KR102147868B1 - Vasodilator and antiphlogistics containing extract of luffa cylindrica - Google Patents
Vasodilator and antiphlogistics containing extract of luffa cylindrica Download PDFInfo
- Publication number
- KR102147868B1 KR102147868B1 KR1020180007885A KR20180007885A KR102147868B1 KR 102147868 B1 KR102147868 B1 KR 102147868B1 KR 1020180007885 A KR1020180007885 A KR 1020180007885A KR 20180007885 A KR20180007885 A KR 20180007885A KR 102147868 B1 KR102147868 B1 KR 102147868B1
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- KR
- South Korea
- Prior art keywords
- extract
- hot water
- scrubber
- vascular
- vasodilator
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Abstract
본 발명은 수세미 추출물을 유효 성분으로 함유하는 혈관이완제 및 항염제에 관한 것으로, 더욱 상세하게는 혈관 내피 세포에서 NO(nitric oxide) 생성을 유도함으로써 혈관 이완 효능을 나타낼 수 있는 혈관이완제와 면역세포에서 NO(nitric oxide)에 생성을 저해함으로써 항염 효능을 나타내는 항염제에 관한 것이다. 본 발명에 따른 혈관이완제는 고혈압, 동맥경화, 혈액순환 장애, 두통, 뇌졸중, 뇌경색, 뇌출혈, 심근경색 및 심부전 등과 같은 혈관 수축으로 인환 질환의 예방, 치료 또는 개선용으로 사용될 수 있다.The present invention relates to a vasodilator and an anti-inflammatory agent containing a loofah extract as an active ingredient, and more particularly, to a vasodilator that can exhibit vascular relaxation efficacy by inducing NO (nitric oxide) production in vascular endothelial cells and NO in immune cells. It relates to anti-inflammatory drugs showing anti-inflammatory effects by inhibiting the production of (nitric oxide). The vasodilator according to the present invention can be used for the prevention, treatment or amelioration of blood vessel constriction such as hypertension, arteriosclerosis, blood circulation disorder, headache, stroke, cerebral infarction, cerebral hemorrhage, myocardial infarction and heart failure.
Description
본 발명은 수세미 추출물을 유효 성분으로 함유하는 혈관이완제 및 항염제에 관한 것으로, 더욱 상세하게는 혈관 내피 세포에서 NO(nitric oxide) 생성을 유도함으로써 혈관 이완 효능을 나타낼 수 있는 혈관이완제와 면역세포에서 NO(nitric oxide)에 생성을 저해함으로써 항염 효능을 나타낼 수 있는 항염제에 관한 것이다.The present invention relates to a vasodilator and an anti-inflammatory agent containing a loofah extract as an active ingredient, and more particularly, to a vasodilator that can exhibit vascular relaxation efficacy by inducing NO (nitric oxide) production in vascular endothelial cells and NO in immune cells. It relates to anti-inflammatory drugs that can exhibit anti-inflammatory effects by inhibiting the production of (nitric oxide).
산화질소 (Nitric Oxide, NO)는 혈관 확장, 신경신호전달, 면역 조절 등과 같은 다양한 생물학적 기능을 조절하는 생체 내 자유 라디컬로서 다양한 염증 반응에 관여하는데, 과도하게 생성되면 염증 반응을 유발하여 조직 손상을 촉진하고 그 결과 만성 염증을 유발한다.Nitric Oxide (NO) is a free radical in the body that regulates various biological functions such as vasodilation, nerve signal transmission, and immune regulation, and is involved in various inflammatory reactions.If excessively produced, it causes inflammatory reactions and damages tissues. And, as a result, chronic inflammation.
또한, 산화질소는 세포 독성 이외에도 세포 분화나 세포 내 신호전달물질로 알려져 있으며 염증을 유도하는 Lipopolysaccharide (LPS)를 처치하여 대식세포(macrophage)를 활성화시켜 NO 생성을 확인 할 수 있는데, iNOS와 cyclooxygenase-2 (COX-2)는 면역 세포의 대표적인 염증인자로 염증 반응이 일어나면 다양한 염증인자들(pro-inflamatory mediatos)이 만들어지고 유도성 산화질소 합성효소인 iNOS에 의해 만들어지는 NO와 COX-2에 의해 만들어지는 prostagrandin E2 (PGE2) 등으로 나뉜다. iNOS의 경우, LPS와 같은 여러 가지 염증성 사이토카인의 자극이 있을 경우 발현된다.In addition to cytotoxicity, nitric oxide is also known as a cell differentiation or intracellular signal transducer. It can activate macrophages by treating inflammation-inducing Lipopolysaccharide (LPS) to confirm NO production. iNOS and cyclooxygenase- 2 (COX-2) is a representative inflammatory factor of immune cells. When an inflammatory reaction occurs, various inflammatory factors (pro-inflamatory mediatos) are produced and produced by NO and COX-2 by iNOS, an inducible nitric oxide synthase. It is divided into prostagrandin E2 (PGE2) and others. In the case of iNOS, it is expressed when there is stimulation of various inflammatory cytokines such as LPS.
한편, 혈관 평활근의 긴장도는 신경전달물질 (norepinephrine, adenosine triphophate, NO), 내피인자(endothelium-derived relaxing factor; EDRF, endothelium-derived hyperpolarrizing factor: EDHF, endothelins), 대사성 영향 (PO2, PCO2. pH), 체액성 물질 (norepinephrine, epinephrine, vasopressin), 근육성 영향 (혈관의 신축성, 내압) 등 여러 중요인자에 의해 결정 된다). 특히 혈관 내피세포는 혈관 내피유래 이완인자 (endothelium-derived relaxing factor)와 수축인자 (endothelium-derived constricting factor)를 방출하여 혈압조절에 중요한 역할을 한다고 알려져 있다. 이러한 EDRF (endothelium-derived relaxing factor)의 본체는 산화질소 (NO)인데 NO는 혈관 내피세포 외에 평활근과 혈구 그리고 중추신경계의 뉴런 등으로부터 생성될 수 있으며, 적어도 3가지 이상의 산화질소합성효소 동위효소들의 작용에 의해 아미노산인 L- 아르기닌(L-arginine)으로부터 합성 된다. 또한 NO와 같은 혈관 이완 인자는 정상 상태에서도 내피세포에서 합성 및 분비가 이루어지고 아세틸콜린(acetylcholine), 히스타민(histamine), P 물질(substance P) 및 이소프로테레롤(isoproterenol) 등의 효능제에 의해서 합성 및 분비가 증가 된다. 고혈압 치료에 사용되어온 유기 나이트레이트(nitrate)의 작용은 가용성 구아닐산 고리화효소(guanylate cyclase)를 활성화시켜 cGMP를 상승시킴으로써 이루어지며, 또한 이 약제는 비 효소 작용에 의해 NO를 발생시키므로, EDRF의 혈관이완작용도 가용성 guanylate cyclase의 활성에 의한 cGMP에 의한 것으로 밝혀졌다. 최근 혈관 내피 세포에서 산화질소의 생성을 증가시켜 혈관을 이완시키는 몇 가지의 한약이나 생약들이 보고된 바 있다. Kuramochi 등은 조구등(釣鉤藤) 전탕액(추출물)이 산화질소 의존적으로 혈관이완효과를 증가시킨다는 보고를 하였으며, Goto 등은 일련의 연구결과에서 釣鉤藤 전탕액이 자연발증 고혈압 백서의 혈압을 강하시키고 열수 추출물이 산화질소 의존적으로 흉부 대동맥의 혈관을 이완시킨다고 보고하였다. 또한 단삼의 lithospermic acid B, 동충하초(冬蟲夏草)의 단백질 성분 등도 산화질소 의존적으로 혈관 이완을 증가시키는 것으로 알려져 있다.On the other hand, the tonicity of vascular smooth muscle is neurotransmitter (norepinephrine, adenosine triphophate, NO), endothelium-derived relaxing factor (EDRF, endothelium-derived hyperpolarrizing factor: EDHF, endothelins), metabolic effects (PO 2 , PCO 2 . pH), humoral substances (norepinephrine, epinephrine, vasopressin), and muscular effects (determined by several important factors such as blood vessel elasticity, internal pressure)). In particular, vascular endothelial cells are known to play an important role in blood pressure control by releasing endothelium-derived relaxing factor and endothelium-derived constricting factor. The main body of this EDRF (endothelium-derived relaxing factor) is nitric oxide (NO). NO can be produced from smooth muscle, blood cells, and neurons of the central nervous system in addition to vascular endothelial cells, and at least three kinds of nitric oxide synthase isotopes It is synthesized from the amino acid L-arginine by action. In addition, vascular relaxation factors such as NO are synthesized and secreted in endothelial cells even under normal conditions, and are used in agonists such as acetylcholine, histamine, P substance P, and isoproterenol. Synthesis and secretion are increased. The action of organic nitrate, which has been used in the treatment of hypertension, is achieved by increasing cGMP by activating soluble guanylate cyclase. Also, since this drug generates NO by non-enzymatic action, the blood vessels of EDRF The relaxation action was also found to be due to cGMP by the activity of soluble guanylate cyclase. Recently, several herbal or herbal medicines have been reported that relax blood vessels by increasing the production of nitric oxide in vascular endothelial cells. Kuramochi et al. reported that the extract of Jogu-deung (釣鉤藤) decoction (extract) increases blood vessel relaxation effects in a nitric oxide-dependent manner, and Goto et al. reported that in a series of research results, 釣鉤藤 decoction solution lowered blood pressure in spontaneous hypertensive white papers. It was reported that hot water extract relaxes blood vessels in the thoracic aorta in a nitric oxide-dependent manner. In addition, lithospermic acid B of Dansam and protein components of Cordyceps sinensis are known to increase vascular relaxation in a nitric oxide-dependent manner.
