下丘脑腹内侧核损毁对大鼠nesfatin-1/NUCB2表达的影响

目的:观察下丘脑腹内侧核(VMH)损毁对大鼠脂肪组织nesfatin-1/NUCB2表达的影响及其机制。方法:电损毁VMH,观察大鼠体重和脂肪组织变化,采用Western blot检测脂肪组织中nesfatin-1/NUCB2表达改变。腹腔注射6-羟多巴胺(50 mg/kg)以阻断交感神经;持续外周注射卡巴胆碱(180μg/kg)用以模拟VMH损毁,观察其对大鼠皮下脂肪nesfatin-1/NUCB2表达的影响。结果:与对照组和假手术组比较,VMH损毁后大鼠体重明显增加(P0.05),皮下脂肪(P0.05)和肠系膜脂肪(P0.05)也显著增多;Western blot分析结果显示,nesfatin-1/NUCB2在胰腺和肝脏中表达较多,但皮下、肠系膜脂肪和肩胛间棕色脂肪组织(i BAT)中表达较少,骨骼肌(腓肠肌)中鲜有表达;与对照组和假手术组比较,VMH损毁组大鼠nesfatin-1/NUCB2在肝脏、胰腺、骨骼肌和i BAT中表达无显著差异(P0.05),皮下脂肪(P0.05)和肠系膜脂肪(P0.05)nesfatin-1/NUCB2表达显著增多与对照组相比,6-羟多巴胺组nesfatin-1/NUCB2表达显著升高(t=3.43,P0.05),而卡巴胆碱组nesfatin-1/NUCB2表达无显著差异(t=0.37,P=0.72)。结论:VMH损毁后大鼠脂肪组织nesfatin-1/NUCB2表达改变可能通过抑制交感神经活动介导。     

Ghrelin对心肌梗死后心肌重塑及心脏功能的影响及其机制研究

目的:观察ghrelin对心肌梗死(MI)大鼠心肌重塑和心脏功能的影响,并探讨其可能的机制。方法:应用冠状动脉结扎术创建大鼠MI模型,并设立假手术组作为对照;造模成功后每天2次注射ghrelin(100μg/kg),持续4周,以此作为MI-ghrelin组,并以每天注射生理盐水的MI大鼠作为MI-生理盐水组。检测和比较各组大鼠左心室重塑和血流动力学的改变情况;非梗死心肌中白介素(IL)-1β、肿瘤坏死因子-α(TNF-α)、基质金属蛋白酶(MMP)-2、MMP-9 mRNA和蛋白的表达;梗死边界心肌细胞的凋亡情况。结果:Ghrelin可使心肌梗死后的MI大鼠降低的缩短分数(FS)、左室内压最大变化率均显著下降(dP/dtmax)、疤痕厚度明显升高,增加左室舒张末压(LVEDP)、左室收缩末内径(LVESD)、左室舒张末期内径(LVEDD)、梗死边界心肌细胞的凋亡指数显著降低。此外,ghrelin可抑制心肌梗死后的MI大鼠非梗死心肌中白介素(IL)-1β、肿瘤坏死因子-α(TNF-α)、质金属蛋白酶(MMP)-2和MMP-9的mRNA和蛋白的表达。结论:Ghrelin可缓解MI后大鼠LV功能紊乱及心室重塑,这可能与其抑制炎症反应及基质金属蛋白酶的表达有关。     

慢性充血性心力衰竭大鼠模型的建立

目的:探讨建立慢性充血性心力衰竭大鼠模型的方法。方法:采用腹主动脉缩窄法制备CHF大鼠模型。于右肾动脉分支处上方缩窄腹主动脉至0.6mm,同时设立假手术组及正常对照组。12周后行一般情况观察,超声心动图及血液动力学检测心脏结构和功能、计算心脏肥厚指数,HE及Masson染色检测心肌病理改变,综合评价CHF大鼠心功能。结果:与假手术及正常对照组比较,CHF模型组术后12周均出现进食减少、精神萎靡、少动、被毛无光;IVS、LVPW、LVM、LVEDD、LVESD、SV显著增加,EF、FS显著降低;HR显著增加;VSP、+dP/dtmax显著降低,T-dP/dtmax显著延长;LVEDP显著升高,-dP/dtmax绝对值显著降低;心脏湿重及心脏肥厚指数均增加;病理结果表明CHF模型组心肌细胞肥大、排列紊乱、心肌胶原纤维增多。结论:应用腹主动脉缩窄术可成功制备CHF大鼠模型。     

