肾上腺髓质素对大鼠损伤性心肌肌浆网功能的改善

通过观察下述五个指标,评价肾上腺髓质素(adrenomedullin,Adm)对大鼠损伤性心肌肌浆网功能的改善程度左心室压力最大变化速率(±dp/dtmax)、肌浆网钙摄取和释放及钙泵活性.皮下注射异丙肾上腺素(isoproterenol,ISO,69μmol/kg体重)制备大鼠心肌损伤坏死模型.摘取心脏后用Adm灌流,观察左心室压力最大变化速率(±dp/dtmax);制备并提纯心肌肌浆网(sarcoplasmicreticulum,SR)膜,测定SRCa2+摄取和释放速率、SR钙泵活性和钙通道蛋白～3H-ryanodine受体的最大结合量.结果发现,5×10-5mol/LAdm灌流能使ISO损伤的大鼠心脏左室±dp/dtmax分别增加16.9%(2?135±281vs1?980±302)和29.2%(1?375±267vs1?064±355,均P<0.05);SRCa2+摄取和释放率分别增加23.0%(15.0±1.4vs12.2±1.2)和43.5%(6.6±1.0vs4.6±0.6,均P<0.01);SRCa2+-ATPase活性和～3H-ryanodine受体最大结合量(Bmax)分别增加24.2%(P<0.01)和42.2%(P<0.05).提示Adm对ISO诱导的大鼠心肌损伤具有保护作用,其机制可能与Adm增加SRCa2+-ATPase活性、增加～3H-ryanodine所致SRCa2+摄取和释放升高有关.外源性给予Adm对损伤心肌可能具有临床治疗作用.     

延髓腹外侧头端区注射肾上腺髓质素对大鼠血压、心率和肾交感神经活动的影响

本研究在 3 4只麻醉Sprague Dawley大鼠观察了延髓腹外侧头端区内微量注射肾上腺髓质素 ( 10μmol/L ,2 0 0nl)对平均动脉压 (MAP)、心率 (HR)和肾交感神经放电 (RSNA)的影响。实验结果如下 :( 1)延髓腹外侧头端区内微量注射肾上腺髓质素可引起MAP、HR、和RSNA明显增加 ,分别由 99 0 9± 3 3 2mmHg ,3 70 78± 7 84bpm和 10 0± 0 %增至 113 5 7± 3 64mmHg (P <0 0 0 1) ,3 83 2 8± 7 3 8bpm (P <0 0 0 1)和 12 3 72±2 74% (P <0 0 0 1) ;( 2 )降钙素基因相关肽受体阻断剂CGRP8 3 7( 10 0 μmol/L ,2 0 0nl)不能阻断肾上腺髓质素的上述效应 ;( 3 )静脉注射NO前体L 精氨酸 ( 10 0mg/kg ,0 2ml)可消除肾上腺髓质素的上述效应。以上结果提示 ,肾上腺髓质素作用于延髓腹外侧头端区可产生显著的心血管作用 ,此作用不是由降钙素基因相关肽受体介导 ,但可被NO所阻断     

