L-精氨酸对缺氧性肺动脉高压大鼠内皮素释放的影响

目的：探讨Ｌ－精氨酸（Ｌ－Ａｒｇ）对缺氧性肺动脉高压（ＨＰＨ）大鼠血浆内皮素－１（ＥＴ－１）释放的影响。方法：将Ｗｉｓｔａｒ大鼠４０只分为：对照组,缺氧组,缺氧＋Ｎ＾ω－硝基－Ｌ－精氨酸甲脂（Ｌ－ＮＡＭＥ）组和缺氧Ｌ－Ａｒｇ组。结果：缺氧组的肺动脉平均压（ｍＰＡＰ）显著高于对照组（Ｐ〈０．０５）,缺氧组＋Ｌ－Ａｒｇ组的ｍＰＡＰ显著低于缺氧组（Ｐ〈０．０５）及缺氧＋Ｌ－ＮＡＭＥ组（Ｐ〈０．０１）,缺     

牛磺酸抗缺氧及防治肺动脉高压的研究及其细胞机制初探

目的通过动物模型观察牛磺酸对缺氧性肺动脉高压的治疗作用,同时观察其对体外培养牛肺动脉平滑肌细胞(PASMC)和内皮细胞(PAEC)增殖的影响。方法采用模拟高原5 000 m制作缺氧大鼠模型,缺氧2周。设平原(C组)及缺氧对照组(H组),观察牛磺酸治疗后(T组)的肺动脉压(mPAP)、血浆乳酸脱氢酶(LDH)活性、脂质过氧化产物丙二醛(MDA)、肺匀浆一氧化氮(NO)含量、右心室肥大指数的变化。体外培养PASMC和PAEC用3H-TdR掺入法比较牛磺酸对缺氧PASMC和PAEC增殖的影响。结果H组大鼠LDH活性升高为C的10.1倍(P<0.01);肺匀浆NO含量降低为C组的32%(P<0.01);血浆MDA含量显著升高为C组的1.64倍(P<0.01);mPAP显著增高,约为C组的2.74倍(P<0.01);右心室肥大指数是C组的1.56倍(P<0.01)。T组与H组相比较:LDH活性、血浆MDA、右心室肥大指数均显著降低(P<0.01);mPAP显著降低(P<0.05)。高浓度(10～20 mmol/L)的牛磺酸抑制缺氧内皮及平滑肌细胞的3H-TdR掺入,而低浓度的牛磺酸促进缺氧时PAEC的3H-TdR掺入(P<0.05),抑制缺氧时PASMC的3H-TdR掺入(P<0.05)。结论牛磺酸有抗缺氧及防治肺动脉高压的作用。缺氧抑制内皮细胞的增殖而促进平滑肌细胞的增殖,适当剂量的牛磺酸可以对抗缺氧对PAEC和PASMs的作用:减弱缺氧对PAEC的增殖抑制作用,抑制缺氧的促PASMC增殖作用,使之接近常氧水平。这可能是牛磺酸防治肺动脉高压的细胞机制。提示牛横酸对于高山病缺氧性肺血管收缩和血管结构改建的预防和治疗,可能具有广阔的应用前景。     

缺氧性肺动脉高压时一氧化氮合酶,左旋精氨酸及亚硝基左旋？…

研究一氧化氮在缺氧肺动脉高压发病中的作用。方法烟酰胺腺嘌呤二核苷酸磷酸－黄递酶和免疫组化ＡＢＣ方法检测原生型和诱型一氧化氮合酶在正常和缺氧在鼠肺内的表达和分布。     

缺氧性肺动脉高压大鼠右心室重构

摘要目的：研究缺氧性肺动脉高压大鼠右心室重构情况。方法：常压间断缺氧法复制缺氧性肺动脉高压大鼠模型，采用右心导管法测定平均肺动脉压力，通过测量右心室流入及流出道长度、左心室壁和右心室壁厚度、右心室和左心室 室间隔重量对其右心室重构情况进行定性研究。结果：缺氧14d后大鼠平均肺动脉压力显著升高，右心室流出道长度及右心室肥大指数显著增加，缺氧21d后右心室游离壁重量显著增加；右心室流人道长度及左、右心室壁厚度与对照组无统计学差异。结论：缺氧性肺动脉高压大鼠右心室早期表现为离心性肥大。     

