Hexarelin对心脏功能调节的研究进展

生长素释放肽(GHRP)是一种人工合成的促使垂体生长素的释放的促分泌肽类物质,对心脏有与生长素类似的作用。它对于心脏的作用主要是通过存在于心脏的一种特殊的受体介导的,而且与其促生长素释放的作用无关。海沙瑞林(Hexarelin)是一种高度稳定的GHRP修饰物。近些年的国内外实验研究表明Hexarelin对心脏具有较为全面的保护和调控作用;可以有效的减少心肌细胞Ca2+的转运并调控收缩耦联过程,增强心肌细胞对Ca2+的调控作用;可以控制血管高反应性,对心肌缺血损伤有相应的的保护作用;Hexarelin可以促进心肌细胞损伤后的修复,而且具有抑制心肌细胞凋亡作用;Hexarelin能有效的升高每搏输出量、增加心脏收缩能力和心脏指数,延缓心脏恶病质的进程发展,体现了对心脏的正性肌力作用。本文综述了Hexarelin对心脏作用的研究进展及在临床心血管疾病的治疗上的良好应用前景。     

生长素释放肽的发现、发展及展望

生长素释放肽（Growth hormone-releasing peptides,GHRP)于70年代末、80年代初依据蛋氨酸－亮氨酸脑啡肽（met-enkephalin）的结构首次合成。以后又合成了数种类型的GHRP，其结构已远不同于met-enkephalin的结构。但均可强烈刺激生长素（growth hormone,GH）分泌。由于1982年下丘脑生长素释放激素的发现，GHRP研究在80年代进展不大。在90年代，由于制药界的努力和驱动，GHRP研究进展较快，非肽类生长素释放刺激剂（non-peptide GH secretagogues）于1994年首次合成，第一个GHRP受体也于1996年首次克隆成功。1999年从胃内分泌细胞首次发现可能的内源性GHRP,命名为ghrelin。Glrelin可激动GHRP受体并刺激GH分泌。最近几年，GHRP对生长素轴以外的外周组织的作用有诸多报道。GHRP的这些外周作用包括对心血管功能、摄食、脂肪细胞分化、胃酸分泌和胃肠运动的调节等。     

胰高血糖素样肽-1及其类似物对心血管系统的影响

心血管病变是糖尿病常见的并发症,胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)作为一种肠促胰素,不仅具有葡萄糖浓度依赖性降糖作用、促进胰腺β细胞增生和修复、改善胰岛素抵抗,而且还可减轻体质量、调节脂质代谢、改善心血管危险因素。研究表明GLP-1可直接作用于血管内皮细胞和心肌细胞,对心血管系统可能具有保护效应。     

生长激素释放肽对心力衰竭大鼠血清和心肌组织中脂联素的影响

目的研究生长素释放肽(GHRP)对脂联素(APN)的影响,探讨GHRP在慢性充血性心力衰竭(CHF)发生、发展中的作用,以期为临床更好地防治CHF提供理论依据。方法采用腹腔注射阿霉素(Adriamycin,ADR)方法建立大鼠CHF模型,采用酶联免疫吸附剂测定(ELISA)检测大鼠血清和心肌组织匀浆中APN含量的变化。结果各组间血清和心肌组织匀浆中APN的含量比较结果显示:模型组APN明显低于对照组和治疗组(P<0.05);治疗组APN比对照组轻度降低,但无明显差异(P>0.05)。结论APN在CHF发生过程中有着重要作用,GHRP具有保护和改善CHF大鼠心功能的作用。     

生长激素释放肽对心衰大鼠植物神经重构的影响

本研究观察了生长激素释放肽(GHRP)的应用对心衰动物胆碱能神经和肾上腺素能神经支配的影响。Wistar大鼠50只,随机分为:假手术组10只;GHRP组30只;模型组10只。心衰模型成功后4周,Karnovsky-Roots法及免疫组织化学方法分别显示心肌胆碱能神经纤维及肾上腺素能免疫阳性纤维,应用多功能真彩色病理图像分析系统分析两种神经纤维密度。结果显示,模型组大鼠心肌中胆碱能神经纤维和肾上腺素能神经纤维密度明显低于假手术组(P<0.01);GHRP组大鼠心肌中两种神经纤维密度较模型组明显增高(P<0.01),但略低于假手术组神经纤维密度(P<0.05)。上述研究表明GHRP可延缓大鼠心衰后的去神经支配,改善神经重构。     