自发性高血压大鼠心肌胶原与血管紧张素Ⅱ的关系

目的　观察成年 (16周龄 )自发性高血压大鼠 (spontaneouslyhypertensiverat,SHR)与同龄对照组 (WKY)大鼠之间细胞外基质成分的差异及血管紧张素Ⅱ (AngiotensinⅡ ,AngⅡ )在SHR大鼠左室肥厚形成过程的作用。方法　用尾袖法间接测定大鼠血压 ;检测左心室组织及血浆中的血管紧张素转化酶 (angiotensinconvertingenzyme ,ACE)活性 (紫外分光光度法 ) ;放免法测定左室心肌AngⅡ含量。免疫组化测定左室心肌胶原含量 ,用3H -Proline掺入量测定体外培养心肌成纤维细胞 (cardiacfibroblast,CFB)胶原的合成率。结果　 (1) 16周龄SHR大鼠血压明显高于对照组 (WKY)大鼠 ,分别为 (2 7.6 3± 2 .6 7)kPa和 (16 39± 0 54)kPa ,P <0 .0 5;(2 )SHR大鼠左室心肌AngⅡ含量明显高于WKY组 ,分别为 (2 6 6± 75)pg/ 10 0mg和 (134± 4 1)pg/ 10 0mg ,P <0 .0 5;(3)左室重量 (Leftventricalarmass,LVM)SHR明显高于WKY组 ,分别为 (10 14.3± 6 2 .1)mg和 (895.7± 86 .4 )mg ,P <0 .0 5;(4 )心体比 (Letventricrlarmass/bodyeight,LVM/BW )SHR明显高于WKY组 ,分别为 (3.4 4± 0 .15)mg/g和 (2 .17± 0 .11)mg/g ,P <0 .0 5;(5)体外细胞培养的心肌成纤维细胞3H -Proline掺入量随着AngⅡ浓度升高而增加 ,1μmol/L的AngⅡ使SH     

左旋硝基精氨酸诱导的高血压大鼠心肌和血管的肾上腺髓质素与受体活性修饰蛋白2表达的变化

探讨高血压大鼠心肌和血管的肾上腺髓质素（adrenomedullin,ADM）与受体活性修饰蛋白2（receptoractivity-modifying protein 2,RAMP2）mRNA的变化。用一氧化氮合酶（NOS）竞争性抑制剂左旋硝基精氨酸（L-NNA）阻断NOS制备大鼠高血压模型。用放射免疫分析方法测定血浆、心肌和血管ADM含量,及竞争性定量RT-PCR方法测定心肌和血管ADM mRNA与RAMP2 mRNA含量。结果表明,NOS阻断剂L-NNA应用4周后动物血压明显升高、心肌肥厚。心重（mg）/体重（g）比值增加35.5％（P<0.01）。血浆、心肌和血管的ADM-ir较对照组分别增加80％、72％和57％（均P<0.01）。高血压大鼠心肌和血管ADM mRNA含量显著增加,分别较正常大鼠高50％（P<0.05）和102.9％（P<0.05）。高血压大鼠心肌和血管的RAMP2　mRNA含量均显著增加,分别较正常大鼠高132％（P<0.01）和87％（P<0.01）。高血压大鼠心肌和血管ADM的升高与RAMP2的升高程度呈明显的正相关,其相关系数分别为0.741和0.885。上述观察结果表明,高血压时血浆、心肌和血管ADM水平升高,心肌和血管ADM与RAMP2基因表达上调,提示ADM/RAMP2系统在高血压发病中可能具有重要作用。     

慢性低氧性肺动脉高压大鼠肺组织肾上腺髓质素-2的变化

目的：研究新的小分子生物活性肽肾上腺髓质素-2（ADM2／IMD）及其受体在慢性低氧性肺动脉高压大鼠肺组织中的变化和可能的作用。方法：SD大鼠随机分成2组（n=10）：正常对照（NC）组和低氧四周（4H）组;放射免疫法测定血浆和肺组织ADM2／IMD和肾上腺素髓质素（ADM）蛋白水平;逆转录-多聚酶链反应（RT-PCR）法测定肺组织ADM2／IMD、ADM及其受体（CRLR,RAMP1,2,3）mRNA表达;免疫组化法测定ADM2／IMD在肺细小动脉的定位表达：结果：①4H组平均肺动脉压（mPAP）、右心室与左心室加室间隔重量比[RV／（LV＋S）]高于NC组（P均〈0．01）。②4H组血浆和肺组织匀浆ADM水平分别为NC组的2．3倍和3．2倍（P均〈0．01）,ADM2／IMD水平分别比NC组高89．6％和45．0％（P分别〈0．01、〈0．05）。③4H组肺组织ADM2／IMD与ADMmRNA表达高于NC组（P分别〈0．01、〈0．05）,CRLR和RAMP1mRNA表达显著低于NC组（P均〈0．01）,而RAMP2和RAMP3mRNA表达水平两组间差异无显著性。①ADM2／IMD主要在大鼠肺细小动脉内皮细胞及血管外膜表达。结论：ADM2／IMD与ADM相似,与大鼠慢性低氧性肺动脉高压病理过程密切相关;ADM2／IMD及其受体CRLR／RAMP1基因表达和／或蛋白合成、代谢的改变可能参与了大鼠慢性低氧性肺动脉高压的发生发展.     