西拉普利和牛磺酸对慢性缺氧肺组织细胞凋亡的影响

目的：初步观察西拉普利和牛磺酸对慢性缺氧肺组织细胞凋亡的影响。方法：采用原位末端民法。结果：缺氧模型及普利组细胞凋亡明显高于其他各组,而牛磺酸组、自然恢复组册与正常对照无差异。结论：西拉普利可能诱发细胞凋亡的作用,细胞凋亡的发生与否可能与肺动脉高压的形成与发展有关。     

川芎嗪防治大鼠慢性缺氧性肺动脉高压的作用

本文研究了川芎嗪对大鼠慢性缺氧性肺动脉高压的预防及治疗效果。结果显示,川芎嗪经口服(100mg/kg)和腹腔注射(80mg/kg),每日二次,均可防止慢性缺氧性肺动脉高压及右心室肥大的发生。在已患慢性肺动脉高压的大鼠,静脉注射川芎嗪(80mg/kg)显著增加心输出量,降低肺血管阻力及肺动脉压力,其降压作用比正常及急性缺氧性肺动脉高压时更为明显。这提示川嗪芎可用于预防及治疗慢性缺氧性肺动脉高压及肺压病。     

CO/HO体系影响缺氧性肺动脉高压幼年大鼠肺动脉超微结构的研究

目的 探讨血红素加氧酶，一氧化碳(HO/CO)体系对缺氧性肺动脉高压幼年大鼠肺动脉超微结构的影响。方法 将26只Wistar大鼠随机分为4组：对照组、低氧组、低氧 锌原卟啉(ZnPP)组和低氧 一氧化碳(CO)组。以右心导管法测定肺动脉压力，并对大鼠肺动脉进行超微结构观察。结果 低氧组大鼠肺动脉超微结构发生明显改变：内皮细胞呈柱状，部分核突入管腔，排列呈栅状，内皮细胞肿胀，胞浆内可见大量空泡，线粒体肿胀，内质网扩张；平滑肌细胞胞体肥大，胞浆中肌丝和致密斑减少。线粒体、粗面内质网和游离核糖体等三田胞器增多。约半数平滑肌细胞处于收缩表型，余呈过渡表型或合成表型，有肺血管结构重构形成。低氧 ZnPP组肺血管结构重建程度较低氧组加重：内皮细胞呈柱状，呈栅状排列，部分脱落致管腔，胞浆内可见大量空泡，线粒体肿胀，内质网扩张；平滑肌细胞形态不规则，胞体肥大，胞浆中肌丝和致密斑明显减少，粗面内质网和游离核糖体等细胞器明显增多。低氧组 CO组肺血管结构重建程度较低氧组减轻；内皮细胞胞体扁平，内衬血管内壁，其肿胀程度较低氧组减轻，空泡明显减少；平滑肌细胞改变较低氧组为轻，约半数平滑肌细胞处于收缩表型，余呈合成表型或过渡表型。结论 HO/CO系统对缺氧性肺动脉高压的形成以及缺氧性肺血管结构重建有重要的调节作用。     