短篇综述Ghrelin对心衰恶液质的治疗作用

生长素(Ghrelin)能促进生长激素的释放,舒张血管和降低血压以改善心脏功能,刺激食欲、增加体质量并参与糖和脂肪代谢的调节。Ghrelin通过改善血管内皮功能、抑制炎性细胞因子、抑制心肌肥厚以防止心脏构型重建。作为一种内源性的心脏保护物质,Ghrelin能通过多种机制改善心衰心脏功能、引起正向能量平衡,以延缓心脏恶液质的发生发展。其逆转和拮抗代谢重构的有益作用,是心衰恶液质治疗的一条新途经。作为一种监测指标,Ghrelin可对其病情严重程度和预后进行评估。     

降钙素基因相关肽对高脂复合缺氧/复氧诱导乳鼠心肌细胞凋亡的影响

背景:前期研究表明,结扎冠状动脉可诱发大鼠传入神经纤维末梢逆向释放降钙素基因相关肽,提示降钙素基因相关肽参与了急性心肌缺血的病理生理过程。目的:观察降钙素基因相关肽对氧化低密度脂蛋白孵育缺氧/复氧诱导的乳鼠心肌细胞凋亡的影响。方法:20孔原代培养的乳鼠心肌细胞随机分为5组:正常对照组、氧化低密度脂蛋白组、氧化低密度脂蛋白+缺氧/复氧组、降钙素基因相关肽组和CGRP8-37组。后4组均用氧化低密度脂蛋白孵育24 h,再建立心肌细胞缺氧/复氧模型;降钙素基因相关肽组在缺氧/复氧前30 min加入10-8 mol/L降钙素基因相关肽,CGRP8-37组在给予降钙素基因相关肽前30 min加入10-7 mol/L的降钙素基因相关肽1受体的竞争性拮抗剂CGRP8-37。采用流式细胞仪检测心肌细胞凋亡率并测定caspase-3活性。结果与结论:降钙素基因相关肽能明显抑制氧化低密度脂蛋白和缺氧/复氧处理的乳鼠心肌细胞caspase-3的激活,从而阻止凋亡的发生,并且该作用能被降钙素基因相关肽1受体的竞争性拮抗剂CGRP8-37部分逆转,说明降钙素基因相关肽通过与降钙素基因相关肽1受体结合产生抗凋亡效应,进而抑制心肌细胞凋亡,对氧化低密度脂蛋白孵育乳鼠心肌细胞的缺氧/复氧损伤具有保护作用。     

促甲状腺素释放激素增强失血性休克大鼠心脏受体功能及其机理

本文用失血性休克大鼠离体左房观察了促甲状腺素释放激素（ｔｈｙｒｏｔｒｏｐｉｎｒｅｌｅｎｓｉｎｇｈｏｒ－ｍｏｒｅ，ＴＲＨ）对肾上腺素能和多巴胺受体激动剂正性肌力作用的影响，用全细胞记录式膜片钳制技术研究了ＴＲＨ对豚鼠单一心肌细胞慢钙内流的作用及对肾上腺素能和多巴胺受体激动剂促钙内流作用的影响。结果显示，ＴＲＨ本身对失血性休克大鼠离体左房仅有轻微的正性肌力作用，但却可增强异丙肾上腺素和多巴胺的正性肌力作用，但不增强苯肾上腺素的正性肌力作用。表明ＴＲＨ对休克大鼠心脏β－肾上腺素能和多巴胺受体具有一定的增敏作用。ＴＲＨ可延长豚鼠单一心肌细胞的钙通道开放时间，增强异丙肾上腺素和多巴胺的促钙内流作用，这可能是ＴＲＨ增敏心脏β和ＤＡ受体，增加其受体激动剂正性肌力作用的重要原因。     

