Microwave digestion polarography for determining seven trace elements in Salvia Miltiorrhiza Root and compound Salvia Miltiorrhiza Root injection simultaneously

The sensitive second derivative waves of Cu(Ⅱ),Pb(Ⅱ),Cd(Ⅱ),Ni(Ⅱ),Zn(Ⅱ),Fe(Ⅱ)and Mn(Ⅱ),forming in the substrate solution(pH=9.26)consisting of ammonia,ammonium chlorid,gelatin and ascorbic acid were researched.The peak potentials of the polarographic waves of the seven ions are at about 0.48,0.63,0.79,1.04,1.28,1.44 and 1.60 V respectively.Combining with microwave technique,a new method for the simultaneous determination of the seven trace elements in Chinese traditional medicine was developed.The method is easy to operate,rapid,simple and convenient.When the signal-to-noise rate equals 3,the detection limits of Cu,Pb,Cd,Ni,Zn,Fe and Mn are 4.2×10 3,5.3×10 3,2.1×10 3,5.8×10 4,3.0×10 3,7.7×10 4 and 1.1×10 3 μg/mL respectively.Well linear relationships exist between the concentrations and the peak currents when Cu,Pb,Cd,Ni,Zn,Fe and Mn concentrations are within 8.5×10 3 10,9.7×10 3 10,4.5×10 3 10,1.2×10 3 10,6.4×10 3 10,1.5×10 3 10 and 2.8×10 3 10 μg/mL,respectively.The method has been used to the simultaneous determination of the seven trace elements in Salvia Miltiorrhiza Root and compound Salvia Miltiorrhiza Root injection,the relative standard deviations(RSDs)of the Cu,Pb,Cd,Ni,Zn,Fe and Mn in the two medicines are 3.9% and 5.8%,4.0% and 4.1%,4.3% and 5.7%,4.9% and 5.3%,4.4% and 4.7%,3.5% and 4.0%,0.51% and 2.8%,respectively;the comparisons of the determination results with the values obtained by the standard method indicate that the presented method has very well veracity.

Therapeutic Effects of Pefusing Compound Salvia Miltiorrhiza Injection Through the Hepatic Artery in the Late Stage of Hepatocarcinoma

In the treatment of 20 patients with advanced hepatocarcinoma, whose conditions wors-ened affer chemotherapy, with hepatic artery intubation, by injection of Compound Salvia Miltiorrhizathrough the hepatic artery, it can be seen that their signs were relaxed and tumor masses were diminishedand biochemical indices were improved. The test group had a 65% rate of general efficiency, while thecontrol group had only 25%. There is a significant difference (P<0. 01) between the two groups. There-fore the method of treatment for such patients is thought to be worthy of being further studied.

Study on Optimization of Ethanol Reflux Extraction of Phenolic Acids from Salvia miltiorrhiza

The extraction technology of phenolic acid compounds from Salvia miltiorrhiza by ethanol reflux was studied. In this experiment, salvianolic acid B standard was used to make the standard curve. Single factor experiment and orthogonal experiment were used to study the extraction of different ethanol concentrations, reflux times and material-to-liquid ratios. The OD value of salvianolic acid compounds was measured with a spectrophotometer. The extraction rate of phenolic acid compounds under different extraction conditions was calculated through a regression equation, so as to obtain the optimal conditions for the ethanol reflux extraction process of Salvia miltiorrhiza. The experimental data can provide a reference for the ethanol reflux extraction process of salvianolic acids in the industry. According to the experiment, the extraction rate of phenolic acids in Salvia miltiorrhiza was the highest when the ethanol concentration was 60%, the reflux time was 1.5 hours, and the ratio of material-to-liquid was 1:10.

