NOVEL CARDIAC MYOFILAMENT DESENSITIZING SUBSTANCE RELEASED BY ENDOCARDIAL CELLS

心内膜细胞释放的新型心肌肌丝脱敏物质

• 批准号: 3745560
• 负责人: E LAKATTA
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3745560
• 关键词: calcium flux; endocardium; heart cell; heart contraction; laboratory rat; muscle cells; muscle relaxation; myofibrils; nitric oxide; papillary muscles; tissue /cell culture; vascular endothelium

To search for novel paracrine modulators of heart cell function. We studied the effects of effluent of superfused of normoxic and hypoxic endocardial and vascular endothelial cultured cells on contraction and intracellular calcium transients of isolated adult rat cardiac myocytes. We found that EEC synthesize and release endothelin, which accounts for a positive inotropic effect of sheep EEC effluent. Additionally, both endocardial and vascular endothelial cells tonically release a novel substance which rapidl and reversibly decreases the amplitude of myocytes twitch contraction by inducing earlier relaxation, and also increase diastolic cell length. Thes effects are not associated with any change in the intracellular calcium transient, indicating cardiac myofilament "desensitization". The activity of endothelial cell effluent remained stable at 37xC for several hours or a 4xC for at least 48 hours. The action of this substance did not involve nitric oxide, cyclic GMP or prostanoids, nor changes in intracellular pH. These properties suggest that endothelial cells may rapidly modulate cardia contraction-relaxation coupling and diastolic tonus by altering myofilament properties, as well as exert distant effects because of the unusual stability of this substance. Superfusates of hypoxic endocardial and vascular endothelial cells induced rapid, reversible reduction in myocyte twitch amplitude (-67.0 q 4.9%; mean q S.E.M.), and decreased diastolic length (-1.5q0.3fm; both P <0.001; n=18). Ca2+ transients were however unchanged indicating altered myofilament properties. This effect was not attributable to known endothelial agents, nor to changes in pH1 in SNARF- loaded myocytes. Superfusate of hypoxic cells (to 1/20 dilution), but not normoxic cells, completely and reversibly inhibited the in vitro sliding of F-actin over rat cardiac myosin, and dramatically reduced actin-activated myosin S1 ATPase activity. Neither effect was observed with smooth muscle myosin. These data suggest a novel endothelial cell-mediated feed forward mechanism which senses hypoxia and depresses myocyte contraction, by releasing factors(s) that directly inhibit crossbridge cycling. This may explain the clinical phenomenon of myocardial hibernation, i.e., depressed contraction of viable myocardium during reduced coronary flow.

寻找心脏细胞功能的新型旁分泌调节剂。我们学习了 常氧和低氧心内膜灌流流出液的作用 和血管内皮细胞收缩和细胞内培养 分离的成年大鼠心肌细胞的钙瞬变。我们发现 EEC合成和释放内皮素，这是一种积极的 绵羊EEC流出物的变力作用。此外，心内膜和心脏 血管内皮细胞张力释放一种新物质，该物质可迅速 并通过可逆性地降低心肌细胞的收缩幅度 诱导更早的松弛，并增加舒张期细胞长度。牛膝 这种影响与细胞内钙离子的任何变化无关。 一过性，表明心肌肌丝“脱敏”。活动 内皮细胞流出物的百分比保持在37xC几个小时或一年 4xC，至少48小时。这种物质的作用并不涉及 一氧化氮、环GMP或前列腺素，以及细胞内pH的变化。 这些特性表明，内皮细胞可能会迅速调节心脏 改变肌丝的收缩-松弛偶联和舒张张力 属性，并产生遥远的影响，因为 这种物质的稳定性。低氧心内膜超灌注液和 血管内皮细胞诱导的心肌细胞快速、可逆性减少 抽动幅度(-67.0Q 4.9%；平均Q S.E.M.)，舒张压下降 长度(-1.5q0.3fm；均为P&lt；0.001；n=18)。然而，Ca2+的瞬变 没有变化，表明肌丝特性发生了变化。这种影响并不是 可归因于已知的内皮药物，也不是由于SNARF中PH1的变化- 加载的肌细胞。低氧细胞的超灌流液(稀释到1/20)，但不 常氧细胞可完全可逆地抑制小鼠肾小管上皮细胞 F-肌动蛋白对大鼠心肌肌球蛋白的影响，并显著减少肌动蛋白的激活 肌球蛋白S1ATPase活性。这两种作用在平滑肌方面都没有观察到。 肌球蛋白。这些数据表明了一种新的内皮细胞介导的前馈 感觉缺氧和抑制心肌细胞收缩的机制，通过 直接抑制过桥骑行的释放因子(S)。今年5月 解释心肌冬眠的临床现象，即抑郁 冠脉流量减少时存活心肌的收缩。