大鼠隔核中肽能神经元的分布与形态测量

用免疫组织化学方法研究了大鼠隔核各亚核中降钙素基因相关肽，血管活性肠肽，生长抑素，神经降压肽，促皮质释放因子，Ｐ物质，亮氨酸－脑腓肽，黄体生成素释放因子，甘丙肽，胆囊收缩素，促甲状腺素释放因子，甲硫氨酸－脑腓肽，等１２种肽能神经元的分布，并用图象分析仪对肽能神经元的面积，周长，最大径，最小径和灰度进行了测量。肽能神经元主要分布在外侧隔核中间部，内侧隔核；而隔伞核及三角隔核中较少。图象分析仪测量表明     

脑利钠肽评估充血性心力衰竭患者的临床应用

脑利钠肽（brain natriuretic peptide，BNP）是继心钠素之后发现在心血管疾病中起重要作用的又一利钠系统成员^[1]，是心室容量扩张和压力负荷增加时由心室释放的一种心脏神经激素，具有利尿、利钠效应，能舒张血管，抑制醛固酮分泌和肾素活性。本研究评价血BNP作为血标志物在心力衰竭时的浓度变化，并探讨其临床诊断价值。     

Activity of growth hormone-releasing peptide-2 in cultured human pituitary adenoma cells and its interaction with growth hormone-releasing hormone and somatostatin

Experiments on primary cultures of human pituitary adenoma cells producing growth hormone (GH) or GH and prolactin showed that similarly to GH-releasing hormone (GHRH) synthetic hexapeptide GH-releasing peptide-2 (GHRP) directly enhance secretion of GH but not of prolactin by human pituitary cells. The effect of various doses of GHRP and GHRH applied in combination was additive or slightly synergistic in nature. Somatostatin inhibits secretion of GH induced by GHRP, GHRH, or their combination. A dissociation is found between the inhibitory effects of somatostatin on basal and stimulated GH secretion. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 2, pp. 207–212, February, 1998     

Growth hormone and the heart

Until a few years ago, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) were considered essential only to the control of linear growth, glucose homeostasis, and for the maintenance of skeletal muscle mass. A large body of evidence recently coming from animal and human studies has unequivocally proven that the heart is a target organ for the GH/IGF-1 axis. Specifically GH exerts both direct and indirect cardiovascular actions. Among the direct effects, the ability of GH to trigger cardiac tissue growth plays a pivotal role. Another direct effect is to augment cardiac contractility, independent of myocardial growth. Direct effects of GH also include the improvement of myocardial energetics and mechanical efficiency. Indirect effects of GH on the heart include decreased peripheral vascular resistance (PVR), expansion of blood volume, increased glomerular filtration rate, enhanced respiratory activity, increased skeletal muscle performance, and psychological well-being. Among them, the most consistently found is the decrease of PVR. GH may also raise preload through its sodium-retaining action and its interference with the hormonal system that regulates water and electrolyte metabolism. Particularly important is the effect of GH on skeletal muscle mass and performance. Taking into account that heart failure is characterized by left ventricular dilation, reduced cardiac contractility, and increase of wall stress and peripheral vascular resistance, GH may be beneficial for treatment of heart failure. Animal studies and preliminary human trials have confirmed the validity of the GH approach to the treatment of heart failure. Larger placebo-controlled human studies represent the main focus of future investigations.     