Research advances in antiplatelet activation of water soluble compounds in Salvia miltiorrhiza

Platelets are fragments of cytoplasm that are released from the mature megakaryocyte of the bone marrow.The main function of platelets is coagulation and hemostasis.Platelets play a central role in formation of pathological thrombosis.Many ischemic diseases are caused by excessive activa.tion of platelets,which can lead to thrombosis and death.Salvia miltiorrhiza Bunge,the dry roots and rhizomes of the Salvia miltiorrhiza plants,includes some water-soluble compounds,which play positive effects on diverse diseases such as neurodegenerative diseases,diabetic complications or cardiovas.cular diseases.In this paper,the components of the water-soluble in Salvia miltiorrhiza,as well as the applications in thrombotic diseases are summarized.The results show that water-soluble compounds include salvianolic acid A,salvianolic acid B,protocatechuic aldehyde,Danshensu,etc.The water-soluble compounds are applied to ischemic stroke,myocardial infarction and other diseases caused by thrombus.We also discussed the mechanisms of water-soluble compounds on the platelets based on our research results and the data obtained from references.The results indicate that water soluble compounds in Salvia miltiorrhiza play the antiplatelet and antithrombotic effects via different mechanisms,for example,salvianolic acid A inhibits platelet aggregation without promoting bleeding by increasing cAMP,inhibiting phosphoinositide 3-kinase(PI3K) and affecting GPCRs(G protein-coupled receptors) signaling path.ways;salvianolic acid B inhibit platelets as a P2Y12 antagonist and PDE inhibitor;Danshensu inhibits platelet activity may be related to inhibition of calcium influx.In conclusion,thrombotic diseases seriously affect human life and health.The existing antiplatelet drugs have some disadvantages.For example,aspirin may cause intracranial hemorrhage,and clopidogrel may play a slower role.Salvia miltiorrhiza as a traditional Chinese medicine has positive pharmacological activity and exerts antiplatelet aggrega.tion through different mechanisms.In the future,we will develop the new drugs which prevent and treat thrombotic diseases with the further study of the pharmacological effects and mechanisms of Salvia miltiorrhiza.

Compound Astragalus and Salvia miltiorrhiza extract exerts anti-tumor activity by intervening the interaction of microRNA-145/microRNA-21 and Smad3C/3L phos-phorylation in hepatocellular carcinoma

OBJECTIVBE To investigate the intervention of compound Astragalus and Salvia miltiorrhiza extract(CASE) consisted of astragalosides,astragalus polysaccharides and salvianolic acids on the interaction of microRNA-145/microRNA-21(miR-145/miR-21) and Smad3 C/3 L phosphorylation(pSmad3 C/pSmad3 L) down-stream of transforming growth factor-β(TGF-β)/mitogen activated protein kinase(MAPK) signaling in hepatocellular carcinoma(HCC) progression by in vitro and in vivo experi.ments.METHODS In HepG2 cells and xenografts of nude mice,antagomir/agomir and plasmids of Smad3 C/3 L phosphorylation site mutation(Smad3 3 S-A/Smad3 EPSM) were used to intervene miR-145/miR-21 and pSmad3 C/pSmad3 L expression respectively,then incorporative CASE treatment.Cell proliferation,migration,apoptosis,tumor growth and histopathologic characteristics of xenografts,relevant proteins of TGF-β/Smad pathway and miR-145/miR-21 were evaluated.RESULTS CASE up-regulated miR-145 while down-regulated miR-21,inhibited cell proliferation,migration and tumor growth,accelerated cell apoptosis in HepG2 cells respectively transfected with Smad3 WT,Smad3 EPSM,Smad3 3 S-A plasmids in cultured dishes and xenografts of nude mice,the above effects were more evident in HepG2 cells with increased pSmad3 C.In TGF-β1-stimulated HepG2 cells and xenografts of nude mice,CASE antagonized the facilitating effects of miR-145 antagomir/miR-21 agomir on cell migration,proliferation,tumor growth and inhibiting effects of miR-145 antagomir/miR-21 agomir on cell apoptosis;CASE increased miR-145 down-regulated by miR-145 antagomir and decreased miR-21 up-regulated by miR-21 agomir,reduced protein level of pSmad3 L and their proteins including TβRⅡ,pERK1/2,pJNK1/2 and pp38 while elevated pSmad3 C expression.CONCLUSION These results suggest that pSmad3 C/pSmad3 L maybe interact with miR-145/miR-21 in HCC progression,which may be one of important molecular mechanisms of CASE's anti-HCC effects.

TREATMENT OF 40 CASES OF CHRONIC ECZEMA WITH POINT-INJECTION OF COMPOUND RADIX SALVIAE MILTIORRHIZAE INJECTION

The authors have used point-injection of compound Radix Salviae Miltiorrhizae Injection to treat 40 cases of chronic eczema and achieved a satisfactory therapeutic effect. The total effective rate was 95%.