肾上腺髓质素对大鼠延髓头端腹外侧区压力反射敏感神经元的作用

采用多管微电泳结合细胞外记录的方法研究了肾上腺髓质素(adrenomedullin,ADM)对大鼠延髓头端腹外侧区(rostral ventrolateral medulla,rVLM)压力反射敏感性神经元电活动的作用及其可能机制.结果显示在29个rVLM压力反射敏感神经元中,20个神经元在30、60和90 nA的电流微电泳大鼠ADM(rADM)过程中,放电频率由(10.8±2.7)spikes/s分别增加到(14.6±3.6)、(19.8±4.7)和(31.9±6.4)spikes/s(P＜0.05,n=20).微电泳rADM特异性受体阻断剂人ADM(human ADM,hADM)(22-52)可明显减小神经元放电频率的增加幅度,比正常放电频率仅增加15.4%[(11.4±2.5)sipkes/s,P＜0.05,n=10],而降钙素基因相关肽1(CGRP1)受体阻断剂hCGRP(8-37)对rADM兴奋性神经元电活动影响较小.在另外23个神经元中,10个神经元的放电频率在10、20和40 nA电流微电泳神经型NOS(nNOS)抑制剂7-NiNa过程中放电减少,由正常的(10.1±3.5)spikes/s分别减少为(7.5±2.5)、(5.3±2.1)和(3.1±1.4)spikes/s(P＜0.05,n=10).在微电泳7-NiNa过程中同时微电泳rADM,则rADM增加神经元放电频率的效应减弱,增加幅度为基础水平的17%[(6.2±1.9)spikes/s].8个神经元在10、20和40 nA电流微电泳诱导型NOS抑制剂(iNOS)aminoguanidine(AG)过程中放电频率由(11.5±5.1)spikes/s增加到(17.8±5.6)、(22.5±6.3)和(29.1±6.4)spikes/s(P＜0.05,n=8),rADM与AG同时微电泳时,AG对rADM本身增加神经元放电的效应无明显影响.上述结果提示,rADM在rVLM可通过其特异性受体或来源于nNOS的NO作用于压力反射敏感神经元,使其活动增强而发挥调节心血管活动的作用.     

外源性Apelin-13 对心力衰竭大鼠血浆血管紧张素Ⅱ 和肾上腺髓质素的影响

目的:研究给予外源性Apelin-13治疗对血流动力学、血浆血管紧张素Ⅱ(Angiotensin-Ⅱ,AngⅡ)和肾上腺髓质素(Adrenomedulin,ADM)水平的影响。方法:将50只大鼠随机分为3组:心衰组(n=20)、治疗组(n=20)和正常对照组(n=10),阿霉素(ADR)腹腔注射建立大鼠心衰模型,治疗组给药外源性Apelin-13治疗,检测大鼠血浆AngⅡ和ADM水平(ELISA法)以及血流动力学的水平。结果:心衰组和治疗组血浆AngⅡ和ADM水平比正常对照组增高,但治疗组血浆AngⅡ和ADM水平比心衰组明显降低,治疗组左心室内压最大升降速度(LV±dp/dtmax)、左室最大收缩压(LVESP)比心衰组增高,左室舒张末期压(LVEDP)比心衰组低(P均<0.05)。结论:外源性apelin-13抑制体内的AngⅡ和ADM水平可能对ADR诱导的大鼠心衰有保护作用。     