Neuroendocrinology of the pituitary gland

The hypophysial-portal chemotransmitter hypothesis of control of the anterior pituitary was first set forth in the 1940s on the basis of physiological studies of the effects of lesions of the hypothalamus, and of section of the pituitary stalk on pituitary function. Morphological demonstration of specific neuropeptide pathways in the hypothalamus, which project to the median eminence, and the chemical identification of releasing hormones in the hypothalamus have fully established this theory. Specific neuropeptides have been isolated which stimulate the secretion of ACTH (CRF, corticotrophin releasing hormone), TSH (TRH, thyrotropin releasing hormone), GH (GHRH, growth hormone releasing hormone), and the gonadotropins (LHRH, luteinizing hormone releasing hormone; GnRH, gonadotropin releasing hormone). Prolactin secretion is regulated by both an inhibitory hormone (dopamine), and by one or more releasing factors. A factor inhibitory to GH and TSH secretion has also been identified. All factors except for the prolactin inhibitory hormone (which is a biogenic amine) are peptides, all synthesized as part of large prohormones. These substances have all been introduced into medical and veterinary practice where they are useful for regulation of pituitary abnormalities, and study of normal physiology.     

Influence of physical training,aortic constriction and exogenous anterior pituitary hormones on the heart weights of hypophysectomized rats

Summary Studies were conducted with hypophysectomized rats to determine the effects of chronic exercise (training), injections of exogenous hormones, aortic constrictions and combinations there of on the weight of the heart. In addition, the role of growth hormone on cardiac weight was reinvestigated. The hypophysectomized rats that were trained for 10 weeks or longer had significantly heavier heart weights than their nontrained counterparts. When daily injections of a single exogenous hormone of ACTH, GH, ICSH or TSH were made into trained and nontrained animals, there was no trained group that had significantly heavier heart weights than their control group. Rats having aortic constrictions or receiving DOCA injections also had significantly heavier heart weights than their controls. When various dosages of GH (0.2 mg to 6.0 mg) were injected daily for three weeks, no evidence was obtained that indicated that the presence of this hormone resulted in cardiac enlargement. It was concluded that under the experimental condition of this study, cardiac enlargement can occur in hypophysectomized rats when the work demands on the heart have been increased.Supported in part by funds provided by the Iowa Heart Association.     

Myocyte proliferation in the developing heart

Regulation of organ growth is critical during embryogenesis. At the cellular level, mechanisms controlling the size of individual embryonic organs include cell proliferation, differentiation, migration, and attrition through cell death. All these mechanisms play a role in cardiac morphogenesis, but experimental studies have shown that the major determinant of cardiac size during prenatal development is myocyte proliferation. As this proliferative capacity becomes severely restricted after birth, the number of cell divisions that occur during embryogenesis limits the growth potential of the postnatal heart. We summarize here current knowledge concerning regional control of myocyte proliferation as related to cardiac morphogenesis and dysmorphogenesis. There are significant spatial and temporal differences in rates of cell division, peaking during the preseptation period and then gradually decreasing toward birth. Analysis of regional rates of proliferation helps to explain the mechanics of ventricular septation, chamber morphogenesis, and the development of the cardiac conduction system. Proliferation rates are influenced by hemodynamic loading, and transduced by autocrine and paracrine signaling by means of growth factors. Understanding the biological response of the developing heart to such factors and physical forces will further our progress in engineering artificial myocardial tissues for heart repair and designing optimal treatment strategies for congenital heart disease. Developmental Dynamics 240:1322–1334, 2011. © 2011 Wiley‐Liss, Inc.     

Ghrelin: a recently discovered gut-brain peptide (review)

In the 70s, several new, both peptidyl and non-peptidyl, derivatives that stimulate and amplify pulsatile growth hormone (GH) secretion, independently from growth hormone releasing hormone (GHRH), were synthesized. The family of these molecules have been named growth hormone secretagogues (GHSs). The subsequent discovery of the natural receptor for GHSs (GHS-R) suggested existence of a new regulatory system, participating in GH secretion control. Three years later a natural ligand for GHS-R was identified and was designated 'ghrelin'. Subsequently, it has been found that ghrelin exerts pleiotropic activity. It influences not only GH release but also food intake, function of gastrointestinal tract and cardiovascular system, sleep patterns as well as cancer proliferation. The current knowledge on ghrelin, its structure and function, is reviewed in this article.