수세미는 박과(Cucurbitaceae) Luffa cylindrica Roemer의 열매로 식약처 고시 식용 가능한 식품원료로 음료 및 기타 식재료로도 많이 활용되고 있다. 또, 한방에서는 사과락(絲瓜絡)이라는 약재명으로 통용되며 맛은 달고 성질이 순하고 독성이 없어 껍질을 제거한 망상조직을 말려 약용으로 사용해왔다. 한방에서 수세미는 가슴과 옆구리의 통증, 복통, 요통 등의 통증을 경감시키고, 어혈을 삭히며, 간열을 내리고, 폐의 열을 내리고 가래와 기침을 멈추게하는 효능이 있어, 폐, 위, 간의 염증성 질환에 주로 사용되어왔다. 약리 성분으로 그물망사 조직에는 사포닌, 루테인, 시트룰린등이 포함되어 있으며, 종자에는 지방유가 20~40% 포함되어 있고, 리놀산, 팔미틴산, 스테아린산, 올레인산 등의 성분이 포함되어있다. 수세미에 대한 연구는 주로 화장품 원료로 미백, 염증의 감소에 치중되며, 한방에서 기침, 가래, 천식 등에 사용한 것을 활용하는 정도에 그치고 있어 아직 수세미의 심혈관계에 대한 효능은 제대로 보고된 바가 없다.The loofah is a fruit of the Cucurbitaceae family Luffa cylindrica Roemer. It is an edible food ingredient notified by the Ministry of Food and Drug Safety and is widely used as a beverage and other food ingredients. In addition, in oriental medicine, it is commonly used as a medicinal name, apple-lac (絲瓜絡), and it has a sweet taste, mild nature, and non-toxicity, so it has been used for medicinal purposes by drying the reticulum from which the skin was removed. In oriental medicine, scrubbers relieve pain in the chest and sides, abdominal pain, and back pain, clear blood stagnation, reduce liver fever, reduce heat in the lungs, stop phlegm and cough, and are inflammatory in the lungs, stomach, and liver. It has been mainly used for diseases. As a pharmacological ingredient, the mesh tissue contains saponin, lutein, and citrulline, and the seeds contain 20 to 40% of fatty oil, and ingredients such as linoleic acid, palmitic acid, stearic acid, and oleic acid are included. Research on loofah is mainly focused on whitening and reducing inflammation as a cosmetic ingredient, and it is only used for coughing, phlegm, and asthma in oriental medicine, so the efficacy of loofah on the cardiovascular system has not been properly reported.
본 발명은 수세미 추출물을 유효 성분으로 함유하는 혈관이완제와 항염제를 제공한다.The present invention provides a vasodilator and an anti-inflammatory agent containing a scrubber extract as an active ingredient.
또한 본 발명은 수세미 추출물을 유효 성분으로 함유하는 염증 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving inflammation containing a scrubber extract as an active ingredient.
또한 본 발명은 수세미 추출물을 유효 성분으로 함유하는 혈관이완용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for vascular relaxation containing a scrubber extract as an active ingredient.
본 발명은 수세미 추출물을 유효 성분으로 함유하는 혈관이완제를 제공한다.The present invention provides a vasodilator containing a scrubber extract as an active ingredient.
상기 수세미 추출물은 물, 에탄올, 메탄올, 플로필렌글리콜, 에테르, 클로르포름, 석유에테르, 헥산, 벤젠, 메틸렌클로라이드, 에틸아세테이트, 아세톤, 부탄올, 이소프로판올 및 이들의 혼합물로 이루어진 군으로부터 선택된 용매로 추출될 수 있다. 가장 바람직하게는 물을 용매로 하여 추출된 추출물일 수 있다.The scrubber extract may be extracted with a solvent selected from the group consisting of water, ethanol, methanol, flophyllene glycol, ether, chlorform, petroleum ether, hexane, benzene, methylene chloride, ethyl acetate, acetone, butanol, isopropanol, and mixtures thereof. I can. Most preferably, it may be an extract extracted using water as a solvent.
상기 수세미 추출물은 eNOS(endothelial nitric oxide synthase) 증진 활성을 가질 수 있다.The scrubber extract may have an endothelial nitric oxide synthase (eNOS) enhancing activity.
상기 수세미 추출물은 혈관 내피 세포에서 산화질소(NO)의 생성을 증가시킬 수 있다.The scrubber extract may increase the production of nitric oxide (NO) in vascular endothelial cells.
상기 수세미 추출물은 혈관 내피 세포에서 NO-cGMP 패스웨이 (nitric oxide-cyclic guanosine monophosphate)를 조절함으로써 혈관 이완 효능을 나타낼 수 있다.The scrubber extract may exhibit vascular relaxation effects by regulating the NO-cGMP pathway (nitric oxide-cyclic guanosine monophosphate) in vascular endothelial cells.
상기 혈관이완제는 혈관 수축으로 인한 질환의 치료, 예방 또는 개선용으로 사용될 수 있다.The vasodilator may be used for treatment, prevention or improvement of diseases caused by vasoconstriction.
상기 혈관 수축으로 인한 질환은 고혈압, 동맥경화, 혈액순환 장애, 두통, 뇌졸중, 뇌경색, 뇌출혈, 심근경색 및 심부전으로 이루어진 군에서 선택될 수 있다.The disease caused by the vasoconstriction may be selected from the group consisting of hypertension, arteriosclerosis, blood circulation disorder, headache, stroke, cerebral infarction, cerebral hemorrhage, myocardial infarction, and heart failure.
또한 수세미 추출물을 포함하는 혈관이완용 건강기능식품을 제공할 수 있다.In addition, it is possible to provide a health functional food for relaxation of blood vessels including a scrubber extract.
또한 본 발명은 수세미 추출물을 유효 성분으로 함유하는 항염제를 제공한다.In addition, the present invention provides an anti-inflammatory agent containing the scrubber extract as an active ingredient.
상기 수세미 추출물은 물, 에탄올, 메탄올, 플로필렌글리콜, 에테르, 클로르포름, 석유에테르, 헥산, 벤젠, 메틸렌클로라이드, 에틸아세테이트, 아세톤, 부탄올, 이소프로판올 및 이들의 혼합물로 이루어진 군으로부터 선택된 용매로 추출된 추출물일 수 있고, 더욱 바람직하게는 에탄올 또는 메탄올로 추출된 추출물일 수 있다.The scrubber extract is extracted with a solvent selected from the group consisting of water, ethanol, methanol, flophyllene glycol, ether, chlorform, petroleum ether, hexane, benzene, methylene chloride, ethyl acetate, acetone, butanol, isopropanol, and mixtures thereof. It may be an extract, more preferably an extract extracted with ethanol or methanol.
상기 수세미 추출물은 iNOS(inducible nitric oxide synthase) 억제 활성을 가질 수 있다.The scrubber extract may have iNOS (inducible nitric oxide synthase) inhibitory activity.
상기 수세미 추출물은 면역 세포에서 산화질소의 생성을 억제시킬 수 있다.The scrubber extract can inhibit the production of nitric oxide in immune cells.
또한 본 발명은 수세미 추출물을 포함하는 염증 예방 또는 개선용 건강기능식품을 제공할 수 있다. In addition, the present invention can provide a health functional food for preventing or improving inflammation comprising a scrubber extract.
또한 본 발명은 수세미 추출물을 유효성분으로 함유하는 혈관이완용 식품조성물 또는, 염증 예방 또는 개선용 식품조성물을 제공할 수 있다. In addition, the present invention can provide a food composition for relaxation of blood vessels or a food composition for preventing or improving inflammation containing a scrubber extract as an active ingredient.
상기 건강기능식품은 상기 식품 조성물을 이용하여 제조할 수 있다.The health functional food can be prepared using the food composition.
상기 식품 조성물에는 식품학적으로 허용 가능한 식품첨가제가 포함될 수 있다. The food composition may contain food additives acceptable food.
구체적으로 상기 식품 조성물에는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드, 록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 포함될 수 있다.Specifically, the food composition includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline as a carrier, excipient, and diluent. Cellulose, polyvinyl pyrrolidone, water, methylhydroxy, hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
상기 식품 조성물은 추출물은 혈관 이완을 위한 식품 및 음료 등에 다양하게 이용될 수 있다. 구체적으로 껌, 차, 비타민 복합제 또는 건강보조 식품류 등이 있고, 분말,과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The food composition extract may be used in various ways such as food and beverage for relaxation of blood vessels. Specifically, there are gum, tea, vitamin complexes or health supplements, and may be used in the form of powders, granules, tablets, capsules, or beverages.
상기 식품 조성물을 이용하여 건강 음료를 제조하는 경우 수세미 추출물을 함유하는 것 외에 액체 성분에 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In the case of manufacturing a health drink using the food composition, there is no particular limitation on the liquid component other than containing the scrubber extract, and various flavoring agents or natural carbohydrates, etc. may be included as an additional component, as in a conventional beverage.
상기 외에 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제, 착색제 및 증진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 일긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜 또는 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition to the above, the food composition includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and salts thereof, ilginic acid and salts thereof, organic acids, protection It may contain colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, carbonates used in alcohol or carbonated beverages, and the like.
그 밖에 본 발명의 조성물들은 천연 과일 쥬스 및 채소 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. In addition, the compositions of the present invention may contain pulp for the production of natural fruit juice and vegetable beverages. These components may be used independently or in combination.
또한 본 발명은 수세미 추출물을 유효성분으로 하는 혈관이완용 의약외품 조성물 또는 약학적 조성물을 제공할 수 있다. 또한, 수세미 추출물을 유효성분으로 하는 염증 예방 또는 개선용 의약외품 조성물과, 염증 예방 또는 치료용 약학적 조성물을 제공할 수 있다.In addition, the present invention can provide a quasi-drug composition or pharmaceutical composition for vascular relaxation using a scrubber extract as an active ingredient. In addition, it is possible to provide a quasi-drug composition for preventing or improving inflammation using a scrubber extract as an active ingredient, and a pharmaceutical composition for preventing or treating inflammation.
상기 조성물에는 약학적으로 허용된 첨가제가 첨가될 수 있다. A pharmaceutically acceptable additive may be added to the composition.
상기 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. Each of the above compositions may be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, and sterile injectable solutions according to a conventional method.
상기 조성물에는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드, 록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 첨가될 수 있다.The composition includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, poly Vinyl pyrrolidone, water, methylhydr, oxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, and the like may be added.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제 또는 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.In the case of formulation, it can be prepared using diluents or excipients such as generally used fillers, extenders, binders, wetting agents, disintegrants or surfactants.
경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전부, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 섞어 조제될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules and capsules, and such solid preparations include at least one or more excipients, such as all, calcium carbonate, sucrose, and lactose. It can be prepared by mixing (lactose) or gelatin.
경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 또는 보존제 등이 포함될 수 있다.Liquid preparations for oral administration include suspensions, liquid solutions, emulsions and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances or preservatives may be included. have.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제 동결건조제제 및 좌제가 포함될 수 있다.Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions lyophilized formulations, and suppositories.
현탁제로는 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.As the suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지 또는 글리세로제라틴 등이 사용될 수 있다.As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper or glycerogelatin may be used.
상기 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르나, 통상의 기술자(당업자)에 의해 적절하게 선택될 수 있다.The preferred dosage of the composition varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the route and duration of administration, but may be appropriately selected by a person skilled in the art (a person skilled in the art).