复方丹参滴丸联合丁苯酞治疗急性脑梗死的疗效及对患者血清炎性因子的影响

目的基于核转录因子(NF-κB)信号通路探究复方丹参滴丸联合丁苯酞对急性脑梗死(ACI)患者炎性反应的影响。方法选取2020年7月至2022年5月平顶山市第一人民医院收治的ACI患者118例,按随机数表法分为观察组和对照组各59例。对照组患者予以丁苯酞注射液治疗,观察组患者在对照组治疗的基础上联合复方丹参滴丸治疗,均连续治疗两周。治疗两周后,比较两组患者的疗效,以及治疗前、治疗一周后、两周后的美国国立研究院卒中量表(NIHSS)、简易智能状态量表(MMSE)、Barthel指数(BI)评分、脑神经因子[神经生长因子(NGF)及神经营养因子(NTF)]、NF-κB信号通路相关蛋白、mRNA和NF-κB信号通路相关因子[白细胞介素(IL)-1β、IL-6、IL-8、肿瘤坏死因子(TNF)-α]水平,同时比较两组患者治疗期间的不良反应发生情况。结果观察组患者的临床治疗总有效率为94.92%,明显高于对照组的81.36%,差异有统计学意义(P<0.05);治疗一周和两周后,两组患者的NIHSS评分均呈下降趋势,且观察组明显低于对照组,MMSE及BI评分呈升高趋势,且观察组明显高于对照组,差异均有统计学意义(P<0.05);治疗一周和两周后,两组患者的NGF、NTF均呈升高趋势,且观察组明显高于对照组,差异均有统计学意义(P<0.05);治疗一周后、两周后,两组患者的NF-κB p50蛋白、NF-κB p50 mRNA、NF-κB p65蛋白、NF-κB p65 mRNA均呈下降趋势,且观察组明显低于对照组,差异均有统计学意义(P<0.05);治疗一周后、两周后,两组患者的NF-κB信号通路相关因子IL-1β、IL-6、IL-8、TNF-α均呈下降趋势,且观察组明显低于对照组,差异均有统计学意义(P<0.05);治疗期间,观察组患者不良反应总发生率为11.86%,略高于对照组的8.47%,但差异无统计学意义(P>0.05)。结论复方丹参滴丸联合丁苯酞可通过调控NF-κB信号通路,抑制炎性反应,加速神经功能缺损恢复,临床应用效果显著且安全性较高。

利用MINITAB多元统计法分析不同企业复方丹参片质量

基于单因素方差分析、相关性分析、主成分分析和聚类分析等多元统计分析,评价不同企业多批次复方丹参片的质量。用高效液相色谱法测定不同企业复方丹参片中指标成分丹参酮ⅡA和丹酚酸B、人参皂苷Rg_1及人参皂苷Rb_1、三七皂苷R1及人参皂苷Re的含量,通过统计分析、聚类分析,对不同企业复方丹参片质量进行评价。11家企业20个批次复方丹参片中各指标成分均符合《中华人民共和国药典》2020年版规定,但存在较大差异。以样品编号为12的主成分综合评价得分最高(2.32),质量评价最优。主成分分析和聚类分析结果可为复方丹参片的质量控制、优劣评价提供科学依据。

中药专利复方治疗糖尿病周围神经病变的用药规律分析

【目的】采用数据挖掘方法分析国家专利中药复方治疗糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)的用药规律,为临床用药提供参考。【方法】在国家知识产权局网站检索中药复方治疗DPN的专利,使用Excel 2021进行频数统计,运用RAW Graphs 2.0制作高频中药功效的桑基图,运用SPSS Statistics 25.0软件进行药物的系统聚类分析,基于Cytoscape 3.9.1挖掘核心处方。【结果】共纳入101首中药专利复方,涉及243味中药。出现频次居前3位的中药为丹参、黄芪、白芍。治疗DPN的专利复方药物的药性以温、平为主,药味以甘、苦、辛为主,归经以归肝、心、脾经居多。药物按功效主要可分为补虚药、活血化瘀药、解表药、平肝熄风药、清热药、止血药、安神药、利水渗湿药。关联规则分析中支持度最高的药物组合为黄芪-当归;系统聚类分析将出现频次居前31位的中药分成7组,挖掘得到的核心处方包含黄芪、川芎、鸡血藤、丹参、牛膝、桂枝、当归共7味药。【结论】专利中药复方治疗DPN以补虚、活血化瘀为主,兼以温通经络,重视后天之本,健脾更不忘疏肝;临证时可选用黄芪-当归及白芍-丹参药对;核心方(黄芪、川芎、鸡血藤、丹参、牛膝、桂枝、当归)可加减用于DPN的全病程治疗。