冠心病患者肾上腺髓质素前体N端20肽变化的临床研究

目的:观察不同类型冠心病与肾上腺髓质素前体N端20肽(Proadrenomedullin N Terminal 20 Peptide,PAMP)的关系。方法:选择稳定型心绞痛组(SA)14例,不稳定型心绞痛组(UA)22例,急性心肌梗死组(AMI)12例,正常对照组20例,用放免方法分别测定其外周血中PAMP含量。结果:稳定型心绞痛、不稳定型心绞痛、急性心肌梗死血浆PAMP含量分别为20．34±3．41ng/L、27．46±2．54ng/L、32．12±3．63 ng/L。不稳定型心绞痛及急性心肌梗死患者血浆中PAMP含量与正常对照组相比差别有明显统计学意义(P＜0．01);单支病变组、双支病变组、三支病变组血浆PAMP含量分别为30．54±1．98ng/L、30．54±1．98ng/L、21．80±3．54 ng/L,前两者PAMP水平较正常对照组差别有显著统计学意义(P＜0．01),PAMP水平与病变支数无明显相关性。结论:不稳定型心绞痛和急性心梗患者PAMP浓度明显升高,有助于冠心病的危险分层,对评估冠状动脉严重程度及预后可能有意义。     

肾上腺髓质素对豚鼠心室肌细胞L-型钙通道的调制

应用全细胞膜片钳技术研究了肾上腺髓质素 (ADM )对豚鼠心室肌细胞L 型钙电流 (ICa ,L)的影响及其信号传导机制。结果发现 :ADM ( 1～ 10 0nmol/L)浓度依赖性抑制ICa,L(P <0 0 5 ) ,并可被ADM特异受体阻断剂ADM2 2 52 ( 10 0nmol/L)完全阻断。用蛋白激酶A特异拮抗剂H 89( 10 μmol/L)预处理 ,对ADM抑制ICa ,L的作用无影响。但用蛋白激酶C (PKC)特异性拮抗剂PKC19 36 预处理 ,可完全阻断ADM的抑制效应 ;而PKC特异性激动剂PMA则可以模仿ADM的抑制效应 (P <0 0 5 )。上述结果提示 :ADM作用于特异性ADM受体可浓度依赖性地抑制豚鼠心室肌细胞ICa ,L,而此作用可能是PKC介导的。     

肾上腺髓质素和降钙素基因相关肽受体在血管平滑肌细胞的脱敏—受体活性修饰蛋白的作用

新近研究发现,肾上腺髓质素（adrenomedullin,ADM)和降钙素基因相关肽（calcitonin gene-related peptide,CGRP)均能与降钙素受体样受体（calcitoni receptor-like receptor,CRLR)结合,其配体特异性由受体活性修饰蛋白（receptor activity-modifying protein RAMP)调控,本工作在离体培养的大鼠胸主动脉血管平滑肌细胞（vsacular smooth muscle cells,VSMCs)上观察ADM和CGRP受体脱敏现象,以探讨CRLR／RAMP假说在心血管组织方面的意义,用无血清培养基（serum-free medium,SFM)和含有10^-8mol/L ADM,CGRP和肾上腺髓素质前体原N－末端20肽（proadrenomedullin N-terminal 20 peptide PAMP）的SFM培养,再用10^-8mol/L ADM或 CGRP和磷酸二酯酶的抑制剂异丙基次黄苷（isobutyryl methyxanthine,IBMX)与VSMCs进行第二次孵育,然后收集细胞,测定VSMCs cAMP含量。10^-8mol/LADM,CGRP和PAMP单独与VSMCs孵育,VSMCs cAMP含量分别较SFM组高191％（P＜0．01）,385％（P＜0．01）和67％（P＜0．05）,预先用10^-8mol/L ADM ak CGRP与VSMCs孵育可降低随后的CGRP刺激VSMCs产生cAMP,分别较单次CGRP育少44％（P＜0．05）和48％（P＜0．01）,预先用100nmol/L蛋白激酶A（PKA）抑制剂H－89处理VSMCs,可完全阻断ADM和CGRP预处理诱导的第二次CGRP刺激的VSMCs cAMP含量减少,表明VSMCs对CGRP的脱敏过程是通过PKA途径实现的,预先用ADM,CGRP处理VSMCs后,用ADM第二次孵育,细胞内cAMP含量与单次ADM孵育无明显改变,PKA抑制H－89与VSMCs孵育,无论对欠ADM刺激或对ADM和CGRP处理的第二次刺激的cAMP生成均无影响,用PAMP处理VSMCs后,ADM和CGRP的第二次刺激的VSMCs cAMP水平无明显改变（P＞0．05）。结果提示,在离体培养的大鼠VSMCs,ADM epc wsg i euk txgtdmj CGRP受体对预先用ADM和CGRP处理后的激动剂的第二次刺激都脱敏,表明ADM和CGRP的脱敏现象不一致。     