또한 본 발명의 조성물은 쥐, 생쥐, 가축 또는 인간 등의 포유동물에 다양한 경로로 투여될 수 있수 있으며, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사 등에 의해 투여될 수 있다.In addition, the composition of the present invention may be administered to mammals such as mice, mice, livestock, or humans by various routes, and by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerebroventricular injection. Can be administered.
상기 조성물에서, 첨가제의 비율은 수세미 추출물 100 중량부에 대하여 0.1 ~ 20 중량부로 범위로 선택하는 것이 일반적이나 이에 제한되는 것은 아니다.In the above composition, the ratio of the additive is generally selected in the range of 0.1 to 20 parts by weight based on 100 parts by weight of the scrubber extract, but is not limited thereto.
본 발명에 따르면 수세미 추출물을 유효 성분으로 함유하는 혈관이완제 또는 항염제를 제공할 수 있다. 본 발명에 따른 혈관이완제는 혈관 내피 세포에서 산화질소의 생성을 증가시킴으로써 혈관 이완 효능을 구현할 수있다. 또한 본 발명에 따른 혈관이완제는 고혈압, 동맥경화, 혈액순환 장애, 두통, 뇌졸중, 뇌경색, 뇌출혈, 심근경색 및 심부전 등과 같은 혈관 수축으로 인환 질환의 예방, 치료 또는 개선용으로 사용될 수 있다. 또한 본 발명에 따른 수세미 추출물은 면역 세포에서 산화질소의 생성을 증가시킴으로써 항염 효능을 구현할 수 있다.According to the present invention, it is possible to provide a vasodilator or anti-inflammatory agent containing the scrubber extract as an active ingredient. The vasodilator according to the present invention can realize vascular relaxation effect by increasing the production of nitric oxide in vascular endothelial cells. In addition, the vasodilator according to the present invention can be used for the prevention, treatment or amelioration of blood vessel constriction such as hypertension, arteriosclerosis, blood circulation disorders, headache, stroke, cerebral infarction, cerebral hemorrhage, myocardial infarction and heart failure. In addition, the scrubber extract according to the present invention can implement anti-inflammatory effects by increasing the production of nitric oxide in immune cells.
도 1은 페닐레프린(Phenylephrine, 1 x 10-6 M)을 전처리하여 수축시킨 백서의 흉부대동맥 절편에서 수세미 열수 추출물의 혈관 평활근 이완 효과를 분석한 결과를 나타내는 그래프이다(e(-):혈관내피세포가 제거된 상태, e(+): 혈관내피세포가 제거되지 않은 상태), WLC: water extract of Luffa cylindrica. 각 값(Each value): 4회 실험의 mean ± S.E, *P<0.05, **P<0.01, vs. control.
도 2는 L-NAME 와 MB 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± S.E, *P<0.05, **P<0.01, vs. control.
도 3은 베라파밀 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 4a는 글리벤클라미드 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 4b는 TEA 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 4c는 4AP(4-Aminopyridine) 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control
도 5a는 프로프라놀롤(propranolol) 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 5b는 아트로핀(atropine) 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 6은 인도메타신(indomethacin) 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 7은 ODQ를 전처리에 의한 수세미 열수 추출물의 혈관 이완효과 변화를 분석한 결과를 나타내는 그래프이다. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 8은 수세미 열수 추출물이 페닐레프린(phenylephrine)에 의한 혈관 수축에 미치는 영향을 분석한 결과를 나타내는 그래프이다. vehicle: thoracic aortic rings, WLC: water extract of Luffa cylindrica. 각 값(Each value): 4회 실험의 mean ± SEM, *P<0.05, **P<0.01, vs. control.
도 9, 도 10은 수세미 추출물의 추출 용매별 세포독성 확인한 결과를 나타내는 그래프이다.
도 11은 수세미 추출물의 추출 용매별 NO 생성에 미치는 영향을 분석한 결과를 나타내는 그래프이다.
도 12는 수세미 추출물의 추출 용매별 iNOS 및 COX-2 발현 수준을 확인한 결과를 나타내는 그림이다. (A) 메탄올 추출물, (B) 에탄올 추출물, (c) 열수 추출물.FIG. 1 is a graph showing the results of analyzing the vascular smooth muscle relaxation effect of hot water scrubber extract in a thoracic aortic section of a rat contracted by pretreatment with phenylephrine (1 x 10 -6 M) (e(-): blood vessels Endothelial cells are removed, e(+): vascular endothelial cells are not removed), WLC: water extract of Luffa cylindrica. Each value: mean ± SE of 4 experiments, *P<0.05, **P<0.01, vs. control.
FIG. 2 is a graph showing the results of analyzing changes in the blood vessel relaxation effect of hot water extracts of loofah by L-NAME and MB pretreatment. Each value: mean ± SE of 4 experiments, *P<0.05, **P<0.01, vs. control.
3 is a graph showing the results of analyzing changes in the blood vessel relaxation effect of hot water extracts of scrubbers by pretreatment with verapamil. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
4A is a graph showing the results of analyzing changes in the blood vessel relaxation effect of hot water extracts of scrubbers by pretreatment with glibenclamide. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
Figure 4b is a graph showing the results of analyzing the change in the blood vessel relaxation effect of the hot water scrubber extract by TEA pretreatment. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
Figure 4c is a graph showing the results of analyzing changes in the blood vessel relaxation effect of the hot water scrubber extract by 4AP (4-Aminopyridine) pretreatment. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control
FIG. 5A is a graph showing the results of analyzing changes in the blood vessel relaxation effect of hot water extract of loofah by pretreatment of propranolol. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
5B is a graph showing the results of analyzing changes in the blood vessel relaxation effect of hot water extracts of scrubbers by atropine pretreatment. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
6 is a graph showing the results of analyzing changes in the blood vessel relaxation effect of hot water extracts of scrubbers by pretreatment of indomethacin. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
7 is a graph showing the results of analyzing the change in the blood vessel relaxation effect of the hot water extract of the scrubber by pretreatment with ODQ. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
8 is a graph showing the results of analyzing the effect of the hot water extract of the scrubber on the vasoconstriction by phenylephrine. vehicle: thoracic aortic rings, WLC: water extract of Luffa cylindrica. Each value: mean ± SEM of 4 experiments, *P<0.05, **P<0.01, vs. control.
9 and 10 are graphs showing the results of checking the cytotoxicity of each extraction solvent of the scrubber extract.
11 is a graph showing the results of analyzing the effect of the scrubber extract on NO generation by extraction solvent.
12 is a diagram showing the results of confirming the expression levels of iNOS and COX-2 by extraction solvent of the scrubber extract. (A) methanol extract, (B) ethanol extract, (c) hot water extract.
이하, 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 본 발명의 목적, 특징, 장점은 이하의 실시예를 통하여 쉽게 이해될 것이다. 본 발명은 여기서 설명하는 실시예에 한정되지 않고, 다른 형태로 구체화될 수도 있다. 여기서 소개되는 실시예는 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 본 발명의 사상이 충분히 전달될 수 있도록 하기 위해 제공되는 것이다. 따라서 이하의 실시예에 의해 본 발명이 제한되어서는 안 된다.Hereinafter, the present invention will be described in more detail through examples. Objects, features, and advantages of the present invention will be easily understood through the following examples. The present invention is not limited to the embodiments described herein, but may be embodied in other forms. The embodiments introduced herein are provided in order to sufficiently convey the spirit of the present invention to those of ordinary skill in the art. Therefore, the present invention should not be limited by the following examples.
실시예 1. 수세미 추출물의 제조Example 1. Preparation of scrubber extract
실험에 사용된 수세미는 국내산(경북 경산)을 구매하여 실험에 사용하였다. 수세미를 잘 씻어 잡질을 제거하고 말린 후 건조중량 100 g을 1차 증류수 (또는 메탄올 또는 에탄올) 1L에 수침 30 후 2시간 동안 무압 상태로 전기 탕전기로 추출한 열수 수출물, 메탄올 추출물, 에탄올 추출물을 각각 수득하였다. 수세미는 추출한 후 Advantec Filter paper NO.2 (Toyo Roshi Kaisha Ltd, Japan)로 여과하고, 여과액을 회전증발농축기 (Buchl, Swiss)로 농축하여, 그 농축액을 Ultra-low temperature freezer (Operon, Korea)에 동결한 후 Freeze Dryer (Operon, Korea)를 이용하여 동결건조물을 수득하였다. (61.4 g, 수율 6.14%). 이를 각 실험 시 적당량 3차 증류수에 녹여서 사용하였다. The scrubber used in the experiment was purchased domestically (Gyeongsan, Gyeongbuk) and used for the experiment. Wash the scrubber well to remove impurities, dry, and dip 100 g of dry weight in 1 liter of first distilled water (or methanol or ethanol) for 30 hours, and then extract hot water exports, methanol extracts, and ethanol extracts with an electric kettle for 2 hours without pressure. Respectively obtained. After the scrubber is extracted, it is filtered with Advantec Filter paper NO.2 (Toyo Roshi Kaisha Ltd, Japan), and the filtrate is concentrated with a rotary evaporator (Buchl, Swiss), and the concentrate is converted into an ultra-low temperature freezer (Operon, Korea). After freezing in, a freeze-dried product was obtained using a Freeze Dryer (Operon, Korea). (61.4 g, yield 6.14%). This was dissolved in an appropriate amount of tertiary distilled water in each experiment and used.
실험예 1. 수세미 열수 추출물의 혈관 이완 효과 분석Experimental Example 1. Analysis of Vascular Relaxation Effect of Hot Water Extract of Scrubber
생리 영양액의 제조Preparation of physiological nutrient solution
흉부대동맥 혈관의 안정적인 생리활성 유지를 위해 Krebs 용액(Krebs-Henseleit Solution)을 사용하였으며, 그 조성은 다음과 같다. (118 mM NaCl, 4.7 mM KCl, 1.1 mM MgSO4, 1.2 mM KH2PO4, 1.5 mM CaCl2, 25 mM NaHCO3, 10 mM glucose이고, pH 7.4)Krebs solution (Krebs-Henseleit Solution) was used to maintain stable physiological activity of thoracic aortic vessels, and the composition is as follows. (118 mM NaCl, 4.7 mM KCl, 1.1 mM MgSO 4 , 1.2 mM KH 2 PO 4 , 1.5 mM CaCl 2 , 25 mM NaHCO 3 , 10 mM glucose, pH 7.4)
혈관조직 절편의 제작Fabrication of vascular tissue section
실험동물은 250~330g 정도의 건강한 Sprague-Dawley계 수컷 백서를 이용하였다. 실험 시작 전 이산화탄소 과포화 상태에서 마취시켜 희생시켰으며, 즉시 복강을 열고 흉부 대동맥을 분리하였다. 분리된 흉부 대동맥을 산소가 공급되는 4℃의 Kreb's 용액에 넣고 연결 조직과 지방을 제거한 후 약 3~4 mm정도 길이의 고리형태의 절편으로 만들었다.The experimental animals used healthy Sprague-Dawley male white papers of about 250 to 330 g. Before the start of the experiment, anesthesia was performed under carbon dioxide supersaturation, and the abdominal cavity was immediately opened and the thoracic aorta was separated. The separated thoracic aorta was put in Kreb's solution at 4℃ supplied with oxygen, and the connective tissue and fat were removed, and then a ring-shaped section of about 3-4 mm in length was made.
