颈动脉球囊扩张与支架置入术后血清一氧化氮和内皮素变化的实验与临床观察

目的:观察小型猪颈动脉球囊扩张前后和颈动脉狭窄患者狭窄扩张、支架置入术前后血清一氧化氮(NO)和内皮素(ET)的变化.方法:选取12头广西巴马小型猪,分别于颈动脉球囊损伤前、损伤后2周和3周检测静脉血血清中NO和ET的浓度.同样方法检测19例颈动脉狭窄患者支架置入术前、术后静脉血及支架置入处动脉血血清中NO和ET的浓度.结果:小型猪颈动脉损伤后2周NO浓度较损伤前显著降低(P<0.05),ET浓度较损伤前升高,但无显著差异;损伤后3周ET浓度明显升高(P<0.01).支架置入患者中,术前、术后即刻和术后6 h周围静脉血的NO浓度和同一时间点的ET浓度变化差异均尢统计学意义.结论:小型猪颈动脉球囊损伤后可观察到NO降低和ET升高,可能与猪颈动脉粥样硬化性狭窄的发生相关;人颈动脉狭窄支架置入术后NO、ET的变化及其在术后动脉冉狭窄中的作用尚需进一步研究.     

阿托伐他汀对血脂正常的老年早期糖尿病肾病尿蛋白及相关因素的影响

目的探讨阿托伐他汀对血脂正常老年患者早期糖尿病肾病（DN）尿蛋白、内皮素（ET）、一氧化氮（NO）、C反应蛋白（CRP）的影响。方法血脂正常的50例2型糖尿病老年患者,随机分为常规用药组（常规组）25例;在常规组基础上加用阿托伐他汀组（联合组）25例,另设健康老年人为对照组25例。测定治疗前后血脂（CH、TG、LDL、HDL）、ET、NO、CRP、尿白蛋白排泄率（UAER）。结果DN患者血ET、CRP显著高于对照组,NO明显低于对照组。常规组治疗12周后与治疗前比较血脂、ET、NO、CRP、UAER差异无显著性,联合组治疗后CH、TG、LDL、ET、CRP、尿UAER显著降低,NO、HDL明显升高。结论阿托伐他汀可改善ET、NO失衡,改善血脂水平,减轻炎症反应,减少早期糖尿病肾病患者的尿微量白蛋白,有保护肾脏的作用。     

哮喘患者血液中ET、TXB_2、6-K-PGF-1α检测的临床意义

目的测定哮喘病情严重程度不同的患者血液中的内皮素(ET)、血栓素B2(TXB2)、6-酮-前列腺素(6-K-PGF-1α)的水平,以探讨其在哮喘中的监测意义及相互作用。方法共选择轻度哮喘组患者32例,中重度哮喘组患者23例,健康对照组共18例,每例研究对象抽取清晨空腹静脉血5 mL。将其分为2部分,其中3 mL用于测定TXB2、6-K-PGF1α;2 mL用于测定ET。数据统计分析采用单因素方差分析。结果①三组血浆中ET水平比较:轻度哮喘组与中重度哮喘组高于健康对照组,差异有统计学意义(P<0.01),轻度哮喘组低于中重度哮喘组,差异有统计学意义(P<0.01)。②三组血浆中6-K-PGF1α水平比较:轻度哮喘组与中重度哮喘组低于健康对照组,差异有统计学意义(P<0.01),轻度哮喘组高于中重度哮喘组,差异有统计学意义(P<0.01)。③三组血浆中TXB2水平比较:轻度哮喘组与中重度哮喘组高于健康对照组,差异有统计学意义(P<0.01),轻度哮喘组低于中重度哮喘组,差异有统计学意义(P<0.01)。结论ET、TXB2与哮喘的病情严重程度呈正相关,并可能在气道炎症方面影响哮喘的发生、发展。6-K-PGF1α与哮喘的病情呈负相关,说明是机体的一种保护机制。     

冠心病患者血浆内皮素浓度观察

目的观察内皮素（ET）在冠心病患者中及不同心功能状态下血浆ET浓度变化。方法采用特异性放射免疫分析法测定36例冠心病患者血浆ET浓度，其中30例应用彩色多普勒超声心动图仪测定左室射血分数。结果冠心病组与正常对照组比较，血浆ET浓度明显增高（P＜001），尤以不稳定型心绞痛和急性心肌梗塞组增高明显，两组与稳定型心绞痛比较均有显著性差异（P＜001）。同时发现血浆ET浓度随左室射血分数下降而明显增高。结论ET在冠心病的发生、发展中起重要作用。血浆ET浓度高低可作为临床判断病情危重状态的指标之一.     

