ml in concentration of 17 -estradiol. The contraction by high potassium solution 35mM was also inhibited by estrogen in concentration-dependent manner. The vasorelaxation effect of 17 -estradiol on the contraction evoked by both norepinephrine and potassium revealed reduction according to the increase of age.Conclusion : The results of this study suggested that the decrease of the vasorelaxant effect according to age might be correlated with increase of cardiovascular disease in old age group.