Changes of adrenomedullin and receptor activity modifying protein 2 (RAMP2) in myocardium and aorta in rats with isoproterenol-induced myocardial ischemia

Adrenomedullin is a potent vasodilator peptide originally isolated from a pheochromocytoma. Recently, a novel adrenomedullin receptor has been identified as a complex of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 2 (RAMP2). To explore the pathophysiological roles of adrenomedullin and its receptor component RAMP2 in ischemic cardiovascular diseases, we studied the changes of adrenomedullin and RAMP2 mRNA in myocardium and aorta in rats with isoproterenol (ISO)-induced myocardial impairment. In ISO-treated rats, heart became enlarged markedly, the ratio of heart to body weight was increased by 54% (P<0.01), and myocardial malondialdehyde content and plasma lactate dehydrogenase activity was elevated by 43% (P<0.01) and 138% (P<0.01), respectively. Immunoreactive adrenomedullin (ADM) in plasma, myocardium and aorta was augmented by 116.7% (P<0.01), 50.8% (P<0.01) and 12.5% (P>0.05), respectively. ADM mRNA in myocardium and aorta was increased by 96.8% (P<0.01) and 38.5% (P<0.01), respectively. RAMP2 mRNA in myocardium and aorta was increased by 19.6% (P<0.05) and 15.8% (P<0.01), respectively. These results suggest that the increase of ADM level and the up-regulation of ADM and RAMP2 gene in myocardium and aorta may be significant in the pathogenesis of ischemic myocardiopathy.     

The role of adrenomedullin and its receptor system in cardiovascular calcification of rat induced by Vitamin D(3) plus nicotine

Adrenomedullin (ADM) is a potent vasodilatory peptide which regulates blood pressure, cell growth and bone formation. Our work was aimed to explore the production of ADM, changes and pathophysiological significance of ADM mRNA and ADM receptor components--calcitonin receptor like receptor (CRLR) and receptor activity modifying proteins (RAMPs) mRNA in calcified myocardium and aorta of rats induced by Vitamin D3 plus nicotine. Contents of ADM in plasma, myocardium and aorta were measured by radioimmunoassay (RIA). The amount of ADM, CRLR and RAMPs mRNA was determined by semi-quantitative RT-PCR. The calcium content and alkaline phosphatase activity in myocardium and aorta of rats were measured. The results showed that the contents of calcium in calcified myocardium and aorta were increased by 3.5- and 6-fold (all P < 0.01), respectively, and alkaline phosphatases activity in calcified myocardium and aorta were increased by 66.5 and 82.7% (all P < 0.01 ), respectively, compared with control. Contents of ADM in plasma, myocardium and aorta were increased by 58% (P < 0.01), 14.3% (P < 0.01) and 27.8% P < 0.05). Furthermore, it was found that the amount of ADM, CRLR and RAMP2 mRNA in calcified myocardium was elevated by 90.6, 157.5 and 119.6% (all P < 0.01), RAMP3 mRNA was decreased by 14.1% (P < 0.01), respectively, compared with control. The amount of ADM, CRLR, RAMP2 and RAMP3 mRNA in calcified aorta was elevated by 37.7% (P < 0.01), 41.4% (P < 0.01), 60.1% (P < 0.05) and 13% P < 0.01), respectively, compared with control. The elevated level of CRLR and RAMP2 mRNA were in positive correlation with that of ADM mRNA (r = 0.992 and 0.882, respectively, P < 0.01) in calcified myocardium. The elevated level of CRLR and RAMP3 mRNA were also in positive correlation with that of ADM mRNA (r = 0.727, P < 0.05 and 0.816, P < 0.01, respectively) in calcified aorta. These results demonstrated that calcified myocardium and aorta generated an increased amount of ADM, up-regulated gene expressions of ADM, CRLR and RAMP2 mRNA. While the alteration of RAMP3 mRNA in calcified myocardium and aorta was different. These suggested that ADM and its receptor system might involve in the regulation of calcification in heart and aorta.     

Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats

Because apelin may play an important regulatory role in human cardiac dysfunction, we investigated alterations in cardiovascular content of apelin and its receptor, APJ, during hypertension and the effect of exercise training on the cardiovascular apelin/APJ system in hypertensive animals. Spontaneously hypertensive rats (SHRs) underwent swimming training consisting of 54 swimming sessions of 60 min each (6 days/week for 9 weeks). Systolic blood pressure (SBP) was verified weekly by tail-cuff plethysmography. Apelin levels in plasma and cardiovascular tissues were determined by radioimmunoassay. The level of apelin/APJ mRNA was determined by RT-PCR. SHRs showed severe hypertension and pathological cardiomegaly. The level of apelin immunoreactivity (apelin-ir) in plasma and ventricular and aortic tissues was lower, by 40%, 40% and 42% (all P<0.01), respectively, in SHRs than in control Wistar-Kyoto rats, and the mRNA level of apelin and APJ in myocardium and aorta was markedly decreased. Compared with sedentary SHRs, swimming-trained SHRs showed decreased SBP and elevated mRNA expression of apelin and APJ in cardiovascular tissues and elevated apelin-ir level in plasma, myocardium and aorta (all P<0.01). SBP and level of apelin-ir in plasma and cardiovascular tissues were negatively correlated. Long-term swimming training relieved the pathogenesis of hypertension and reversed the downregulation of the cardiovascular apelin/APJ system induced by hypertension, which suggests that the improving effect of exercise training on hypertension could be mediated by upregulating the cardiovascular apelin/APJ system.     

Role of plasma renin activity and the renal nerves in the natriuresis of L-NMMA infusion in rats

The objective of this study was to determine the effect of N(G)-monomethyl-L-arginine (L-NMMA) infusion on plasma renin activity (PRA) in the presence or absence of the renal nerves in normotensive Wistar-Kyoto (WKY) rats and Okamoto spontaneously hypertensive rats (SHR). All rats were unilaterally nephrectomized two weeks before the acute experiment. On the day of the experiment, acute renal denervation (Dnx) of the remaining kidney was performed in one group of WKY rats (Dnx-WKY; n= 10) and one group of SHRs (Dnx-SHR: n=7). The renal nerves were left intact in a group of WKY rats (Inn-WKY; n=8) and SHRs (Inn-SHR; n=9). After a control clearance period, L-NMMA was administered i.v. (15 mg/kg bolus followed by 500 microg/kg/min infusion) and another clearance period of 20 min was taken. In all experimental groups L-NMMA infusion resulted in a significant natriuresis. L-NMMA infusion increased fractional excretion of sodium (FE(Na)) to a greater extent in the Inn-SHR than in the Inn-WKY (delta FE(Na) = 5.23+/-0.87% vs delta FE(Na) = 2.87+/-0.73% respectively; P=0.05), PRA did not change in the SHR with the infusion of L-NMMA. However, in the Inn-WKY group, the natriuresis of L-NMMA infusion was associated with a tendency for lower PRA levels as compared to a group of time control Inn-WKY rats. In Dnx-WKY, the natriuresis of L-NMMA infusion (delta FE(Na) = 4.60+/-0.52%) was associated with a significantly lower level of PRA (4.26+/-1.18 ng AI/ml/hr) as compared to a group of time control Dnx-WKY rats (9.83+/-1.32 ng AI/ml/hr; P<0.05). In the Dnx-SHR, the natriuretic response to L-NMMA infusion was significantly attenuated by renal denervation (delta FE(Na) = 2.36+/-0.34%) and PRA was unchanged. In conclusion, the natriuretic effect of systemic inhibition of nitric oxide (NO) synthesis was associated with decreased PRA in the Dnx-WKY suggesting that a potential interaction exists between NO and the renal nerves in the modulation of PRA in the normotensive WKY rat. Whereas, the natriuretic effect of L-NMMA infusion in the SHR in the presence and absence of the renal nerves, were independent of changes in PRA.     