혈관 장력의 측정Measurement of blood vessel tension
백서의 흉부 대동맥 절편은 95% O2, 5% CO2 혼합가스로 포화시킨 37℃의 Krebs 용액이 들어있는 organ bath의 저부에 한쪽 끝을 고정시키고, 다른 쪽 끝은 force-displacement transducer (Grass FT 03, GRASS Instrument, MA, USA)에 연결하여 고정시켰고, force-displacement transducer와 연결된 생리기록계(Grass Model 7E, Grass Instrument, MA, USA)를 이용하여 혈관의 등척성 장력(isometric tension)을 측정하였다. 이후, 혈관의 안정화를 위해 10분 간격으로 60분 동안 신선한 Kreb's 용액을 공급하면서 혈관절편에는 1g의 기저 긴장도를 부여하였다. 1g의 기저 긴장도가 일정하게 유지되면 1x10-6 M의 페닐레프린(phenylephrine)으로 수축시키고 5분후 1 x 10-6 M의 ACh(아세틸콜린)으로 이완시켜 이완율이 80% 이상이었을 경우 혈관 내피세포가 손상 받지 않은 것으로 판정하고 약물의 실험을 진행하였다. 수세미 열수 추출물의 기전 확인을 위해 전처리 약물을 이용할 때는 해당 약물을 organ bath에 10분간 전처리하고 페닐레프린(phenylephrine)으로 수축시킨 후, 수세미 열수 추출물에 의한 혈관이완반응을 농도 의존적으로 관찰하는 방법으로 측정하였다. 혈관 내피세포 비의존형 실험을 시행할 때에는 혈관 내피세포를 얇은 스테인레스 스틸(stainless steel)로 긁어내어 제거하고, 페닐레프린(phenylephrine)으로 수축시킨 후 ACh로 이완시켜 이완율이 5% 이하 일 때 실험을 진행하였다. 약물의 혈관 이완율은 페닐레프린(phenylephrine, 1 uM)에 의한 혈관의 수축을 기준으로 백분율(%)로 계산하였다.The thoracic aortic section of the white paper was fixed at the bottom of an organ bath containing Krebs solution at 37℃ saturated with 95% O 2 and 5% CO 2 gas, and the other end was a force-displacement transducer (Grass FT). 03, GRASS Instrument, MA, USA), and the isometric tension of blood vessels was measured using a physiological recorder (Grass Model 7E, Grass Instrument, MA, USA) connected to a force-displacement transducer. Thereafter, for stabilization of blood vessels, fresh Kreb's solution was supplied at 10 minute intervals for 60 minutes, and a basal tone of 1 g was applied to the vascular section. When the basal tone of 1g is kept constant, it is contracted with 1x10 -6 M of phenylephrine, and after 5 minutes, it is relaxed with 1 x 10 -6 M of ACh (acetylcholine). If the relaxation rate is more than 80%, the vascular endothelium It was determined that the cells were not damaged and the drug was tested. When using a pre-treatment drug to confirm the mechanism of the hot water scrubber extract, the drug is pretreated in an organ bath for 10 minutes and contracted with phenylephrine, and then the vascular relaxation reaction caused by the hot water scrubber extract is observed in a concentration-dependent manner. Measured. When conducting a vascular endothelial cell-independent experiment, the vascular endothelial cells are scraped off with a thin stainless steel and removed, contracted with phenylephrine, and then relaxed with ACh, where the relaxation rate is less than 5%. Proceeded. The vascular relaxation rate of the drug was calculated as a percentage (%) based on the contraction of blood vessels by phenylephrine (1 uM).
시약reagent
본 실험에서 사용된 ACh, 페닐레프린(phenylephrine), L-NAME(NG-nitroargininemethyl ester), indomethacin, glibenclamide, TEA(tetraethylammonium), verapamil, 4AP, 메틸렌블루(methylenblue), atropine, propranolol 등은 Sigma Chemical Co. (St. Louis, MO, USA)으로부터 구매하였다.ACh, phenylephrine, L-NAME (NG-nitroargininemethyl ester), indomethacin, glibenclamide, TEA (tetraethylammonium), verapamil, 4AP, methylene blue, atropine, propranolol, etc. used in this experiment are Sigma Chemical Co. (St. Louis, MO, USA).
통계 처리Statistical processing
실험 결과는 Sigma Plot을 이용하여 통계적 유의성 검정을 했으며, Students t-test나 one-way ANOVA test를 통하여 p가 0.05 이하일 때 통계적 유의성이 있는 것으로 판정하였다.The experimental results were tested for statistical significance using Sigma Plot, and statistical significance was determined when p was 0.05 or less through the Students t-test or one-way ANOVA test.
1-1. 수세미 열수 추출물의 농도 의존적인 혈관 평활근 이완효과1-1. Concentration-dependent Vascular Smooth Muscle Relaxation Effect of Loofah Hot Water Extract
페닐레프린(Phenylephrine, 1 x 10-6 M)을 전처리 하여 수축시킨 백서의 흉부대동맥 절편에서 수세미 열수 추출물은 농도 의존적으로 혈관을 이완시켰다(도. 1). 또, 수세미 열수 추출물의 혈관이완 효과는 혈관 내피세포를 완전히 제거하였을 시에는 나타나지 않았다(도 1). In the thoracic aortic section of rats contracted by pretreatment with phenylephrine (1 x 10 -6 M), the hot water extract of a loofah relaxed the blood vessels in a concentration-dependent manner (Fig. 1). In addition, the vascular relaxation effect of the hot water scrubber extract did not appear when the vascular endothelial cells were completely removed (FIG. 1).
1-2. 산화질소 합성효소 (nitric oxide synthase, NOS) 억제 시 혈관이완효과1-2. Vascular relaxation effect upon inhibition of nitric oxide synthase (NOS)
수세미 열수 추출물의 흉부대동맥 이완효과가 산화질소계와 연관성이 있는지 확인하기 위하여 비 선택적 산화질소 합성 억제제인 L-NAME (1 x 10-5 M)와 MB (2.5x 10-5 M)를 각각 organ bath에 10분간 전처리하고 혈관 이완효과를 측정한 결과, 수세미의 혈관 이완효과는 L-NAME 와 MB의 전처리에 의해 통계적으로 유의하게 억제되었다(도 2).In order to confirm whether the thoracic aortic relaxation effect of the hot water scrubber extract is related to the nitric oxide system, L-NAME (1 x 10 -5 M) and MB (2.5x 10 -5 M), which are non-selective nitric oxide synthesis inhibitors, were used to organ As a result of pretreatment in a bath for 10 minutes and measurement of vascular relaxation effect, the vascular relaxation effect of the scrubber was statistically significantly suppressed by the pretreatment of L-NAME and MB (FIG. 2).
1-3. Ca1-3. Ca 2+2+ 통로 차단 시 혈관 이완효과 Vascular relaxation effect when the passage is blocked
Ca2+ 통로 차단이 수세미 열수 추출물에 의한 혈관 이완효과에 미치는 영향을 측정하기 위하여 Ca2+ 통로 차단제인 베라파밀(verapamil, 1 x 10-5 M)을 전처리한 후 수세미 열수 추출물에 의한 이완 정도를 측정한 결과 베라파밀(verapamil) 전처리에 의해 수세미의 혈관 이완효과는 유의하게 억제되었다(도 3).To measure the effect of Ca 2+ channel blocking on the vascular relaxation effect by the scourer hot water extract, Ca 2+ channel blocker verapamil (1 x 10 -5 M) was pretreated and then the degree of relaxation by the scourer hot water extract was measured. As a result of the measurement, the vascular relaxation effect of the scrubber was significantly suppressed by the pretreatment of verapamil (FIG. 3).
1-4. K1-4. K ++ 통로 차단 시 혈관 이완효과 Vascular relaxation effect when the passage is blocked
K+ 통로 차단이 수세미 열수 추출물의 혈관 이완효과에 영향을 주는지를 측정하기 위하여 비 선택적 K+ 통로 억제제인 TEA (1 x 10-5 M)과 ATP-감수성 K+ 통로 억제제인 글리벤클라미드(glibenclamide, 1 x 10-5 M), Ca2+ 연관 K+ 통로 억제제인 4AP (1 x 10-5 M)를 각각 전처리한 후 수세미 열수 추출물의 혈관이완효과를 측정한 결과, TEA, 4AP의 경우 전처리하지 않은 군과 유의한 차이가 없었고, 글리벤클라미드(glibenclamide)를 전처리한 경우 수세미의 혈관 이완효과는 유의하게 억제되었다(도 4).To measure whether K + channel blockade affects the vasodilating effect of the scourer hot water extract, the non-selective K + channel inhibitor, TEA (1 x 10 -5 M) and the ATP-sensitive K + channel inhibitor, glibenclamide ( After pretreatment with glibenclamide, 1 x 10 -5 M) and Ca 2 + -associated K + pathway inhibitor 4AP (1 x 10 -5 M), we measured the vasodilating effect of the hot-water scrubber extract, in the case of TEA and 4AP. There was no significant difference from the group without pretreatment, and when pretreatment with glibenclamide, the vascular relaxation effect of the scrubber was significantly suppressed (FIG. 4).