缺氧性肺动脉高压大鼠肺毛细血管超微结构变化

目的研究缺氧对肺毛细血管结构的影响及其在缺氧性肺动脉高压(HPH)发展过程中的作用。方法本实验模拟海拔5km高原连续缺氧 ,制备HPH大鼠动物模型 ,应用电镜观察缺氧后10、20和30d肺毛细血管超微结构变化 ,探讨变化机制及其意义。结果缺氧10d,可见毛细血管内充满红细胞 ,红细胞呈缗钱状 ,相互挤压或套叠 ;内皮细胞 (EC)肿胀 ,胞质呈节段性增厚。缺氧20d与30d病变基本一致 ,但比10d更为明显。可见较多毛细血管充血 ,中性粒细胞 (PMN)滞留、嵌塞 ,有的PMN与EC黏附。毛细血管内易见血小板聚集 ,阻塞管腔。有的毛细血管高度扩张。EC肿账 ,可见胞质电子密度降低 ,饮泡增多 ,连接增宽 ,有的EC胞质形成较多微绒毛突入管腔 ,有的EC胞核核膜增厚 ,呈多边形或乳头状 ,核染色质凝集边移 ,基底膜节段性增厚。毛细血管周围水肿 ,可见大小不一的水肿空泡。结论缺氧可引起肺毛细血管充血、淤血 ,EC肿胀、基底膜增厚使毛细血管管腔狭窄 ,PMN滞留、血小板聚集 ,微循环发生障碍 ,致肺血流阻力增加 ,从而促使HPH的发生和发展目的研究缺氧对肺毛细血管结构的影响及其在缺氧性肺动脉高压(HPH)发展过程中的作用。方法本实验模拟海拔5km高原连续缺氧 ,制备HPH大鼠动物模型 ,应用电镜观察缺氧后10、20和30d肺毛细血管超微结构变化     

高镁饮食对大鼠缺氧性肺血管收缩反应和慢性缺氧性肺动脉高压的影响

本课题观察了高镁饮食对大鼠缺氧性肺血管收缩反应(HPV)和慢性缺氧性肺动脉高压的影响。大鼠进高镁饲料(每公斤普通饲料加镁1000mg)10周后,血浆镁浓度为2.58mEq/L,显著高于对照组大鼠的血浆镁浓度。慢性常压缺氧(吸入气含10%O_2,每天8小时,连续14天)后,与缺氧对照大鼠相比,进高镁饲料盼大鼠的平均肺动脉压(Ppa)和肺血管阻力(PVR)较低,肺血管对缺氧的反应性(△PVR%)较低,同时右心室肥大也较轻。血粘度和红细胞比积在慢性常压缺氧后均增高,但进高镁饲料大鼠的血粘度和红细胞比积与缺氧对照组大鼠无差别。结果表明,镁可以降低PVR和HPV,从而缓解由慢性缺氧引起的肺动脉高压和右心室肥大。     

肾上腺髓质素缓解大鼠低氧性肺动脉高压

目的探讨肾上腺髓质素(ADM)对大鼠低氧性肺动脉高压的防治作用及机制。方法雄性Wistar大鼠18只,分为对照组、低氧组和低氧 ADM组,每组6只。持续皮下注射ADM1-50后,测定平均肺动脉压(mPAP)、右心室肥大指数RV/(LV S)、肺小动脉病理及形态计量学和体循环平均压(mSBP),放免法测定肺动脉血浆ADM水平,原位杂交测定肺动脉ADMR mRNA的表达。结果①低氧组大鼠mPAP,RV/(LV S),管壁厚度与血管外径比值(MT%)及管壁面积与血管面积比值(MA%)均显著升高(P<0.01);ADM组显著缓解以上变化(P<0.01)。②低氧组与低氧 ADM组肺动脉血浆ADM浓度均高于对照组,且低氧 ADM组较低氧组ADM浓度低(P<0.05)。③低氧组与低氧 ADM组的ADMR mRNA表达较对照组增强(P<0.01)。结论持续皮下注射ADM对慢性低氧所致的肺动脉高压及肺血管重塑有预防和部分逆转作用。     