Ghrelin治疗脑出血大鼠脑水肿及MMP-9表达的影响

目的:研究Ghrelin对大鼠脑出血后脑水肿及脑组织中基质金属蛋白酶-9(MMP-9)表达的影响。方法:选取雄性SD大鼠80只,随机分为对照组(NC组)20只、假手术组(SHAM组)20只、脑出血组(ICH组)20只、Ghrelin治疗组(Ghrelin组)20只。利用自体动脉血注入法建立大鼠脑出血模型;Ghrelin组于建立脑出血模型后经股静脉注射Ghrelin 10 nmol/Kg·d。分别于12 h、24 h、3d、5 d、7 d时间点根据Berderson评分法评估各组大鼠神经系统功能;利用干湿重法测定各组大鼠脑组织含水量;利用蛋白质免疫印迹法(WB)检测脑组织中MMP-9表达情况。结果:在12 h、24 h、3 d、5 d、7 d,ICH组、Ghrelin组大鼠Berderson评分及脑组织含水量高于NC组、SHAM组(P0.05);在5 d、7 d,ICH组大鼠Berderson评分及脑组织含水量高于Ghrelin组(P0.05)。WB结果表明在12 h、24 h、3 d、5 d、7 d,ICH组大鼠脑组织中MMP-9的表达均高于NC组、SHAM组(P0.05);Ghrelin组MMP-9的表达在12 h、24 h、3 d高于NC组、SHAM组(P0.05),在5 d、7 d,与NC组、SHAM组无明显差异(P0.05);在5 d、7 d,ICH组MMP-9表达高于Ghrelin组(P0.05)。结论:在本研究中,Ghrelin可以在5 d后降低脑出血大鼠脑组织中MMP-9的表达程度,从而减轻脑水肿,改善脑出血大鼠神经功能。     

慢性心力衰竭大鼠主动脉舒缩功能的变化及其机制

为探讨心力衰竭诱导的血管舒缩功能紊乱的相关机制,本实验对心梗后大鼠慢性心力衰竭(chronic heart failure,CHF)模型胸主动脉血管环的舒缩功能变化及可能的病理学机制进行了研究。将Sprague-Dawley大鼠随机分为两组:假手术(sham)组和慢性心衰(CHF)组。通过冠脉结扎法制作大鼠CHF模型。手术10周后,检测大鼠血流动力学指标及相关参数,之后迅速取出心脏并称重,TTC染色法检测心梗面积。制备大鼠胸主动脉环,利用敏感的肌张力描记技术,比较sham组和CHF组胸主动脉环的舒缩功能,观察血管环对KCl、CaCl2、苯肾上腺素(phenyle phrine,PE)和咖啡因(caffeine)的收缩反应以及对乙酰胆碱(acetylcholine,ACh)的舒张反应。并进一步研究一氧化氮合酶(nitricoxide synthase,NOS)抑制剂N-硝基-L-精氨酸甲酯(N-nitrl-L-arginine methylester,L-NAME)和非选择性环氧合酶(cyclooxy genase,COX)抑制剂吲哚美辛(indomethacin,Indo)对两组胸主动脉环ACh的反应曲线的影响。结果显示:(1)与sham组相比,CHF组大鼠胸主动脉环对血管收缩剂KCl(5～100mmol/L)和PE(1×10-8～3×10-4mol/L)的反应性明显提高,对血管舒张剂ACh(1×10-12～1×10-4mol/L)的反应性显著性降低(P0.01,P0.05);(2)L-NAME(1mmol/L)预处理后,CHF组血管对ACh(1×10-7～1×10-4mol/L)介导的内皮依赖性收缩明显增强(P0.05),加入Indo(10μmol/L)后该现象消失;(3)与Indo未处理组相比,Indo(10μmol/L)预处理后,CHF组血管对ACh(1×10-12～1×10-4mol/L)介导的舒张反应明显增强(P0.05);(4)在无钙K-H液中,与sham组相比,CHF组血管对CaCl2(1×10-4～3×10-2mol/L)介导的钙依赖性收缩曲线明显左移(P0.05);caffeine(30mmol/L)诱导的血管收缩未见显著性变化。以上结果表明,CHF大鼠的胸主动脉血管环收缩异常与内皮功能障碍有关,其机制可能是通过血管内皮细胞COX途径提高内皮收缩因子,和(或)通过电压依赖性钙通道增加外钙流入引起血管收缩性能提高。     