1-5. 자율신경계 수용체 차단 시 혈관 이완효과1-5. Vascular relaxation effect upon blocking autonomic nervous system receptors
수세미 열수 추출물에 의한 혈관 이완효과의 신경계와의 연관성을 알아보기 위하여 비 선택성 β-아드레날린성 길항제인 프로프라놀롤(propranolol), 항 무스카린성 약물인 아트로핀(atropine)을 1 x 10-6 M로 각각 전처리한 후 수세미 열수 추출물의 혈관 이완효과를 측정한 결과, 프로프라놀롤(propranolol), 아트로핀(atropine)의 전처리에 의해 수세미의 혈관 이완효과는 유의하게 억제되었다(도 5).To investigate the relationship between the vascular relaxation effect of the hot water extract of a loofah with the nervous system, propranolol, a non-selective β-adrenergic antagonist, and atropine, an anti-muscarinic drug, were pretreated with 1 x 10 -6 M, respectively. After that, as a result of measuring the vascular relaxation effect of the hot water extract of the scrubber, the vascular relaxation effect of the scrubber was significantly suppressed by pretreatment with propranolol and atropine (FIG. 5).
1-6. COX(Cyclooxygenase) 차단 시 혈관 이완효과1-6. Vascular relaxation effect upon blocking COX(Cyclooxygenase)
수세미 열수 추출물에 의한 혈관 이완효과가 prostacyclin과 연관이 있는지를 관찰하기 위하여 비 선택성 COX(cyclooxygenase) 억제제인 인도메타신(indomethacin, 1 x 10-5M)을 전처리한 후 수세미 열수 추출물의 혈관이완효과를 측정한 결과 인도메타신(indomethacin) 전처리에 의해 수세미의 혈관 이완효과는 유의하게 억제되는 것으로 확인되었다 (도 6).Vascular relaxation effect of hot-water scrubber extract after pretreatment of indomethacin (1 x 10 -5 M), a non-selective cyclooxygenase (COX) inhibitor, to observe whether the vasodilator effect by hot water scrubber extract is related to prostacyclin. As a result of measuring, it was confirmed that the vascular relaxation effect of the scrubber was significantly suppressed by pretreatment of indomethacin (FIG. 6).
1-7. ODQ 전처리에 의한 혈관 수축 억제 효과1-7. Inhibitory effect of vasoconstriction by ODQ pretreatment
가용성 구아닐산 고리화효소 억제제인 ODQ를 전처리한 후 혈관이완효과를 측정한 결과, 수세미에 열수 추출물에 의한 혈관 이완효과가 억제되는 것으로 확인되었다(도 7.)After pretreatment with ODQ, a soluble guanylate cyclase inhibitor, vascular relaxation effect was measured, it was confirmed that the vascular relaxation effect by hot water extract on a scrubber was suppressed (Fig.7).
1-7. 혈관 수축 억제 효과1-7. Vasoconstriction inhibitory effect
수세미 열수 추출물이 페닐레프린(phenylephrine)에 의한 혈관 수축에 영향을 미치는지 알아보기 위하여 수세미 열수 추출물을 각각 1 x 10-4 g/ml, 1 x 10-3 g/ml 처리한 후, 페닐레프린(phenylephrine, 1 x 10-8 M - 1 x 10-5 M)을 투여하였다. 그 결과 대조군(vehicle)과 비교하여 페닐레프린(phenylephrine)으로 인한 혈관 수축이 현저히 감소되었다(도 8).To find out whether the hot-water scrubber extract affects blood vessel constriction by phenylephrine, the hot-water scrubber extract was treated with 1 x 10 -4 g/ml and 1 x 10 -3 g/ml, respectively, and then phenylephrine. (phenylephrine, 1 x 10 -8 M-1 x 10 -5 M) was administered. As a result, blood vessel constriction due to phenylephrine was significantly reduced compared to the control (vehicle) (FIG. 8).
혈관 내피세포에서 분비되는 여러 종류의 혈관 활성인자(vasoactive factor)는 혈관 평활근 이완을 조절할 수 있는데, 이러한 혈관활성 인자에는 산화질소(NO), 프로스타사이클딘(prostacyclin), 내피세포 유래 과분극 인자(endothelium-dependent hyperpolarizing factor, EDHF) 등이 알려져 있다. 상기 실험 결과에서 수세미 열수 추출물은 백서에서 적출한 흉부대동맥에서 페닐레프린(phenylephrine)에 의해 유도된 혈관 수축을 농도 의존적으로 이완시키는 것으로 확인되었다. 그런데 혈관 내피세포를 제거한 후 수세미 열수 추출물의 이러한 혈관 이완효과가 완전히 차단된 것은 수세미의 혈관 이완효과가 이러한 혈관 내피세포 유래 혈관활성 인자들과 밀접하게 연관되어 있음을 의미한다. 또한, 상기 실험한 결과에 의하면 산화질소 합성 억제제인 L-NAME와 MB의 전처리에 의해 수세미 열수 추출물의 혈관이완효과는 통계적으로 유의성 있게 억제되었다. 이 결과는 이러한 내피세포 유래 혈관활성 인자들 중 NO가 결정적으로 수세미 열수 추출물의 혈관이완효과에 연관되어 있음을 알려주는 증거일 수 있다. Various types of vasoactive factors secreted from vascular endothelial cells can regulate vascular smooth muscle relaxation.These vasoactive factors include nitric oxide (NO), prostacyclin, and endothelial cell-derived hyperpolarization factors ( endothelium-dependent hyperpolarizing factor (EDHF) and the like are known. In the above experimental results, it was confirmed that the hot water extract of the scrubber was found to relax the blood vessel constriction induced by phenylephrine in the thoracic aorta extracted from white paper in a concentration-dependent manner. However, after removing vascular endothelial cells, the vascular relaxation effect of the scrubber hot water extract was completely blocked, which means that the vascular relaxation effect of the scrubber is closely related to these vascular endothelial cells-derived vascular activating factors. In addition, according to the experimental results, the vasodilating effect of the hot water extract of the scrubber was statistically significantly suppressed by pretreatment of L-NAME and MB, which are nitric oxide synthesis inhibitors. This result may be evidence indicating that NO among these endothelial cell-derived vascular activating factors is crucially related to the vasodilating effect of the hot water scrubber extract.
또한 내피세포 유래 혈관 이완 인자들과 수세미 열수 추출물의 혈관 이완효과와의 관련성을 알아보기 위하여 자율신경계, 칼슘 이온통로, 칼륨 이온통로, COX(cyclooxygenase), 산화질소 생성 차단제와 같은 여러 가지 약물들이 실험에 사용되었다. 내피세포 유래 혈관 이완 인자의 본체인 산화질소 (NO)가 수세미 열수 추출물의 혈관 이완효과에 관여하는지를 알아보고자 먼저 산화질소 합성 억제제인 L-NAME를 전처리한 후 측정한 결과, 수세미의 혈관 이완효과가 완전히 차단되었다. 생체 내에서 생성되는 작은 분자인 산화질소 (NO)는 내피세포 의존 혈관 이완 인자로서 혈압 강하 효과가 큰 것으로 밝혀졌다. 산화질소는 L-arginine으로부터 산화질소 합성효소(NOS)에 의하여 합성되고 혈관에는 산화질소 합성효소인 3가지의 동위효소가 존재한다. 첫 번째 유형은 뇌형 산화질소 합성효소(bNOS, nNOS, NOS Ⅰ)로 뇌 조직에서 처음 발견되었고 주로신경 전달 물질로서의 산화질소를 합성하는 역할을 하고 있다. 두 번째 동위 효소는 유도형 산화질소 합성효소(iNOS, NOS Ⅱ)로 주로 면역계에 작용하는 산화질소를 합성하고 있다. 세 번째 동위 효소는 혈관 내피세포에 주로 분포하면서 혈관을 이완시키는데 작용하는 혈관 내피세포형 산화질소 합성효소 (ecNOS, eNOS, NOS Ⅲ)로 아세틸콜린(acetylcholine)에 의하여 활성화되어 혈관을 이완시킨다. 이러한 산화질소는 세포질의 구아닐산 고리화효소(guanylate cyclase)를 활성화시켜 cGMP의 생성을 증가시켜 신호 전달체계를 통해 혈관 평활근을 이완 시킨다. 본 실험에서 L-NAME의 전처리에 의해 수세미의 이완효과가 억제되는 것으로 보아 수세미 열수추출물에 의한 혈관 이완효과는 산화질소계를 경유하여 일어나는 것으로 사료된다. 일반적으로 잘 알려진 혈관 이완 효현제인 ACh은 NO 중재 내피 의존성 이완효과를 야기하며 ACh에 의한 NO의 유리는 내피세포 M3 수용체를 경유한다고 알려져 있다. ACh에 의한 내피세포 내 Ca2+ 증가는 IP3에 의한 세포 내 저장소로부터 Ca2+ 유출과 세포외로부터의 Ca2+ 유입의 결과이다. 증가된 Ca2+에 의해 NOS(nitric oxide synthase)가 활성화되고 L-아르기닌(L-arginine)을 기질로 하여 산화질소(NO)가 유리된다. 이 때 생성된 산화질소는 혈관 평활근으로 확산되며, 다시 세포질 구아닐산 고리화효소(guanylate cyclase)를 활성화시킨다. 세포질 구아닐산 고리화효소(guanylate cyclase)는 GTP (guanosinetriphosphate)를 cGMP로 전환시키며, cGMP는 다시 cGMP 의존적 단백질 활성화 효소를 활성화시킨다. 이 효소가 혈관 평활근에 Ca2+ 유입을 억제하고 세포 내 Ca2+의 수축적인 요인에 대한 감수성을 감소시킴으로써 혈관 평활근을 이완 시킨다. NO/cGMP 계가 수세미 열수 추출물에 의한 혈관 이완효과에 관여한다면 산화질소에 의하여 활성화되는 가용성 구아닐산 고리화효소 또한 수세미 열수 추출물에 의한 혈관 이완효과에 관여할 것으로 사료되어 가용성 구아닐산 고리화효소 억제제인 ODQ를 전처리 한 후 혈관이완효과를 측정한 결과, 수세미에 열수 추출물에 의한 혈관 이완효과가 억제되는 것으로 확인되었다. 이러한 결과는, 수세미 열수 추출물에 의한 혈관 이완효과가 NO/cGMP 계를 경유하여 일어나난다는 것을 의미할 수 있다. 이러한 결과로 볼 때, 수세미 열수 추출물은 혈관 내피세포에서 산화질소의 합성을 증가시키고 가용성 구아닐산 고리화효소를 활성화시켜 cGMP의 생성을 증가시킴으로써 혈관을 이완시키는 것으로 사료 된다. In addition, various drugs such as autonomic nervous system, calcium ion channel, potassium ion channel, COX (cyclooxygenase), and nitric oxide production blockers were tested to find out the relationship between endothelial cell-derived vascular relaxation factors and the vascular relaxation effect of the scrubber hot water extract. Was used in To determine whether nitric oxide (NO), the body of endothelial cell-derived vascular relaxation factor, is involved in the vascular relaxation effect of the loofah hot water extract, first pretreatment with L-NAME, a nitric oxide synthesis inhibitor, was measured. Completely blocked. Nitric oxide (NO), a small molecule produced in vivo, was found to have a large blood pressure lowering effect as an endothelial cell-dependent vascular relaxation factor. Nitric oxide is synthesized from L-arginine by nitric oxide synthase (NOS), and there are three isotopes of nitric oxide synthase in blood vessels. The first type is brain-type nitric oxide synthase (bNOS, nNOS, NOS Ⅰ), which was first discovered in brain tissue and plays a role in synthesizing nitric oxide as a neurotransmitter. The second isotope is an inducible nitric oxide synthase (iNOS, NOS Ⅱ), which synthesizes nitric oxide, which mainly acts on the immune system. The third isotope is a vascular endothelial nitric oxide synthase (ecNOS, eNOS, NOS III), which is mainly distributed in vascular endothelial cells and acts to relax blood vessels, and is activated by acetylcholine to relax blood vessels. These nitric oxides activate cytoplasmic guanylate cyclase to increase the production of cGMP and relax vascular smooth muscle through a signaling system. In this experiment, the relaxation effect of the scrubber was suppressed by pretreatment of L-NAME, so it is believed that the vascular relaxation effect by the hot water extract of the scrubber occurs via the nitric oxide system. ACh, a generally well-known vascular relaxation agonist, causes NO-mediated endothelial-dependent relaxation effects, and it is known that the release of NO by ACh is via the endothelial M3 receptor. The increase of Ca 2+ in endothelial cells by ACh is the result of Ca 2+ outflow from intracellular storage and Ca 2+ influx from extracellular by IP3. Nitric oxide synthase (NOS) is activated by increased Ca 2+ , and nitric oxide (NO) is released using L-arginine as a substrate. Nitric oxide produced at this time is diffused to the vascular smooth muscle, and again activates cytoplasmic guanylate cyclase. Cytoplasmic guanylate cyclase converts GTP (guanosinetriphosphate) to cGMP, and cGMP activates cGMP-dependent protein-activating enzymes again. This enzyme relaxes the vascular smooth muscle by inhibiting the influx of Ca 2+ into the vascular smooth muscle and reducing the sensitivity to the contractile factors of intracellular Ca 2+ . If the NO/cGMP system is involved in the vascular relaxation effect by the hot water scrubber extract, soluble guanylate cyclase activated by nitric oxide is also thought to be involved in the relaxation effect of blood vessels by the hot water scrubber extract. After pretreatment, the vascular relaxation effect was measured, and it was confirmed that the vascular relaxation effect by the hot water extract on the scrubber was suppressed. These results may mean that the vascular relaxation effect by the hot water scrubber extract occurs via the NO/cGMP system. From these results, it is believed that the hot-water scrubber extract relaxes blood vessels by increasing the synthesis of nitric oxide in vascular endothelial cells and activating soluble guanylate cyclase to increase cGMP production.