L-精氨酸对高肺血流量大鼠肺动脉平滑肌细胞增殖与凋亡的影响

探讨L－精氨酸（L－Arginine,L-Arg）对高肺血流量所致肺动脉高压平滑肌细胞增殖与凋亡的干预作用。18只雄性SD大鼠随机分为对照组、分流组和分流＋L精氨酸（L－Arg）组。对分流组和分流＋L－Arg组大鼠行腹主动脉－下腔静脉分流术。观察术后11周大鼠肺动脉平均压（mPAP)和右心室肥厚的改变，采用免疫组织化学方法研究肺动脉平滑肌细胞PCNA和Fas的表达，并通过原位缺口末端标记方法（TUNEL）检测大鼠肺动脉平滑肌细胞的凋亡。结果表明分流组大鼠mPAP、右心室（RV）与左心室加室间隔（LV＋S）的比值，肺中、小型动脉平滑肌细胞增殖指数（PI），凋亡指数（AI），PI／AI比值明显高于对照组大鼠（P＜0．05），同时，分流后肺动脉平滑肌细胞Fas表达增高。然后，分流＋L－精氨酸组大鼠mPAP、RV／LV＋S明显低于分流组（P＜0．05及0．01）。并且L－Arg减少了肺中、小型动脉平滑肌细胞的增殖，促进了凋亡（P＜0．01），wviycL-Arg组大鼠PI／AI比值较分流组明显降低（P＜0．01），同时，L－Arg使分流大鼠肺平滑肌细胞Fas表达明显增强。以上结果提示，L－精氨酸通过抑制肺动脉平滑肌细胞的增殖，促进其凋亡，从而对同肺血流量所致肺动脉高压的形成有重要的调节作用。     

Endothelin infusion reduces hypoxic pulmonary hypertension in pigs in vivo

Previous work has shown that the plasma levels of the potent vasoactive peptide endothelin (ET) are increased in pathophysiological conditions with increased pulmonary vascular resistance and it has been speculated that ET may play some part in hypoxic pulmonary hypertension. We have therefore evaluated the effects of ET-infusion in the porcine pulmonary circulation after hypoxia-induced hypertension. Pigs under general anaesthesia were artificially ventilated through an endotracheal tube and hypoxia was induced by decreasing the fraction inhaled 0₂ from 0.21 to 0.10. Haemodynamic parameters were continuously recorded using a Swan-Ganz catheter in combination with thermodilution for cardiac output measurements. ET-1 or ET-3 was given as an i.v. infusion through the Swan-Ganz catheter in the right ventricle. Hypoxia induced a reproducible increase in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP) and right ventricular stroke work (RVSW) while the systemic vascular resistance (SVR) slightly decreased. Cumulative infusion of ET-1 (10, 25 and 50 ng kg^-1 min^-1) dose-dependently decreased MPAP and PVR; at a higher dose (100 ng kg^-1min^-1), the PVR returned to the level observed at hypoxia. ET-infusions at 50 and 100 ng kg^-1 min^-1 evoked an increase in SVR and a decrease in cardiac output (CO) and stroke volume (SV). RVSW also gradually decreased during ET-1 infusion. Infusion of ET-3 evoked effects similar to those of ET-1 infusions, although the response to ET-3 was not that rapid in onset. In a second series of animals, repeated 15 min periods of hypoxia evoked a stable, reproducible response with a consistent increase in PVR, MPAP and RVSW which returned to baseline values during normoxia. Infusion of ET-1 (25 ng kg^-1 min^-1) evoked a rapidly developing decrease in PVR and MPAP which was quickly normalized upon cessation of the ET-infusion. ET-1 infusion at this concentration did not per se influence the haemodynamic parameters during normoxia. It is concluded that in the pig, short-term ET-infusion reduces the pulmonary hypertension associated with acute hypoxia.     

Osteopontin expression in normal and hypobaric hypoxia-exposed rats

Aim: Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodelling of the heart and pulmonary arteries. Osteopontin (OPN) has emerged as a key factor in cardiovascular remodelling in response to pressure or volume overload. We studied the possible effects of HHE on the OPN synthesis system. Methods: One hundred and forty‐eight male Wistar rats were housed in a chamber with conditions equivalent of an altitude of 5500 m for up to 21 days. Results: Plasma OPN protein level was found to be significantly decreased on day 0.5 of exposure to HHE, as was the level in the adrenal gland (which secreted highest levels of OPN protein). In the right ventricle of the heart (mRNA) and the lung (protein), OPN expression was found to be significantly increased only on day 1 and day 5, respectively, of exposure to HHE. By immunohistochemistry, the distribution and intensity of OPN protein in several organs were found to alter during exposure to HHE. However, these changes in OPN synthesis did not coincide with the moderate increase in pulmonary arterial pressure (PAP) (maximal mean PAP, 24.5 mmHg) during HHE. Conclusion: Pulmonary hypertension in HHE with conditions equivalent of an altitude of 5500 m may induce little or no OPN in heart and lung. Sustained induction may require a more severe PAP overload.     