慢性充血性心力衰竭大鼠模型的建立

目的：探讨建立慢性充血性心力衰竭大鼠模型的方法。方法：采用腹主动脉缩窄法制备CHF大鼠模型。于右肾动脉分支处上方缩窄腹主动脉至0.6mm,同时设立假手术组及正常对照组。12周后行一般情况观察,超声心动图及血液动力学检测心脏结构和功能、计算心脏肥厚指数,HE及Masson染色检测心肌病理改变,综合评价CHF大鼠心功能。结果：与假手术及正常对照组比较,CHF模型组术后12周均出现进食减少、精神萎靡、少动、被毛无光;IVS、LVPW、LVM、LVEDD、LVESD、SV显著增加,EF、FS显著降低;HR显著增加;VSP、＋dP/dtmax显著降低,T-dP/dtmax显著延长;LVEDP显著升高,-dP/dtmax绝对值显著降低;心脏湿重及心脏肥厚指数均增加;病理结果表明CHF模型组心肌细胞肥大、排列紊乱、心肌胶原纤维增多。结论：应用腹主动脉缩窄术可成功制备CHF大鼠模型。     

心房钠尿肽通过上调OPA1表达抑制心衰小鼠心肌线粒体分裂并改善心脏功能

目的:探讨心房钠尿肽(Atrial natriuretic peptide,ANP)对后负荷增加引起的心脏功能下降的保护作用及其机制。方法:选择雄性C57小鼠30只,将其随机分为假手术组(sham)、主动脉弓结扎(Transverse aortic constriction,TAC)手术组和主动脉弓结扎手术ANP干预组(TAC+ANP)。ANP通过皮下注射4周,随后超声检测心脏功能、四腔心切片观察心肌重构,电镜观察心肌线粒体的形态与数量,Western-Blot检测心肌组织中融合分裂相关分子的表达。结果:同sham组相比,TAC组射血分数(Ejection fraction,EF)降低,且左室舒张末内径(End-diastolic left ventricular internal diameter,LVIDd)、左室舒张期后壁厚度(End-diastolic left ventricular posterior wall thickness,LVPWd)、左室质量(LV mass)、心肌质量/胫骨长度(Heart weight/tibial length,HW/TL)显著增加(P0.05),线粒体面积减小伴数量增加(P0.05),且线粒体融合相关蛋白OPA1表达量下降(P0.05)。同TAC组相比,TAC+ANP组EF显著增加,且LVIDd、LV mass、HW/TL均显著下降(P0.05),线粒体面积增加伴数量减少(P0.05),且线粒体融合相关蛋白OPA1表达量上调(P0.05)。在离体培养的心肌细胞中,给予ANP处理可减轻H_2O_2诱导的OPA1表达下降,给与ANP竞争性多肽抑制剂anantin后该作用消失。结论:ANP通过上调OPA1的表达抑制线粒体分裂改善后负荷增加导致的心脏功能下降。     