复方丹参喷雾剂/气雾剂治疗冠心病心绞痛有效性与安全性的Meta分析

目的对复方丹参喷雾剂/气雾剂治疗冠心病心绞痛的有效性和安全性进行系统评价。方法系统检索中国知网、万方数据、维普网、中国生物医学文献数据库、Cochrane Library、PubMed、Embase、Web of Science,自建库至2021年5月5日的数据。筛选出复方丹参喷雾剂/气雾剂治疗冠心病心绞痛的随机对照试验进行Meta分析,使用TSA软件对冠心病心绞痛显效率结局指标的样本量进行预测,运用推荐分级评估、发展和评价(GRADE)证据评价方法对纳入的结局指标进行质量评价。结果共纳入9项研究,总样本量为1113例,试验组702例,对照组411例。Meta分析结果显示,复方丹参喷雾剂/气雾剂单用的治疗效果优于复方丹参片;联合硝酸酯类药物治疗冠心病心绞痛在提高冠心病心绞痛显效率、心电图显效率以及药品不良反应发生率与单用硝酸酯类药物无显著差异,但在稳定斑块(降低低密度脂蛋白、血清总胆固醇、血小板黏附率变化)方面优于单用硝酸酯类药物。不良反应主要为鼻咽部不适,可自行缓解,未发生严重不良反应。结论复方丹参喷雾剂/气雾剂治疗冠心病心绞痛有良好的临床疗效和安全性。

Clinical Study of Compound Radix Salvia Miltiorrhizae for Severe Pancreatitis

Compound Radix Salvia Miltiorrhizae injection was administered after operation for 28 casesof severe pancreatitis, and 13 cases were taken as a control group. The results showed that : (1) The differ-ence was not obvious in the morbidity of complications between the two groups, but the mortality (3.6% ) ofthe trial group was significantly lower tlian that ( 30. 8% ) of the control group ( P < 0. 05 ) ; ( 2 ) Hematocritwas clearly decreased from 46. 1 5. 2% to 33. 2 3. 9% in the trial one ( P < 0. 05) , but platelet andhemoglobin showed no statistical signiticance. It is concluded that compound Salvia miltiorrhizae inlectionmight improve hemorheologic abnormalities of the disease, promote the recovery of the pancreatic tissue,and correct the serious complications such as adult respiratory distress syndrome etc.

活血化瘀中药丹参在眼科基础和临床的应用进展

丹参及其复方制剂在临床具有活血化瘀的功效,近年来在眼科的应用范围越来越广泛,疗效显著,现就其在眼科基础及临床应用进展简要综述。

基于网络药理学及体外细胞实验探讨复方菝葜丹参擦剂抗白癜风作用机制

目的基于网络药理学研究复方菝葜丹参擦剂治疗白癜风的作用机制,通过分子对接与体外实验进行验证。方法通过TCMSP数据库搜索复方菝葜丹参中药材的有效成分及其对应作用靶点,利用GEO、OMIM以及GeneCards等数据平台,获得白癜风疾病相关靶点,通过映射药材成分对应靶点与疾病相关靶点获得治疗疾病的潜在靶点。利用Cytoscape 3.8.0软件构建菝葜丹参与白癜风的“有效成分-潜在靶点”作用网络;通过STRING数据库建立潜在靶点间的蛋白相互作用(PPI)网络;利用R语言及其相关依赖包对潜在靶点进行GO富集分析和信号通路富集分析。通过CytoNCA拓扑分析筛选出主要活性成分与核心潜在靶点进行分子对接,验证复方菝葜丹参活性成分与疾病靶点的结合效能,通过体外药理实验探究复方提取液对黑色素细胞的作用。结果复方菝葜丹参擦剂中有106个有效成分作用于STAT3、AKT1、RELA等8个核心靶点,GO富集结果显示潜在靶点参与了氧化应激、活性氧代谢过程等反应。信号通路富集结果表明,靶点涉及AGE-RAGE通路、Th17细胞分化等多条信号通路。分子对接结果显示,复方主要活性成分与核心靶点结合紧密。复方菝葜丹参对黑色素细胞有较好的促增殖作用,其中有效成分木樨草素对酪氨酸酶激活作用较强,芒柄花素可提高黑素含量。结论复方菝葜丹参擦剂是多种成分通过多种途径作用到多靶点对白癜风产生的治疗作用,其中丹参与鸡血藤为君药,木樨草素与芒柄花素为重要活性成分。