牛磺酸对大鼠慢性缺氧性肺动脉高压的预防作用

目的：进一步研究牛磺酸对慢性缺氧性肺动脉高压的防治作用。方法：复制大鼠间断缺氧４周模型,采用透射电镜、放射免疫和生化技术研究牛磺酸对肺动脉高压的治疗效果。结果：缺氧４周大鼠肺动脉压力升高,右心肥大,血中ＥＴ－１、ＡＣＥ水平升高,ＮＯ－２／ＮＯ－３和ＳＯＤ水平降低;ＭＰＡＰ与ＥＴ－１呈正相关,与ＮＯ－２／ＮＯ－３呈负相关;牛磺酸可抑制缺氧大鼠ＥＴ－１和ＡＣＥ分泌,增加ＮＯ和ＳＯＤ水平,降低肺动脉压力;透射电镜观察表明牛磺酸能对抗缺氧大鼠的心肺组织损伤。结论：牛磺酸通过减轻缺氧所致细胞损伤,调节血管舒缩物质的平衡,对缺氧性肺高压有一定防治作用。     

红景天苷通过抑制氧化应激防治大鼠低氧性肺动脉高压

目的:观察低氧性肺动脉高压大鼠肺组织及血清中氧化/抗氧化相关指标的变化,研究红景天苷(Sal)能否通过恢复氧化/抗氧化系统平衡防治低氧性肺动脉高压。方法:将32只SD大鼠随机分为4组:常氧(normoxia,N)组、低氧4周(hypoxia for 4 weeks,H_4)组、Sal低剂量(hypoxia for 4 weeks and treatment with Sal at 16mg/kg,H_4S16)组和Sal高剂量(hypoxia for 4 weeks and treatment with Sal at 32 mg/kg,H_4S32)组。造模完成后测定平均肺动脉压(m PAP)、右心室/(左心室+室间隔)[RV/(LV+S)]和血管壁面积/血管总面积(WA/TA);测量肺组织和血清中丙二醛(MDA)和8-异构前列腺素F_(2α)(8-iso-PGF_(2α))含量,并测量血清中超氧化物歧化酶(SOD)活性及肺组织中NADPH氧化酶(NOX4)和SOD1的相对表达量。结果:与N组相比,H_4组的NOX4相对表达量及MDA和8-iso-PGF_(2α)含量均显著升高(P0.05);而与H4组相比,Sal低、高剂量组除m PAP、RV/(LV+S)和WA/TA明显减低外,NOX4的相对表达量及MDA和8-iso-PGF_(2α)含量亦明显减低(P0.05)。与N组相比,H_4组的SOD1相对表达量和SOD活性显著下降,而Sal低、高剂量组的SOD1相对表达量和SOD活性均显著升高并呈剂量依赖性。结论:红景天苷可能通过减轻低氧引起的肺组织氧化应激损伤、恢复氧化/抗氧化系统平衡而起到改善肺动脉高压的作用。     

Ca2+ and ion channels in hypoxia-mediated pulmonary hypertension

Alveolar hypoxia, a consequence of many lung diseases, can have adverse effects on the pulmonary vasculature. The changes that occur in the pulmonary circulation with exposure to chronic hypoxia include reductions in the diameter of the pulmonary arteries due to structural remodeling of the vasculature. Although the structural and functional changes that occur in the development of pulmonary hypertension have been well investigated, less is known about the cellular and molecular mechanisms of this process. This review will discuss the role of several potassium and calcium channels in hypoxic pulmonary vasoconstriction, both in elevating calcium influx into pulmonary artery smooth muscle cells (PASMCs). In addition to other signal transduction pathways, Ca²⁺ signaling in PASMCs plays an important role in the development and progression of pulmonary hypertension due to its central roles in vasoconstriction and vascular remodeling. This review will focus on the effect of chronic hypoxia on ion channels and the potential pathogenic role of Ca²⁺ signaling and regulation in the progression of pulmonary hypertension.