糖尿病大鼠ghrelin和nesfatin-1表达动力学及其调控

目的:探讨STZ诱导糖尿病大鼠ghrelin和nesfatin-1动力学及分泌调节变化。方法:STZ诱导糖尿病大鼠模型;采用葡糖糖脱氢酶分析法测量血浆葡萄糖水平;免疫放射分析检测血浆ghrelin、nesfatin-1、胰岛素、胰岛素样生长因子1(IGF-1)、生长激素(GH)含量;采用real-time PCR检测ghrelin m RNA水平变化;免疫组化观察ghrelin和nesfatin-1免疫活性细胞数量。结果:糖尿病大鼠体重显著降低(t=23.16,P<0.01),血糖水平显著升高(t=22.55,P<0.01),血浆胰岛素和IGF-1水平显著降低(t=6.50,t=24.13,P<0.01),但GH水平显著升高(t=3.30,P<0.05)。糖尿病大鼠血浆总ghrelin(t=7.03,P<0.01)和活性ghrelin(t=3.33,P<0.05)水平均显著升高,血浆nesfatin-1水平则显著降低(t=6.24,P<0.01);糖尿病大鼠血浆总ghrelin与GH(r=0.81,P<0.01)和IGF-1水平(r=-0.58,P<0.01)呈显著相关性;与对照组大鼠相比,糖尿病大鼠胃总ghrelin(t=16.86,P<0.01)和活性ghrelin(t=3.30,P<0.05)水平均显著降低;而胃nesfatin-1(t=7.93,P<0.01)水平则显著升高。胃总ghrelin水平与血浆IGF-1水平呈明显相关性(r=0.65,P<0.01);与对照组大鼠相比,糖尿病大鼠胃ghrelin m RNA表达水平显著升高(t=16.8,P<0.01),胃底ghrelin免疫活性细胞数量显著减少(t=3.98,P<0.01);实验中给予大鼠自由饮食,糖尿病大鼠血浆总ghrelin水平显著增加(t=7.53,P<0.01),nesfatin-1水平显著降低(t=5.46,P<0.01)。糖尿病大鼠注射胰岛素后,可使增加的ghrelin水平(t=1.76,P=0.11)和降低的nesfatin-1水平接近正常(t=1.96,P=0.06);且胰岛素可显著反转糖尿病大鼠胃总ghrelin(t=8.54,P<0.01)和nesfatin-1水平(t=2.42,P<0.05);以及注射胰岛素后,糖尿病大鼠胃底ghrelin细胞显著增加,nesfatin-1细胞明显减少(t=3.21,t=2.59,P<0.05)。结论:Ghrelin或nesfatin-1参与糖尿病大鼠能量平衡调控。     

蜂胶总黄酮对慢性心力衰竭大鼠心肌细胞凋亡的影响及其机制

目的:探讨蜂胶总黄酮(TFP)对慢性心力衰竭大鼠心肌细胞凋亡的影响及其可能机制。方法:随机选取6只雄性SD大鼠为正常对照(NC)组;余下大鼠采用腹腔注射阿霉素造模,将造模成功的大鼠随机分成5组(n=6):慢性心力衰竭模型(CHF)组、蜂胶总黄酮低剂量(LD)组、蜂胶总黄酮中剂量(MD)组、蜂胶总黄酮高剂量(HD)组和地高辛(DIG)组。6周后通过生物信号系统记录大鼠血流动力学相关指标;检测各组大鼠血浆中脑钠肽(BNP)、心肌肌钙蛋白I(c Tn I)、肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)含量;取材后HE和Masson染色观察心脏结构改变及胶原纤维增生情况;Western blot检测缝隙连接蛋白43(P-Cx43)表达水平;TUNEL法检测心肌细胞凋亡。结果:与NC组相比,CHF组大鼠心脏血流动力学指标左室峰压(LVSP)及左室内压变化速率(±d P/dtmax)绝对值明显下降(P0.01),左室舒张期末压(LVEDP)明显升高(P0.01);血浆中BNP、c Tn I、TNF-α及IL-6含量均明显升高(P0.01);与CHF组相比,MD、HD组大鼠心脏血流动力学指标LVSP和±d P/dtmax绝对值明显升高(P0.05),LVEDP明显降低(P0.01),LD组LVEDP明显降低(P0.01),LVSP和±d P/dtmax变化均不明显。MD、HD组大鼠血清中BNP、c Tn I、TNF-α及IL-6含量明显降低(P0.01),LD组各指标变化不明显;Western blot结果显示:与NC组相比,CHF组P-Cx43条带明显增粗,给予TFP灌胃后,随着TFP剂量的增加,TFP各组PCx43条带逐渐变细变淡;进一步半定量分析显示,与NC组相比,各组中P-Cx43表达量显著升高(P0.01);与CHF组相比,TFP各组P-Cx43表达量均降低;MD组P-Cx43表达量低于LD组(P0.01),高于HD组(P0.05);CHF组心肌细胞凋亡指数(%)(22.61±3.39)较NC组(1.12±0.24)明显增高(P0.01);与CHF组相比,蜂胶总黄酮LD、MD、HD组心肌细胞凋亡指数(%)分别为(15.79±2.80)、(9.28±2.10)、(4.73±1.14)均明显低于CHF组(P0.01);大鼠心肌组织P-Cx43表达水平与心肌细胞凋亡指数呈显著正相关(P0.01)。结论:蜂胶总黄酮呈剂量依赖性对阿霉素诱导的大鼠慢性心力衰竭心肌细胞凋亡具有抑制作用,其机制可能与Cx43表达调控特别是磷酸化状态的调控密切相关。     