不停跳冠状动脉旁路移植手术中的内皮素变化

目的 检测不停跳冠状动脉旁路移植(OPCAB)术中、术后不同时段不同部位血浆内皮素水平,观察手术中各个循环内皮素水平的变化.方法 30例冠心病患者分为两组.A组[15例,男13例,女2例,年龄(57.4±8.25)岁]使用左乳内动脉+大隐静脉移植;B组[15例,均为男性,年龄(50.50±7.05)岁]进行全动脉化移植.手术中各桥血管移植前后,分别取冠状静脉、肺动脉、桡动脉血,检测内皮素水平.术后2、24 h分别取肺动脉、桡动脉血,检测内皮素水平.结果 A组,手术中冠状静脉(34.31±15.10)ng/L、肺动脉(35.79±18.89)ng/L、桡动脉(34.65±15.62)ng/L]血内皮素无显著升高;手术后2 h,肺动脉(45.93±20.58)ng/L、桡动脉(52.68±21.46)ng/L血明显升高;手术后24 h,肺动脉(39.21±23.39)ng/L、桡动脉(33.31±21.54)ng/L血下降至术前水平.B组,搭桥前、左乳内动脉搭桥开放后,冠状静脉(36.77±21.45)ng/L、肺动脉(35.50±24.39)ng/L、桡动脉(33.17±20.80)ng/L血内皮素无明显变化;在剩余移植桥开放后,冠状静脉(52.00±20.86)ng/L、肺动脉(48.84±23.26)ng/L、桡动脉(49.66±21.22)ng/L血显著升高.术后2、24 h,肺动脉(52.52±30.34)ng/L、桡动脉(53.72±33.42)ng/L血维持高水平.结论 OPCAB会引起血浆内皮素水平小幅升高.全动脉与乳内动脉+大隐静脉比较术中血浆内皮素升高较早持续时间较长.     

冠心病患者围术期内皮素变化的临床研究

目的研究冠心病患者围术期内皮素（ET）及血流动力学的改变,总结冠心病围术期的一些变化规律,为临床治疗提供参考。方法将37例冠心病患者及10例心瓣膜疾病患者依据不同的手术方式分为5组,冠状动脉旁路移植术＋室壁瘤切除术（CABG＋LVAN组）,体外循环冠状动脉旁路移植术（CABG组）,非体外循环冠状动脉旁路移植术（OPCAB组）,激光心肌打孔术（TMLR组）,对照组为风湿性心脏病行二尖瓣置换术患者。使用放射免疫分析法分别测定术前,主动脉阻断前（血管移植前或打孔前）,主动脉开放时（血管移植结束时或打孔后）,心肌再灌注后3h、6h、24h血ET值;并于术前、心肌再灌注后3h、6h、24h测定心排血指数（CI）。结果ET值组内比较：CABG＋LVAN组主动脉开放时（69．93±7．20pg／ml）,心肌再灌注后3h（89．99±5．76pg／ml）、6h（60．94±8．69pg／ml）、24h（68．99±10．30pg／ml）时ET值显著高于术前（40．17±13．37pg／ml,P〈0．05）;CABG组主动脉开放时（66．59±4．86pg／ml）,心肌再灌注后3h（95．97±10．72pg／ml）、6h（61．51±7．65pg／ml）、24h（57．85±6．34pg／ml）均显著高于术前（43．22±9．13pg／ml,P〈0．05）;OPCAB组血管移植结束时（66．47±5．90pg／ml）显著高于术前（44．80±6．51pg／ml,P〈0．05）;TMLR组打孔术后无显著升高;对照组主动脉开放时（69．92±10．80pg／ml）,心肌再灌注后3h（77．99±7．49pg／ml）、6h（46．76±7．61pg／ml）、24h（52．07±6．94pg／ml）显著高于术前（35．14±8．10pg／ml,P〈0．05）。组间比较：CABG组心肌再灌注后3h显著高于OPCAB组（95．97±10．72pg／ml vs．59．72±4．81pg／ml,P〈0．05）。心肌再灌注后各组CI均较术前明显增加,CABG组心肌再灌注后3h CI明显低于OPCAB组（2．17±0．46L／min·m^2 vs．3．25±0．05L／min·m^2,P〈0．05）。?     