혈관 평활근의 긴장도를 조절하는 또 다른 내인성 인자로는 프로스타사이클린(prostacyclin, PGI2)이 있다. 프로스타사이클린(Prostacyclin)은 아라키돈산(arachidonic acid)로부터 고리형 산소화효소(cyclooxygenase)에 의하여 생성되고, 이 때 생성된 프로스타사이클린(prostacyclin)은 혈관 이완 작용을 갖는다. 수세미 열수 추출물의 혈관 이완효과가 프로스타사이클린(prostacyclin)의 생성과 관련이 있는지를 알아보기 위하여 고리화 산소화효소(cyclooxygenase) 억제제인 인도메타신(indomethacin)을 전처리하고 수세미 이완효과를 측정한 결과 인도메타신(indomethacin) 전처리에 의해 혈관이완효과가 억제되는 것으로 확인되었는 바, 프로스타사이클린(prostacyclin)계는 수세미 열수 추출물의 혈관 이완 작용과는 관련이 있는 것으로 판단된다.Another endogenous factor that regulates vascular smooth muscle tone is prostacyclin (PGI2). Prostacyclin is produced from arachidonic acid by cyclooxygenase, and the produced prostacyclin has a vasodilating action. In order to determine whether the vascular relaxation effect of hot water extract of loofah is related to the production of prostacyclin, indomethacin, a cyclooxygenase inhibitor, was pretreated and the relaxation effect of loofah was measured. It was confirmed that the vasodilating effect was suppressed by pretreatment of indomethacin, and it was determined that the prostacyclin system was related to the vasodilating action of the hot water extract of the loofah.
혈관 평활근의 긴장도는 혈관 평활근 세포막 전위 차이에 의하기 때문에 세포막간의 이온채널의 변화는 직접적인 이완작용의 설명을 가능하게 해준다. Van Breeman 등에 의하면 혈관평활근 세포막의 이온 펌프(ion pump)로는 Na+/K+ pump와 Ca2+ pump 뿐만 아니라 Na+/H+, HCO3 -/Cl-, Na+/Ca2+ exchanger가 있는데, 혈관 평활근의 세포막 전위는 주로 Ca2+ 과 K+ 이온의 유출과 유입에 의하여 조절된다. 혈관 긴장도는 막전위에 의해 조절되며 막전위 증가 시 전압에 의존하는 Ca2+ 채널(channel)인 VOC(Voltage Operated Channel)을 통하여 Ca2+이 증가한다. 이러한 Ca2+의 증가로 수축성 단백질이 활성화되어 수축이 초래되며 이는 전기 기계적으로 일치 (electro-mechanical coupling)를 보인다. 한편 K+ 채널(channel)은 활성화시 세포막의 과분극(hyperpolarization)을 유도하여 VOC를 통한 Ca2+의 유입 억제를 통하여 혈관을 이완시킨다. 이 또한 혈관 긴장도를 조절하는데 있어 중요한 내인성 혈관 이완 기전으로 알려져 있다. 혈관 평활근에서 K+ 통로로는 Ca2+-activated K 통로(KCa), ATP-sensitive K(KATP), voltage-gated K(Kv) 통로 등이 있는데, 내피세포 의존 과분극인자 (endothelium-dependent hyperpolarizing factor, EDHF)는 K+ 통로를 활성화시키고 막 과분극(hyperpolarization)을 유발하게 된다. K+ 통로의 활성화에 의한 K+의 세포 내 유출은 세포막의 과분극을 일으켜, voltage-sensitive Ca2+ 통로의 불활성화로 이어져 세포 내 Ca2+ 농도 감소를 초래하게 되고 결국은 혈관 이완을 유발하게 된다. K+통로에 대한 억제제로는 Kv를 차단하는 4아미노피리딘(4aminopyridine), KCa을 차단하는 TEA와 설포닐유레아(sulfonylurea)계 약물인 글리벤클라미드(glibenclamide)로 글리벤클라미드(glibenclamide)는 혈관 평활근에서 KCa 통로에는 영향을 미치지 않고 KATP 만을 차단한다. 수세미 열수 추출물의 혈관 이완효과가 Kv, KCa 또는 KATP를 경유하여 일어나는지 알아보기 위하여 Kv차단제인 4AP, KCa 차단제인 TEA와 KATP 차단제인 글리벤클라미드를 전처리한 후 혈관 이완효과를 측정한 결과, TEA, 4AP의 경우 전처리하지 않은 군과 유의한 차이가 없었고, 글리벤클라미드를 전처리한 경우 수세미의 혈관 이완효과에 통계적으로 유의하게 영향을 주었다. 이러한 결과로 볼 때 수세미의 혈관 이완효과는 K+ 통로와도 부분적으로 연관되어 있다고 사료 된다. Since the vascular smooth muscle tone is due to the difference in the vascular smooth muscle cell membrane potential, the change of the ion channel between the cell membranes allows a direct explanation of the relaxation action. According Van Breeman ion pump or the like (ion pump) roneun Na + / K + pump and Ca 2+ pump, as well as Na + / H +, HCO 3 of vascular smooth muscle cell membrane - There are, Na + / Ca 2+ exchanger - / Cl , Cell membrane potential of vascular smooth muscle is mainly regulated by the outflow and inflow of Ca 2+ and K + ions. Vascular tonicity is regulated by the membrane potential, and when the membrane potential increases, Ca 2+ increases through VOC (Voltage Operated Channel), which is a voltage-dependent Ca 2+ channel. This increase in Ca 2+ activates the contractile protein, resulting in contraction, which shows electro-mechanical coupling. On the other hand, the K + channel induces hyperpolarization of the cell membrane upon activation and relaxes the blood vessel by inhibiting the inflow of Ca 2+ through VOC. This is also known as an important endogenous vascular relaxation mechanism in regulating vascular tone. The K + pathway in vascular smooth muscle includes the Ca 2+ -activated K pathway (KCa), ATP-sensitive K (KATP), and voltage-gated K (Kv) pathways. The endothelium-dependent hyperpolarizing factor , EDHF) activates the K + pathway and causes membrane hyperpolarization. The outflow of K + into the cell by the activation of the K + channel causes hyperpolarization of the cell membrane, leading to inactivation of the voltage-sensitive Ca 2+ channel, leading to a decrease in the intracellular Ca 2+ concentration, which eventually leads to vascular relaxation. do. Inhibitors for the K+ pathway include 4aminopyridine that blocks Kv, TEA that blocks KCa, and glibenclamide, a sulfonylurea-based drug, and glibenclamide It blocks only KATP without affecting the KCa pathway in smooth muscle. To find out whether the vascular relaxation effect of the hot water scrubber extract occurs via Kv, KCa or KATP, the results of measuring the vascular relaxation effect after pretreatment with Kv blocker 4AP, KCa blocker TEA and KATP blocker glibenclamide were measured. , In the case of 4AP, there was no significant difference from the non-pretreatment group, and the pretreatment of glibenclamide had a statistically significant effect on the vasodilation effect of the scrubber. These results suggest that the vascular relaxation effect of the scrubber is also partially related to the K + pathway.