碱性成纤维生长因子转染骨髓间充质干细胞移植对心肌病心力衰竭大鼠心功能的影响

目的探讨碱性成纤维生长因子(bFGF)转染的骨髓间充质干细胞(BMSCs)移植对心肌病心力衰竭大鼠心功能的影响。方法通过腹腔注射阿霉素建立心肌病心力衰竭SD大鼠模型,存活33只大鼠随机分成3组:模型组、BMSCs组和BMSCs+bFGF组,每组11只。另设正常对照组(n=8)。取体外培养的第三代SD大鼠BMSCs,质粒-bFGF转染BMSCs,BrdU标记后,分别将BMSCs(3×10~6个)、bFGF转染的BMSCs(3×10~6个)或等体积培养基通过尾静脉注射的方法进行移植。用生物信号采集系统检测大鼠心功能,大鼠心脏切片行免疫组化了解移植细胞在受体心脏的存活情况,实时荧光定量PCR和Western Blotting检测心室组织bFGF的表达水平。多组间比较采用单因素方差分析或精确概率法。结果 BMSCs移植4周后,正常对照组大鼠的心功能指标LVSP(121.13±12.28)mmHg,LVDEP(3.86±1.25)mmHg,LV+d P/dt(3671.25±172.50)mmHg/s和LV-d P/dt(3221.63±259.57)mmHg/s;模型组心功能指标LVSP(81.29±12.39)mmHg,LVDEP(16.43±4.12)mmHg,LV+d P/dt(2344.29±98.63)mmHg/s和LV-d P/dt(2244.29±103.10)mmHg/s;BMSCs组心功能指标LVSP(97.00±6.39)mmHg,LVDEP(12.00±2.73)mmHg,LV+d P/dt(2876.25±118.31)mmHg/s和LV-d P/dt(2726.25±303.23)mmHg/s;BMSCs+bFGF组心功能指标LVSP(109.38±12.78)mmHg,LVDEP(9.25±1.67)mmHg,LV+d P/dt(3037.50±161.22)mmHg/s和LV-d P/dt(3000.13±149.77)mmHg/s,移植组各指标均有改善,比较差异有统计学意义(F=17.29、36.61、111.11、26.54,P均0.01)。免疫组织化学检查示细胞移植组大鼠的心室组织切片上可见Brd U阳性细胞存在。模型组大鼠心室心肌组织bFGF mRNA表达水平高于正常对照组(1.28±0.06 vs 1.00±0.00,t=10.46,P0.01),BMSCs组高于模型组(1.37±0.05 vs 1.28±0.06,t=3.39,P0.01),而BMSCs+bFGF组高于BMSCs组(1.44±0.03 vs 1.37±0.05,t=2.86,P=0.01)。Western Blotting示,正常对照组大鼠心室组织bFGF蛋白表达最低,模型组高于正常对照组(1.31±0.09 vs 1.00±0.00,t=5.48,P=0.01),BMSCs组高于模型组(1.46±0.05 vs 1.31±0.09,t=2.68,P=0.03),而BMSCs+bFGF组高于BMSCs组(1.84±0.09 vs 1.46±0.05,t=6.79,P0.01)。结论转染bFGF基因的BMSCs移植可提高阿霉素所致心肌病心力衰竭大鼠心脏的bFGF水平,改善大鼠心功能,其效果优于单纯BMSCs移植。     

Ghrelin对心肌梗死大鼠恶性心律失常和早期左室重构的影响(英文)