基于UPLC法的甘参复方指纹图谱研究

目的基于超高效液相色谱技术(ultra performance liquid chromatography,UPLC)建立12批甘参复方的指纹图谱。方法用Waters T3-C_(18)色谱柱(100 mm×2.1 mm,1.7μm);以乙腈(A)0.5 mL·L^(-1)磷酸水(B)溶液作为流动相,进行梯度洗脱;柱温为40℃;流速为0.3 mL·min^(-1);检测波长为240 nm;进样量为5μL。用“中药色谱指纹图谱相似度评价系统”建立12批甘参复方的指纹图谱,用相似度评价、主成分分析(principal component analysis,PCA)、聚类分析及偏最小二乘法判别分析(partial least squares discriminant analysis,PLS-DA)等化学计量方法进行分析。结果建立了甘参复方UPLC指纹图谱,以芍药苷为内参比峰,共标定了32个共有峰,并对13个色谱峰进行指认,12批甘参复方样品的相似度均在0.90以上,表明其相似度良好。结论建立的甘参复方指纹图谱研究方法简便可靠、重复性良好,用指纹图谱结合化学计量分析的方法,明确了不同产地制备的甘参复方之间的差异,为甘参复方的内在质量评价提供参考。

复方丹参滴丸联合新活素对充血性心力衰竭患者血清学指标及心功能的影响

目的探究复方丹参滴丸联合新活素对充血性心力衰竭(CHF)患者血清学指标及心功能的影响。方法选取2020年2月至2021年12月本院收治的CHF患者92例,按随机数表法分为两组,各46例。对照组予以新活素治疗,研究组在此基础上联合复方丹参滴丸治疗,对比两组临床疗效、血清学指标、心功能指标及不良反应发生率。结果研究组治疗后临床疗效高于对照组(P<0.05);两组治疗后血清B型利钠肽(BNP)、心肌肌钙蛋白I(cTnI)水平均低于治疗前,且研究组低于对照组(P<0.05);两组治疗后心排血量(CO)、每搏输出量(SV)和左心室射血分数(LVEF)水平均高于治疗前,且研究组高于对照组(P<0.05);治疗后两组不良反应发生率对比,无统计学差异(P>0.05)。结论复方丹参滴丸联合新活素治疗CHF可以显著提高临床效果,改善患者血清学指标,提升心肌功能,且无严重不良反应,值得临床推广应用。

Effects of Compound Salviae Miltiorrhizae Injection on Metabolism of Phosphoinosititides in Myocardial Ischemia

Using the model of acute myocardial ischemia in rats formed by ligation of the descending an-terior branch of the left coronary artery, this study showed some effects of compound Salviae miltiorrhizae in-jection ( CSMI) on metabolism of phosphoinositide in myocardial ischemia. The results of the experimentshowed that after 10 minutes of acute ischemia, the function of myocardial messangers ot phosphoinositide in-creased, and the levels of phosphatidylinositol-4, 5-biphosphate ( PIP2 ) and inositol-1, 4, 5-trisphosphate(IP3 ) were obviously higher than those of the non-ischemia control groups ( P < 0. 01 , n = 7) . CSMI (2 glkgbody weight) could markediy inhibit myocardial PIP2 and IP3, whose levels became lower than those of theischemia control groups ( P < 0 . 01 , n = 7 ) .