Possible Protection of Sinusoidal Endothelial Cells by Endothelin B Receptor During Hepatic Warm Ischemia–Reperfusion

Purpose Endothelins (ETs) are important regulators of the hepatic microcirculation. We investigated the pure biological roles of endothelin B receptors (ETB-Rs) on hepatic warm ischemia–reperfusion (I/R) injury using ETB-R deficient spotting lethal (sl) rats. Methods Homozygous (sl/sl) and wild-type (+/+) rats were exposed to 60 min of 92% partial hepatic ischemia and then were killed at 2, 6, and 24 h, and 3 and 7 days after reperfusion. We measured the serum alanine aminotransferase (ALT) levels to assess hepatocyte injury, and the serum hyaluronic acid (HA) levels and factor VIII-related antigen (FVIIIRAg) staining to assess sinusoidal endothelial cell (SEC) injury. We also measured the concentrations of ET-1 and nitrite (NO₂ ⁻) and nitrate (NO₃ ⁻) of liver tissue samples. Results Although no significant difference was observed in the ALT levels, the HA levels were significantly elevated at an early stage after reperfusion in the sl/sl rats. Regarding FVIIIRAg staining, positive SECs were enhanced in the sl/sl rats. The ET-1 levels were also significantly elevated at an early stage after reperfusion in the sl/sl rats. Regarding the NO₂ ⁻ and NO₃ ⁻ levels, no significant difference was observed. Conclusion Endothelin B receptor was shown to have a protective effect on SECs through the inhibition of ET-1 during hepatic warm I/R injury.     

A Phase II study of bosentan, a dual endothelin receptor antagonist, as monotherapy in patients with stage IV metastatic melanoma

There is no effective systemic therapy for disseminated metastatic melanoma. Data suggest that endothelin may play a role in pathophysiology of melanoma and that the dual endothelin receptor antagonist bosentan may have anti-tumor activity. This multicenter, open-label, single-arm, prospective, proof-of-concept study assessed the effects of bosentan monotherapy (500 mg oral tablets, bid) on tumor response in patients with stage IV metastatic melanoma. Patients were treated until disease progression, death or serious adverse event leading to premature study drug discontinuation. Tumor response was assessed at 6-weekly intervals using the Response Evaluation Criteria in Solid Tumors (RECIST). Among the 35 patients included in this study with stage IV metastatic melanoma, 21 (60%) were stage M1C, 10 (29%) stage M1B and 4 (11%) stage M1A (American Joint Committee on Cancer [AJCC] classification). Nine patients (26%) had received prior therapy for stage IV melanoma. Disease stabilization was observed in 6 of the 32 patients analyzed per protocol at week 6 with confirmatory evaluation at week 12, 5 of whom were still stable at > or =24 weeks. Of the 6 patients with disease stabilization, 2 were stage M1A, 1 was stage M1B and the remaining 3 were stage M1C. Partial or complete response was not observed. Progressive disease was observed in 17 (49%) patients at week 12 and in 25 (71%) patients at the end of the study (data base closure). The most frequent adverse events were typical for the underlying disease or known to be associated with bosentan: headache (43%), fatigue (34%), nausea (31%), back pain (23%) and abnormal hepatic function (23%). Bosentan might have benefit in disease stabilization in certain patients with metastatic melanoma and deserves further investigation in combination with other anticancer drugs.     

Endothelin receptor blockade does not affect blood pressure or angiotensin II levels in CYP1A1-Ren-2 transgenic rats with acutely induced hypertension

We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET_A/ET_B in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET_A/ET_B, or with atrasentan, a selective ET_A receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (I3C; 0.3% in rat chow), a natural xenobiotic which activates the Cyp1a1 promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of I3C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.     

Endothelin receptor antagonists in cancer therapy

Endothelins are a family of peptide compounds which exert regulatory control over cellular processes important for growth, survival, invasion, and angiogenesis. In particular, endothelin-1, acting primarily through the endothelin-A receptor, is implicated in the neoplastic growth of multiple tumor types. In preclinical models, endothelin antagonism inhibits tumor cell proliferation, invasiveness, and new vessel formation, as well as attenuates osteoblastic and pain-related responses to tumor. Clinical testing of an orally bioavailable endothelin antagonist has demonstrated benefit in PSA progression, markers of bone turnover, and pain in men with prostate cancer, but has not demonstrated significant improvement in survival or time to cancer progression. Although this class of drugs is promising for targeted anti-cancer therapy, their role in treatment remains to be defined by completion of future clinical trials.