目的:本文主要研究ghrelin对心肌梗死大鼠恶性心律失常和早期左室重构的影响。方法:心肌梗死大鼠模型每天两次注射ghrelin(100μg/kg)或生理盐水。通过超声心动图评估大鼠的心脏重量并且观察大鼠的血流动力学。使用酶免疫分析法测定血清胰岛素生长因子I(IGF-1)、血浆肾上腺素、去甲肾上腺素和多巴胺的浓度。注射药物前后分析大鼠的神经功能。结果:与对照组相比,ghrelin治疗的心肌梗死模型大鼠生存率显著增加(P0.05),心脏功能增强,但心肌梗死面积差异不大(P0.05)。结论:Ghrelin能够提高心肌梗死模型大鼠的生存率、缓解心肌梗死大鼠心率失常、改善心肌梗死大鼠左心室重构。     

GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure

Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 mug/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.     

Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model

Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10–16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output.

Methods

Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a rat model of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics.

Results

Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p<0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9±0.07 for BIM-28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76±0.07 for BIM-28131, 0.68±0.12 for BIM-28125, and 0.48±0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment.

Conclusion

Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM-131) being the most effective compound.     

Ghrelin improves disturbed myocardial energy metabolism in rats with heart failure induced by isoproterenol

To explore the effects of ghrelin on disturbed myocardial energy metabolism during chronic heart failure (CHF). Rats were subcutaneously injected with isoproterenol (ISO) for 10 days with or without ghrelin for another 10 days. Enzyme immunoassay was to measure ghrelin concentrations. Compared with the control group, ISO‐treated rats showed suppressed cardiac function with high ghrelin/GHS‐R expressions. These rats also showed the decreases in food consumption and weight. The decreased levels of plasma glucose and myocardial glucogen, but the high lactate in blood and myocardium showed myocardial metabolic disturbance. Compared with the group given ISO alone, the rats with ghrelin (20 and 100 µg/kg/day) improved cardiac dysfunction and increased food intake by 13.5 and 14.2% (both P < 0.01), and rate of weight gain by 95% (P < 0.05) and 1.71‐fold (P < 0.01), respectively. The plasma glucose were increased by 49.7 and 50.8% (both P < 0.01), and myocardial glucogen, by 40.5 and 51.7% (both P < 0.01), but blood lactate decreased by 1.56‐ and 1.96‐fold (both P < 0.01), and myocardial lactate by 32.1 and 48.7% (both P < 0.05), respectively. Their MCT1 mRNA and protein expressions increased. The myocardial ghrelin/GHS‐R pathway can be upregulated during CHF. The ghrelin can attenuate cardiac dysfunction and energy metabolic disturbance in CHF rats. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats

Ghrelin is a novel growth hormone (GH)-releasing peptide which was isolated from the stomach. We have reported that ghrelin causes vasorelaxation in rats through GH-independent mechanisms. We investigated whether ghrelin improves endothelial dysfunction. Ghrelin was subcutaneously administered to GH-deficient rats for three weeks. After isolation of the thoracic aorta, aortic ring tension was measured to evaluate vasorelaxation. Acetylcholine-induced vasorelaxation was impaired in GH-deficient rats given placebo compared to that in normal rats given placebo. GH-deficient rats treated with ghrelin, however, showed a significant increase in the maximal relaxation as compared with those given placebo. This improvement by ghrelin was inhibited by N(G)-nitro-L-arginine methyl ester, a nonselective nitric oxide synthase (NOS) inhibitor. Western blot analysis demonstrated that treatment with ghrelin increased endothelial NOS (eNOS) expression in the aorta of GH-deficient rats. These results suggest that administration of ghrelin improves endothelial dysfunction and increases eNOS expression in rats through GH-independent mechanisms.     

Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction

A recent study suggests that exogenous ghrelin administration might decrease renal sympathetic nerve activity in conscious rabbits. In the present study, we investigated whether ghrelin administration would attenuate left ventricular (LV) remodeling following myocardial infarction (MI) via the suppression of cardiac sympathetic activity. Ghrelin (100 microg/kg sc, twice daily, n = 15) or saline (n = 15) were administered for 2 wk from the day after MI operation in Sprague-Dawley rats. The effects of ghrelin on cardiac remodeling were evaluated by echocardiographic, hemodynamic, histopathological, and gene analysis. In addition, before and after ghrelin (100 microg/kg sc, n = 6) was administered in conscious rats with MI, the autonomic nervous function was investigated by power spectral analysis obtained by a telemetry system. In ghrelin-treated rats, LV enlargement induced by MI was significantly attenuated compared with saline-treated rats. In addition, there was a substantial decrease in LV end-diastolic pressure and increases in the peak rate of the rise and fall of LV pressure in ghrelin-treated MI rats compared with saline-treated MI rats. Furthermore, ghrelin attenuated an increase in morphometrical collagen volume fraction in the noninfarct region, which was accompanied by the suppression of collagen I and III mRNA levels. Importantly, a 2-wk administration of ghrelin dramatically suppressed the MI-induced increase in heart rate and plasma norepinephrine concentration to the similar levels as in sham-operated controls. Moreover, acute administration of ghrelin to MI rats decreased the ratio of the low-to-high frequency spectra of heart rate variability (P < 0.01). In conclusion, these data suggest the potential usefulness of ghrelin as a new cardioprotective hormone early after MI.     

Ghrelin,a novel growth hormone-releasing peptide,in the treatment of chronic heart failure

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for growth-hormone secretagogues receptor (GHS-R). This peptide also causes a positive energy balance by stimulating food intake and inducing adiposity through growth hormone-independent mechanisms. In addition, ghrelin has some cardiovascular effects, as indicated by the presence of its receptor in blood vessels and the cardiac ventricles. In vitro, ghrelin inhibits apoptosis of cardiomyocytes and endothelial cells. In humans, infusion of ghrelin decreases systemic vascular resistance and increases cardiac output in patients with heart failure. Repeated administration of ghrelin improves cardiac structure and function and attenuates the development of cardiac cachexia in rats with heart failure. These results suggest that ghrelin has cardiovascular effects and regulates energy metabolism through GH-dependent and -independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of severe chronic heart failure (CHF).     

Hemodynamic and hormonal effects of human ghrelin in healthy volunteers

To investigate hemodynamic and hormonal effects of ghrelin, a novel growth hormone (GH)-releasing peptide, we gave six healthy men an intravenous bolus of human ghrelin (10 microg/kg) or placebo and vice versa 1-2 wk apart in a randomized fashion. Ghrelin elicited a marked increase in circulating GH (15-fold). The elevation of GH lasted longer than 60 min after the bolus injection. Injection of ghrelin significantly decreased mean arterial pressure (-12 mmHg, P < 0.05) without a significant change in heart rate (-4 beats/min, P = 0.39). Ghrelin significantly increased cardiac index (+16%, P < 0.05) and stroke volume index (+22%, P < 0.05). We also examined ghrelin receptor [GH secretagogues receptor (GHS-R)] gene expression in the aortas, the left ventricles, and the left atria of rats by RT-PCR. GHS-R mRNA was detectable in the rat aortas, left ventricles, and left atria, suggesting that ghrelin may cause cardiovascular effects through GH-independent mechanisms. In summary, human ghrelin elicited a potent, long-lasting GH release and had beneficial hemodynamic effects via reducing cardiac afterload and increasing cardiac output without an increase in heart rate.     

Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

Calcineurin has recently been implicated as a mediator in the signaling pathways that transform intracellular calcium signals to the phenotype of myocardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertrophy and remodeling during congestive heart failure (CHF) in rats. After ligation of the left coronary artery, rats were randomized to treatment with CsA or vehicle for 14 days. Compared with vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF rats as assessed by alterations in ventricular weight-to-tibial length ratios (P < 0.05). Myocardial gene expression of skeletal alpha-actin was also reduced in the failing left ventricle (LV) after treatment with CsA (P < 0. 05), although the mRNA levels were still substantially elevated relative to those of sham rats. CsA-induced inhibition of compensatory myocardial hypertrophy in the CHF rats led to increased dilatation of the LV cavity and reduced fractional shortening and peak positive and negative first derivatives of LV pressure (P < 0. 05). Plasma renin and endothelin-1 levels were increased in the CHF-CsA rats, providing humoral cues of aggravated cardiac function. Thus this study supports a crucial role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhibition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.