혈관 세포내 Ca2+ 농도는 혈관의 수축과 이완에서 가장 중요한 인자이다. 세포내 Ca2+ 농도가 증가하면 칼모듈린(calmodulin)과 결합하여 MLC(myosine light chain)의 인산화를 촉진시켜 평활근을 수축시킨다. 수세미 열수의 혈관 이완효과가 Ca2+ 통로와 연관이 있는지 알아보기 위하여 L-type Ca2+ 차단제인 베라파밀(verapamil)을 전처리한 후 혈관 이완효과를 측정한 결과, 베라파밀(verapamil)을 전처리한 경우 수세미 열수 추출물의 혈관 이완효과가 유의하게 감소되는 것으로 확인되었는 바, 수세미의 혈관 이완효과는 Ca2+ 통로와 관련이 있는 것으로 판단된다.The concentration of Ca 2+ in blood vessels is the most important factor in the contraction and relaxation of blood vessels. When the intracellular Ca 2+ concentration increases, it binds to calmodulin and promotes phosphorylation of the myosine light chain (MLC), causing smooth muscle contraction. In order to find out whether the vascular relaxation effect of the scrubber hot water is related to the Ca 2+ pathway, pretreatment with verapamil, an L-type Ca 2+ blocker, and then measuring the vascular relaxation effect, pretreatment with verapamil It was confirmed that the vascular relaxation effect of the scrubber hot water extract was significantly reduced, and thus the vasculature relaxation effect of the scrubber was judged to be related to the Ca 2+ pathway.
혈관 평활근의 긴장도는 또한 자율 신경계의 조절에 의해 조절된다. 상기 실험에서서는 수세미 열수 추출물이 자율 신경계의 수용체를 경유하여 혈관을 이완시키는지 여부를 알아보기 위하여 콜린성 수용체 중에서 무스카린성 수용체를 선택적으로 차단하는 아트로핀(atropine)과 β 수용체를 선택적으로 차단하는 항 아드레날린성 약물인 프로프라놀롤(propranolol)과 아트로핀(atropine)을 처리한 경우, 수세미 열수 추출물의 혈관이완 효과를 유의미하게 억제되는 것으로 확인되었는 바, 수세미의 혈관 이완효과는 콜린성 수용체 중에서 무스카린성 수용체와 연관되어 있을 것으로 사료 된다.Vascular smooth muscle tone is also regulated by the regulation of the autonomic nervous system. In the above experiment, in order to find out whether the hot water extract of loofah relaxes blood vessels via receptors in the autonomic nervous system, an anti-cholinergic receptor that selectively blocks atropine and β receptors that selectively blocks muscarinic receptors. Treatment with the adrenaline drugs propranolol and atropine was found to significantly inhibit the vasodilating effect of the hot water extract of the loofah.The vascular relaxation effect of the loofah is related to the muscarinic receptor among cholinergic receptors. It is expected to be.
또한 본 실험에서는 수세미 열수 추출물의 전처리 후, 페닐레프린(phenylephrine)에 의한 혈관 수축이 현저하게 억제되는 것을 알 수 있었다. 흉부 대동맥에서 선택적 α1 효능제인 페닐레프린(phenylephrine)에 의한 수축은 Ca2+ 통로를 통한 세포 내 Ca2+ 농도 증가에 의해 유지되므로 수세미 열수 추출물은 부분적으로 아드레날린성 α1-수용체에 대하여 직접 길항하는 효과를 갖거나 α1 수용체를 통한 세포 내의 Ca2+ 유입을 억제할 것으로 사료 된다.In addition, in this experiment, it was found that after the pretreatment of the hot water extract of the loofah, blood vessel constriction by phenylephrine was significantly suppressed. Since contraction by phenylephrine, a selective α1 agonist in the thoracic aorta, is maintained by increasing the intracellular Ca 2+ concentration through the Ca 2+ pathway, the scourer hot water extract partially directly antagonizes the adrenergic α1-receptor. It is thought to have an effect or inhibit the influx of Ca 2+ into cells through the α1 receptor.
NO/cGMP계는 혈관 평활근의 이완뿐만 아니라, 혈관 평활근 세포의 증식과 혈소판, 백혈구 유착을 억제시키며, 내피세포의 삼투성을 낮추고 세포 외 간질단백의 합성을 억제하는 역할을 하고 있다. 혈관 내피세포에서 NO 생성의 감소는 혈관 내피세포의 기능장애나 손상에 의한 것이며, 이는 동맥경화증과 고혈압의 주요한 병리적인 요인이 된다. 또한 동물의 실험 모델에서 NO 합성효소의 만성적인 억제는 고혈압과 같은 혈관염을 유발한다. 따라서 NO/cGMP계의 회복을 통한 혈관이완인자 활성의 증가는 심혈관계 질환의 치료에 있어서 매우 중요한 의미를 지님을 알 수 있다. The NO/cGMP system not only relaxes vascular smooth muscle, but also inhibits proliferation of vascular smooth muscle cells, platelets, and leukocyte adhesion, lowers osmoticity of endothelial cells, and inhibits the synthesis of extracellular interstitial proteins. The decrease in NO production in vascular endothelial cells is due to dysfunction or damage of vascular endothelial cells, which is a major pathological factor of arteriosclerosis and hypertension. In addition, chronic inhibition of NO synthase in animal models causes vasculitis such as hypertension. Therefore, it can be seen that the increase of the vasodilator activity through the recovery of the NO/cGMP system has a very important meaning in the treatment of cardiovascular diseases.
상기 실험 결과를 종합해보면, 수세미 열수 추출물은 NO/cGMP계를 경유해 혈관 내피세포 의존적인 이완효과를 나타내며, 이러한 결과는 심혈관계 질환의 유용한 치료제가 될 수 있음을 시사한다.Taken together, the experimental results show that the hot water scrubber extract exhibits a vascular endothelial cell-dependent relaxation effect via NO/cGMP system, and these results suggest that it can be a useful therapeutic agent for cardiovascular diseases.
결론적으로 수세미 열수 추출물은 내피세포 의존적으로 혈관 평활근을 이완시켰고, 이와 같은 효과는 농도 의존적으로 나타났으며, NO/cGMP 신호전달계를 차단하면 완전히 억제되었다. 더욱이 혈관 조직을 수세미 열수 추출물과 반응시키면 cGMP의 생성이 증가하였고, 이러한 증가는 혈관 내피세포의 제거나 산화질소합성효소나 세포질 구아닐산 고리화효소 차단 시 나타나지 않았다. 또한 수세미 열수 추출물의 혈관 이완효과는 프로스타사이클린(prostacyclin) 생성 차단이나 K+ 통로 차단, Ca2+ 통로 차단, 무스카린성 수용체 차단 및 β-아드레날린성 수용체 차단제 등에 의해서도 영향을 유의하게 받았다. 이와 같은 결과로 볼 때, 수세미 열수 추출물의 혈관 평활근 이완 기전은 내피세포에서의 NO/cGMP 경로를 활성화시키고 이와 연관된 Ca2+ 통로 및 K+ 통로 등을 통해 나타나는 것으로 사료된다.In conclusion, the scourer hot water extract relaxed vascular smooth muscle in an endothelial cell-dependent manner, and this effect appeared in a concentration-dependent manner, and blocking the NO/cGMP signaling system completely inhibited it. Furthermore, when the vascular tissue was reacted with the hot water extract of the scrubber, the production of cGMP increased, and this increase did not appear when the vascular endothelial cells were removed or when nitric oxide synthase or cytoplasmic guanylate cyclase was blocked. In addition, the vascular relaxation effect of the hot water scrubber extract was significantly influenced by blocking prostacyclin production, blocking K + pathway, blocking Ca 2+ pathway, blocking muscarinic receptors and β-adrenergic receptor blockers. From these results, it is thought that the vascular smooth muscle relaxation mechanism of the scourer hot water extract activates the NO/cGMP pathway in endothelial cells, and appears through the Ca 2+ pathway and K + pathway associated therewith.
실험예 2. 수세미 추출물의 추출 용매별 세포독성 확인 (1)Experimental Example 2. Confirmation of cytotoxicity by extraction solvent of scrubber extract (1)
수세미(사과락) 추출물의 마우스 대식세포(Raw264.7 cell)에 대한 세포 독성을 확인하기 위하여 추출 용매별 MTT assay를 실시하였다. In order to confirm the cytotoxicity of the scrubber (apple) extract to mouse macrophages (Raw264.7 cells), MTT assay was performed for each extraction solvent.
실험 방법으로, Raw264.7 cell을 48 well plate에 2×105 cells/well로 분주하고 37℃, 5% CO2 incubator에서 24시간 동안 배양하였다. 배양한 Raw264.7 cell에 메탄올, 에탄올 및 열수 추출한 수세미 추출물을 각각 10, 30, 50, 100, 300 ug/ml의 농도로 처리하여 배양한 후, MTT 시약을 최종 농도가 0.5 mg/ml 되도록 각 well에 넣고 37℃, 5% CO2 인큐베이터에서 4시간 동안 배양하였다. 배양 후 배양액을 버리고 DMSO를 처리하여 포르마잔(formazan)을 용해시킨 후, ELISA reader로 570 nm에서 흡광도를 측정하였다. 그 결과, 수세미의 메탄올 추출물 300 ug/ml의 농도에서 세포 생존cell viability가 유의성 있게 감소한 것을 제외하고 에탄올 및 열수 추출물은 Raw264.7 cell에서 세포 독성을 나타내지 않았다(도 9).As an experimental method, Raw264.7 cells were dispensed into a 48 well plate at 2×10 5 cells/well and incubated in a 37°C, 5% CO 2 incubator for 24 hours. After treating the cultured Raw264.7 cells with a scrubber extract extracted with methanol, ethanol and hot water at a concentration of 10, 30, 50, 100, and 300 ug/ml, respectively, the MTT reagent was added to a final concentration of 0.5 mg/ml. Put in a well and incubated for 4 hours in a 37°C, 5% CO 2 incubator. After incubation, the culture medium was discarded, treated with DMSO to dissolve formazan, and absorbance was measured at 570 nm with an ELISA reader. As a result, ethanol and hot water extracts did not show cytotoxicity in Raw264.7 cells, except that the cell viability was significantly reduced at a concentration of 300 ug/ml of the methanol extract of the scrubber (Fig. 9).
실험예 3: 수세미 추출물의 추출 용매별 세포 독성 확인 (2)Experimental Example 3: Confirmation of Cytotoxicity by Extraction Solvent of Scrubber Extract (2)
수세미(사과락) 추출물의 마우스 대식세포(Raw264.7 cell)에 대한 염증유도 사이토카인 LPS 처리시 세포 독성을 확인하기 위하여 추출 용매별 MTT assay를 실시하였다. In order to confirm the cytotoxicity of LPS, an inflammation-inducing cytokine on mouse macrophages (Raw264.7 cells) of the loofah (apple) extract, MTT assay was performed for each extraction solvent.