Chronic resveratrol enhances endothelium-dependent relaxation but does not alter eNOS levels in aorta of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHRs) were administered the red wine polyphenol resveratrol in drinking water at 0, 0.448, or 4.48 mg/l (control, low, or high, respectively) for 28 days. The low dosage was chosen to mimic moderate red wine consumption. After the treatment period, thoracic aorta rings were excised for in vitro assessment of vasomotor function. Chronic resveratrol significantly improved endothelium-dependent relaxation to acetylcholine (Ach), increasing maximal values to 80.8% +/- 5.2% and 80.8% +/- 5.0% in low and high groups, respectively, compared with 60.7% +/- 1.4% in controls (P<0.01). This treatment effect was eliminated in the presence of the endothelial nitric oxide synthase (eNOS) blocker N(omega)-nitro-L-arginine methyl ester. Resveratrol did not affect relaxation to sodium nitroprusside or systolic blood pressure in SHRs. In contrast to the SHR results, chronic resveratrol in Sprague Dawley rats did not affect vasomotor function in aorta rings in response to Ach. Hydrogen peroxide was reduced in the SHR thoracic aorta by a high dosage of resveratrol (P<0.05), but it was not significantly altered in other tissues tested. Thoracic aorta immunoblots revealed no significant treatment effects in SHRs on eNOS, superoxide dismutases 1 and 2, gp91phox, or Hsp90. Thus, these data provide novel evidence of improved endothelium-dependent vasorelaxation in hypertensive, but not normotensive, animals as a result of chronic resveratrol consumption mimicking dosages resulting from moderate red wine consumption. This response was not dependent on increases in eNOS expression but was dependent on improved NO bioavailability.     

Adrenomedullin protects against fructose-induced insulin resistance and myocardial hypertrophy in rats

Adrenomedullin (ADM) has been recognized as a multipotent multifunctional peptide. To explore the pathophysiological roles of ADM in insulin resistance (IR), we studied the changes in ADM mRNA level in the myocardium and vessels and the effect of ADM supplementation on rats with IR induced by fructose feeding. Rats were fed 4% fructose in drinking water for 8 weeks, and ADM was administered subcutaneously in pure water through an Alzet Mini-osmotic Pump at 300 ng/kg/h for the last 4 weeks. Compared with controls, rats with IR showed increased levels of fasting blood sugar and serum insulin, by 95% and 67%, respectively (all P < 0.01), and glycogen synthesis and glucose transport activity of the soleus decreased by 54% and 55% (all P < 0.01). mRNA level and content of brain natriuretic peptide (BNP) in myocardial were all increased significantly. Fructose-fed rats showed increased immunoreactive-ADM content in plasma by 110% and in myocardia by 55% and increased mRNA level in myocardia and vessels (all P < 0.01). ADM administration ameliorated the induced IR and myocardial hypertrophy. The glycogen synthesis and glucose transport activity of the soleus muscle increased by 41% (P < 0.01) and 32% (P < 0.05). ADM therapy attenuated myocardial and soleus lipid peroxidation injury and enhanced the antioxidant ability. Our results showed upregulation of endogenous ADM during fructose-induced IR and the protective effect of ADM on fructose-induced IR and concomitant cardiovascular hypertrophy probably by its antioxidant effect, which suggests that ADM could be an endogenous protective factor in IR.     

