NOVEL CARDIAC MYOFILAMENT DESENSITIZING SUBSTANCE RELEASED BY ENDOCARDIAL CELLS

寻找新的旁分泌心脏细胞功能调节剂。我们研究 常氧和低氧内皮素灌流流出液的影响 和血管内皮细胞培养的细胞收缩和细胞内 分离的成年大鼠心肌细胞的钙瞬变。 我们发现 EEC合成并释放内皮素， 绵羊EEC流出物的正性肌力作用。 此外，内分泌和 血管内皮细胞紧张性地释放一种新的物质， 并可逆地降低肌细胞颤搐收缩的幅度， 诱导较早的舒张，并增加舒张期细胞长度。 Thes 作用与细胞内钙的任何变化无关 一过性，表明心肌肌丝“脱敏”。 活动 的内皮细胞流出物在37 ℃下保持稳定数小时或 4xC至少48小时。 这种物质的作用不涉及 一氧化氮、环GMP或前列腺素类，也不改变细胞内pH值。 这些特性表明，内皮细胞可以快速调节心脏， 通过改变肌丝的收缩-舒张偶联和舒张张力 属性，以及发挥遥远的影响，因为不寻常的 这种物质的稳定性。 缺氧性内皮素超灌注， 血管内皮细胞诱导的心肌细胞快速、可逆性减少 抽搐幅度（-67.0 q 4.9%;平均q S.E.M.），舒张压降低 长度（-1.5q0.3fm;均P <0.001; n=18）。 然而，Ca 2+瞬变 未改变，表明肌丝性质改变。 这种影响不是 归因于已知的内皮因子，也不归因于SNARF中pH 1的变化- 负载的肌细胞。 缺氧细胞的超灌注液（稀释至1/20），但不 常氧细胞，完全和可逆地抑制体外滑动 F-actin超过大鼠心肌肌球蛋白，并显着减少肌动蛋白激活 肌球蛋白S1 ATP酶活性。 两种效应均未观察到平滑肌 肌球蛋白 这些数据表明，一种新的内皮细胞介导的前馈 感觉缺氧并抑制肌细胞收缩的机制， 释放直接抑制跨桥循环的因子。 这可能 解释心肌冬眠的临床现象，即，沮丧 冠状动脉血流减少时存活心肌收缩。

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.