실험 방법으로, Raw264.7 cell을 48 well plate에 2×105 cells/well로 분주하고 37℃, 5% CO2 incubator에서 24시간 동안 배양하였다. 배양한 Raw264.7 cell에 메탄올, 에탄올 및 열수 추출한 수세미 추출물을 각각 10, 30, 50, 100 μg/ml의 농도로 처리하고, 1시간 후에 LPS 1 μg/ml을 처리한 후에 배양하였다. 배양 후 MTT 시약을 최종 농도가 0.5 mg/ml 되도록 각 well에 넣고 37℃, 5% CO2 인큐베이터에서 4시간 동안 배양한 후 배양액을 버리고 DMSO를 처리하여 포르마잔(formazan)을 용해시킨 후, ELISA reader로 570 nm에서 흡광도를 측정하였다. 그 결과, 수세미의 메탄올, 에탄올 및 열수 추출물의 경우 농도 의존적(10, 30 ug/ml)으로 LPS에 의한 세포 독성을 억제하였다. 이와 같은 결과로, 수세미 추출물은 메탄올, 에탄올 및 열수 추출물에서 세포 독성을 농도 의존적으로 유의성 있게 억제함을 보여준다.As an experimental method, Raw264.7 cells were dispensed into a 48 well plate at 2×10 5 cells/well and incubated in a 37°C, 5% CO 2 incubator for 24 hours. Methanol, ethanol, and hot water-extracted scrubber extracts were treated in the cultured Raw264.7 cells at concentrations of 10, 30, 50, and 100 μg/ml, respectively, and 1 hour later, 1 μg/ml of LPS was treated and then cultured. After incubation, the MTT reagent was added to each well so that the final concentration was 0.5 mg/ml, incubated in a 37°C, 5% CO 2 incubator for 4 hours, discarded, and treated with DMSO to dissolve formazan, followed by ELISA The absorbance was measured at 570 nm with a reader. As a result, in the case of methanol, ethanol and hot water extracts of the scrubber, the cytotoxicity by LPS was suppressed in a concentration-dependent manner (10, 30 ug/ml). As a result, it was shown that the scrubber extract significantly inhibited cytotoxicity in a concentration-dependent manner in methanol, ethanol and hot water extracts.
실험예 4: 수세미 추출물의 추출 용매별 NO 생성 확인Experimental Example 4: Confirmation of NO generation by extraction solvent of scrubber extract
염증 반응은 자극에 대한 생체 내 방어기전으로 과반응시 다양한 염증성 질환을 유발할 수 있다. LPS는 염증유발물질로 Raw264.7 cell에서 NO, PGs, 염증유도 사이토카인 IL-6, IL-β등의 다양한 염증매개물질이 유도된다.Inflammatory response is an in vivo defense mechanism against stimuli, and can cause various inflammatory diseases when overreacted. LPS is an inflammatory substance, and various inflammatory mediators such as NO, PGs, and inflammation-inducing cytokines IL-6 and IL-β are induced in Raw264.7 cells.
실험 방법으로, Raw264.7 cell을 48 well plate에 2×105 cells/well로 분주하고 37℃, 5% CO2 incubator에서 24시간 동안 배양한 후 Raw264.7 cell에 메탄올, 에탄올 및 열수 추출한 수세미 추출물을 각각 10, 30, 50, 100 μg/ml의 농도로 처리하고, 1시간 후에 LPS 1 μg/ml을 처리한 후 배양하였다. 배양액 50 μl와 같은 양의 Griess reagent를 넣고 10분간 상온에서 반응시킨 후 ELISA reader로 540 nm에서 흡광도를 측정하였다. 그 결과,메탄올 및 에탄올 추출물의 경우 LPS에 의하여 NO 생성이 농도 의존적(10~300 ug/ml)으로 유의성 있게 감소시키는 것이 확인되었다(도 11).As an experimental method, Raw264.7 cells were dispensed into a 48 well plate at 2×10 5 cells/well, incubated in a 37°C, 5% CO 2 incubator for 24 hours, and then methanol, ethanol and hot water extracted into Raw264.7 cells The extracts were treated at concentrations of 10, 30, 50, and 100 μg/ml, respectively, and 1 hour later, 1 μg/ml of LPS was treated and cultured. After adding the same amount of Griess reagent as 50 μl of the culture solution and reacting at room temperature for 10 minutes, the absorbance was measured at 540 nm with an ELISA reader. As a result, it was confirmed that, in the case of methanol and ethanol extracts, the production of NO by LPS was significantly reduced in a concentration-dependent manner (10-300 ug/ml) (FIG. 11).
실험예 5: 수세미 추출물의 추출 용매별 iNOS 및 COX-2 발현 수준 확인Experimental Example 5: Confirmation of iNOS and COX-2 expression levels by extraction solvent of scrubber extract
NO생성 억제에 대한 iNOS 및 COX-2 단백질의 발현 수준을 확인하기 위해 6well plate에 배양한 Raw264.7 cell에 메탄올, 에탄올 및 열수 추출한 사과락 추출물을 각각 10, 30, 100 μg/ml의 농도로 처리하고, 1시간 후에 LPS 1 μg/ml을 처리하여 배양한 후 정량한 sample을 Immunoblot assay법을 이용하여 발현량을 확인하였다. 그 결과, LPS에 의하여 증가된 iNOS 발현량을 농도 의존적(10~300 ug/ml)으로 유의성 있게 감소하였으나 COX-2의 경우, 추출 용매별 발현량 변화의 차이가 없음을 확인할 수 있었다(도 12)In order to check the expression level of iNOS and COX-2 protein for inhibition of NO production, methanol, ethanol and hot water extracts of apple rock extracts extracted with methanol, ethanol and hot water were added to Raw264.7 cells cultured in 6 well plates at concentrations of 10, 30, and 100 μg/ml, respectively. After the treatment, 1 µg/ml of LPS was treated and cultured after 1 hour, and the quantified sample was checked for expression using the Immunoblot assay. As a result, the iNOS expression level increased by LPS was significantly decreased in a concentration-dependent manner (10-300 ug/ml), but in the case of COX-2, it was confirmed that there was no difference in the expression level change by extraction solvent (Fig. 12). )
용매별 추출법을 달리 하였을 때 메탄올 추출물일 경우 300 ug/ml 농도에서 세포 성을 나타내었고, 에탄올 및 열수 추출물의 경우 세포 독성을 나타내지 않았다. LPS 처치하여 NO 생성 유도 하였을 때, 메탄올, 에탄올 및 열수 추출물은 낮은 농도에서 세포 독성을 유의성 있게 억제하였으며, NO 생성은 메탄올 및 에탄올 추출물에서 NO 생성은 농도 의존적으로 유의성 있게 감소하였다. 또한 대표적인 염증인자인 iNOS와 COX-2의 발현 수준을 확인하였을 때, iNOS의 경우 메탄올 및 에탄올 추출물의 경우 농도 의존적으로 LPS에 의해 증가된 iNOS 단백질의 발현 수준을 감소시키는 것을 확인하였으나 COX-2의 경우 추출 용매별 또는 농도에 관계없이 차이가 없음을 확인할 수 있었다. 위의 결과를 토대로 수세미 추출물은 메탄올 및 에탄올 추출물의 경우 LPS로 유도된 NO 생성을 억제하는 것을 나타내었으며 추후 염증 반응기전 확인 및 PGs, 염증유도 사이토카인 IL-6, IL-β 등의 다양한 염증매개물질이 유도되는데 확인이 필요할 것으로 보인다.When the extraction method for each solvent was different, the methanol extract showed cellularity at a concentration of 300 ug/ml, and the ethanol and hot water extract did not show cytotoxicity. When inducing NO production by LPS treatment, methanol, ethanol and hot water extracts significantly inhibited cytotoxicity at low concentrations, and NO production in methanol and ethanol extracts significantly decreased in a concentration-dependent manner. In addition, when checking the expression levels of iNOS and COX-2, which are representative inflammatory factors, in the case of iNOS, it was confirmed that methanol and ethanol extracts decreased the expression level of the iNOS protein increased by LPS in a concentration-dependent manner. In the case, it was confirmed that there was no difference regardless of the extraction solvent or concentration. Based on the above results, the scrubber extract showed that methanol and ethanol extracts inhibited LPS-induced NO production, and later confirmed before inflammatory reactions and various inflammatory mediators such as PGs, inflammation-inducing cytokines IL-6 and IL-β. The substance is induced, but it seems that confirmation is necessary.
Claims (14)
상기 혈관이완제는 혈관 수축으로 인한 질환의 예방 또는 치료용 혈관이완제이고,
상기 혈관 수축으로 인한 질환은 고혈압, 동맥경화, 혈액순환 장애, 두통, 뇌졸중, 뇌경색, 뇌출혈, 심근경색 및 심부전으로 이루어진 군에서 선택되는 것을 특징으로 하는 혈관이완제.
As a vasodilator containing hot water extract of loofah fruit as an active ingredient,
The vasodilator is a vasodilator for preventing or treating diseases caused by vasoconstriction,
The disease caused by constriction of blood vessels is a vasodilator, characterized in that it is selected from the group consisting of hypertension, arteriosclerosis, blood circulation disorder, headache, stroke, cerebral infarction, cerebral hemorrhage, myocardial infarction and heart failure.
상기 수세미 열매 열수 추출물은 eNOS(endothelial nitric oxide synthase) 증진 활성을 갖는 것을 특징으로 하는 혈관이완제.
The method according to claim 1,
The loofah fruit hot water extract is a vasodilator, characterized in that it has an endothelial nitric oxide synthase (eNOS) enhancing activity.
상기 수세미 열매 열수 추출물은 혈관 내피 세포에서 산화질소의 생성을 증가시키는 것을 특징으로 하는 혈관이완제.
The method according to claim 1,
The loofah fruit hot water extract increases the production of nitric oxide in vascular endothelial cells.
상기 건강기능식품은 혈관 수축으로 인한 질환의 예방 또는 개선용 건강기능식품이고,
상기 혈관 수축으로 인한 질환은 고혈압, 동맥경화, 혈액순환 장애, 두통, 뇌졸중, 뇌경색, 뇌출혈, 심근경색 및 심부전으로 이루어진 군에서 선택되는 것을 특징으로 하는 건강기능식품.
As a health functional food containing hot water extract of loofah fruit,
The health functional food is a health functional food for preventing or improving diseases caused by vasoconstriction,
The disease caused by constriction of blood vessels is a health functional food, characterized in that it is selected from the group consisting of hypertension, arteriosclerosis, blood circulation disorder, headache, stroke, cerebral infarction, cerebral hemorrhage, myocardial infarction and heart failure.
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