Garofalo F, Parisella M L, Amelio D, Tota B, Imbrogno S
Department of Cell Biology, University of Calabria, , 87030 Arcavacata di Rende, Cosenza, Italy.
Proc Biol Sci. 2009 Nov 22;276(1675):4043-52. doi: 10.1098/rspb.2009.1189. Epub 2009 Sep 2.
The Frank-Starling mechanism is a fundamental property of the vertebrate heart, which allows the myocardium to respond to increased filling pressure with a more vigorous contraction of its lengthened fibres. In mammals, myocardial stretch increases cardiac nitric oxide (NO) release from both vascular endothelium and cardiomyocytes. This facilitates myocardial relaxation and ventricular diastolic distensibility, thus influencing the Frank-Starling mechanism. In the in vitro working heart of the eel Anguilla anguilla, we previously showed that an endogenous NO release affects the Frank-Starling response making the heart more sensitive to preload. Using the same bioassay, we now demonstrate that this effect is confirmed in the presence of the exogenous NO donor S-nitroso-N-acetyl penicillamine, is independent from endocardial endothelium and guanylate cyclase/cGMP/protein kinase G and cAMP/protein kinase A pathways, involves a PI(3)kinase-mediated activation of endothelial NO synthase and a modulation of the SR-CA(2+)ATPase (SERCA2a) pumps. Furthermore, we show that NO influences cardiac response to preload through S-nitrosylation of phospholamban and consequent activation of SERCA2a. This suggests that in the fish heart NO modulates the Frank-Starling response through a beat-to-beat regulation of calcium reuptake and thus of myocardial relaxation. We propose that this mechanism represents an important evolutionary step for the stretch-induced intrinsic regulation of the vertebrate heart, providing, at the same time, a stimulus for mammalian-oriented studies.
弗兰克 - 斯塔林机制是脊椎动物心脏的一项基本特性，它使心肌能够通过其拉长的纤维更有力地收缩来应对增加的充盈压力。在哺乳动物中，心肌拉伸会增加血管内皮细胞和心肌细胞释放心脏一氧化氮（NO）。这有助于心肌舒张和心室舒张期扩张性，从而影响弗兰克 - 斯塔林机制。在欧洲鳗鲡（Anguilla anguilla）的离体工作心脏中，我们之前表明内源性NO释放会影响弗兰克 - 斯塔林反应，使心脏对前负荷更敏感。使用相同的生物测定法，我们现在证明在存在外源性NO供体S - 亚硝基 - N - 乙酰青霉胺的情况下这种效应得到证实，它独立于心内膜内皮细胞以及鸟苷酸环化酶/cGMP/蛋白激酶G和cAMP/蛋白激酶A途径，涉及PI(3)激酶介导的内皮型一氧化氮合酶激活以及肌浆网 - 钙（2 +）ATP酶（SERCA2a）泵的调节。此外，我们表明NO通过受磷蛋白的S - 亚硝基化作用以及随后SERCA2a的激活来影响心脏对前负荷的反应。这表明在鱼类心脏中，NO通过对钙再摄取从而对心肌舒张的逐搏调节来调节弗兰克 - 斯塔林反应。我们提出这种机制代表了脊椎动物心脏牵张诱导的内在调节的一个重要进化步骤，同时为以哺乳动物为导向的研究提供了一个刺激因素。