Sympathoadrenomedullary hyper-responsiveness to yohimbine in juvenile spontaneously hypertensive rats

We examined responses of arterial plasma levels of the sympathetic neurotransmitter, norepinephrine (NE), of the adrenomedullary hormone, epinephrine (E), and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG), after intravenous administration of the alpha-2 adrenoceptor antagonist, yohimbine, in conscious, freely-moving juvenile (4-week old) or mature (12-week old) rats with spontaneous hypertension (SHRs) and their normotensive Wistar-Kyoto (WKY) controls. Mature SHRs and WKY rats had similar levels of plasma catechols at rest, whereas juvenile SHRs had significantly higher levels of NE (400 +/- 109 (SD) vs 233 +/- 62 pg/ml), E (371 +/- 168 vs 148 +/- 67 pg/ml), and DHPG (800 +/- 147 vs 589 +/- 54 pg/ml). After yohimbine, average responses of NE in the juvenile SHRs were more than 5 times, of E more than 7 times, and of DHPG more than 11 times those of the juvenile WKY rats. The responses of plasma catechols to yohimbine were not excessive in mature 12-week old SHRs. The results demonstrate increased sympathoadrenomedullary activity at rest and markedly enhanced sympathoadrenomedullary responsiveness to yohimbine in juvenile but not mature SHRs and are consistent with the hypothesis that early in the development of hypertension in this laboratory animal model there is an abnormal dependence on central neural alpha-2 adrenoceptors as part of an incompletely successful compensatory mechanism for limiting sympathetic outflow.     

自发性高血压大鼠心肌和血管组织牛磺酸的转运障碍

在自发性高血压大鼠（SHR）的心肌和主动脉血管组织上观察牛磺酸（taurine)转运和牛磺酸转运体（taurine transporter,TAUT) mRNA 的改变,结果显示,与对照组WKY大鼠相比,SHR组血浆牛磺酸水平和牛磺酸释放量增加,而心肌和血管组织牛磺酸水平和TAUT mRNA含量均降低,牛磺酸最大转运速率（Vmax)分别低24％和35％（P＜0．05）,米氏常数（Km)值分别高16％和39％（P＜0．05）,这些结果提示,SHR的心肌和血管组织牛磺酸转运障碍可能与TAUT活性和亲和力降低及TAUT基因水平的下调有关。     

Effects of different peptide fragments derived from proadrenomedullin on gene expression of adrenomedullin gene

Primary culture of vascular smooth muscle cells (VSMC) from rat aorta was used for the study of the effect of different peptides derived from proadrenomedullin on the expression of adrenomedullin (ADM) gene. ADM and preproADM(22-41) (PAMP) secreted by VSMC were measured by radioimmunoassay, and ADM mRNA in VSMC was determined by quantitative RT-PCR. After the incubation of VSMC in 10(-7)M ADM for 24h, PAMP in the medium and ADM mRNA in the VSMC were decreased by 34 and 41.3%, respectively, and cAMP concentration in the VSMC was increased by 385%. After the incubation of VSMC in 10(-7)M PAMP for 24h, ADM in the medium and ADM mRNA in the VSMC were decreased by 12.2 and 39.1%, respectively, and cAMP concentration in the VSMC was increased by 67%. The decreased ADM mRNA in VSMC induced by the ADM and PAMP treatment was completely reversed by the pre-treatment of the cells in 10(-7)M protein kinase inhibitor for 30 min. After the incubation of VSMC in 10(-7)M preproADM(153-185) (ADT) for 24h, however, ADM in the medium and ADM mRNA in the VSMC were increased by 21 and 35.2%. The increased ADM mRNA in VSMC induced by the ADT treatment was partially blocked by the co-incubation in ADM and ADT, and was totally blocked by the co-incubation in PAMP+ADM and ADT, but was not blocked by the co-incubation in PAMP and ADT. Our results suggest that the four peptides derived from proadrenomedullin may have different effects, possibly through a cAMP-dependent pathway, on the expression of ADM gene.