复方丹参注射液治疗重症胰腺炎的临床研究

手术治疗重症胰腺炎后，应用复方丹参注射液治疗２８例，对照组１３例。结果表明：（１）两组并发症的发生率无明显差异，治疗组病死率３．６％，对照组病死率３０．８％，其差异显著（Ｐ＜０．０５）。（２）治疗组的红细胞压积从术前的４６．１±５．２％降低到３３．２±３．９％，其差异显著（Ｐ＜０．０５），而血小板和血红蛋白的变化无统计学意义。认为：复方丹参注射液能够改善重症胰腺炎的血液流变学异常，有助于胰腺组织的康复和成人呼吸窘迫综合征等严重并发症的纠正。

复方丹参注射液对人羊膜上皮细胞水通道蛋白3表达的影响

目的研究复方丹参注射液对人羊膜上皮细胞(human amniotic epithelial cells,hAECs)水通道蛋白3(aquaporin 3,AQP3)表达的影响,探讨复方丹参注射液治疗羊水量过少的机制。方法选取无并发症的8例羊水过少和8名羊水量正常的足月产妇的hAECs进行原代培养,采用RT-PCR和免疫印迹Western blot技术,检测复方丹参注射液不同浓度(0.000、0.001、0.010、0.020、0.060、0.100mg/mL)、不同作用时间(0、6、12、24、48h)作用前后,两组hAECs中AQP3 mRNA和蛋白的表达。结果 (1)羊水过少组hAECs中AQP3的表达较羊水正常组下调(P<0.05)。(2)复方丹参注射液浓度为0.010mg/mL时,两组hAECs中AQP3的表达均达到峰值,与其他浓度作用结果比较,差异有统计学意义(P<0.05)。(3)0.010mg/mL浓度的复方丹参注射液作用12h,两组hAECs中AQP3的表达均达到峰值,与其他作用时间比较,差异有统计学意义(P<0.05)。(4)0.010mg/mL浓度的复方丹参注射液作用12h后,两组hAECs中AQP3的表达均上调,但羊水过少组中AQP3的表达上调较羊水正常组明显(P<0.05)。结论复方丹参注射液可调节hAECs中AQP3的表达,羊水过少时复方丹参注射液对hAECs中AQP3表达的调节作用更加明显。

丹参制剂中丹参酮Ⅱ_A的稳定性影响因素考察

目的 :考察空气 (氧气 )、水、p H及复方成分等对丹参酮 A降解速度的影响。方法 :在 70℃下 ,对丹参及复方丹参片的乙醇提取试样进行恒温加速试验 ,用薄层扫描法测定丹参酮 A的含量变化及降解速度常数 ,比较各因素的影响程度。结果 :在大气中丹参酮 A降解迅速 ,但在较高真空度时明显较慢 ;随着乙醇溶液中水分含量的增加 ,降解速度略有增大 ;不同 p H丹参试样以及复方丹参片试样的降解速度常数之间没有明显差别。结论 :空气 (氧气 )对丹参酮 A的降解有较大影响 ,其次为水分 ,p

复方丹参注射液对冠心病患者血管内皮功能及内皮素和一氧化氮合酶基因表达的影响

为探讨复方丹参注射液对冠心病患者血管内皮功能的影响及其作用机制 ,将 84例冠心病患者随机分为对照组、复方丹参注射液治疗组和维生素C治疗组 ,分别于治疗前、后用彩色多普勒检测血管内皮依赖性舒张功能 ,并采血检测内皮素 1和一氧化氮水平及内皮素 1和内皮型一氧化氮合酶mRNA表达。结果发现 ,治疗前 3组间血管内皮依赖性舒张功能、内皮素 1及一氧化氮水平及其mRNA表达比较差异无显著性 ,治疗后复方丹参注射液和维生素C两治疗组血管内皮依赖性舒张功能明显改善 (16 .7%± 5 .0 %和 13.8%± 5 .1%比 9.4 %± 4 .5 %和 9.7%± 4 .1% ,P <0 .0 5 ) ,高于对照组 (11.2 0 %± 3.90 % ,P <0 .0 5 ) ,前者又优于后者 (P <0 .0 5 ) ;复方丹参注射液治疗组内皮素 1水平及其mRNA表达下降 ,内皮型一氧化氮合酶水平及其mRNA表达升高 ,与对照组及治疗前比较差异有显著性 ;维生素C治疗组一氧化氮水平及内皮型一氧化氮合酶mRNA表达也升高 ,但低于复方丹参注射液治疗组 (P <0 .0 5 )。以上提示复方丹参注射液能改善冠心病患者血管内皮功能 ,其机制之一为调节内皮型一氧化氮合酶和内皮素