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首页> 外文期刊>Circulation journal >Cardiac Ca~(2+) Signaling and Ca~(2+) Sensitizers
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Cardiac Ca~(2+) Signaling and Ca~(2+) Sensitizers

机译：心脏Ca〜（2+）信号传导和Ca〜（2+）敏化剂

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The role of Ca~(2+) in cardiac excitation-contraction (E-C) coupling has been established by simultaneous measurements of contractility and Ca~(2+) transients by means of aequorin in intact myocardium and Ca~(2+) sensitive fluorescent dyes in single myocytes. The E-C coupling process can be classified into 3 processes: upstream (Ca~(2+) mobilization), central (Ca~(2+) binding to troponin C) and downstream mechanism (thin filament regulation and crossbridge cycling). These mechanisms are regulated differentially by various inotropic interventions. Positive force-frequency relationship and effects of beta-adrenoceptor stimulation, phosphodiesterase 3 inhibitors and digitalis are essentially exerted via upstream mechanism. Alpha-adrenoceptor stimulation, endothelin-1, angiotensin II, and clinically available Ca~(2+) sensitizers, such as levosimendan and pimobendan, act by a combination of the upstream and central/downstream mechanism. The Frank-Starling mechanism and effects of Ca~(2+) sensitizers such asEMD 57033 and Org 30029 are primarily induced via the central/downstream mechanism. Whereas the upstream and central mechanisms are markedly suppressed in failing myocytes and under acidotic conditions, Ca~(2+) sensitizers such as EMD 57033 and Org 30029 can induce cardiotonic effects under such conditions. Ca~(2+) sensitizers have high therapeutic potential for the treatment of contractile dysfunction in congestive heart failure and ischemic heart diseases, because they have energetic advantages and less risk of Ca~(2+) overload and can maintain effectiveness under pathological conditions.
机译：通过同时测量完好的心肌中的水母发光蛋白同时测量收缩力和Ca〜（2+）瞬变，已经确定了Ca〜（2+）在心脏兴奋收缩（EC）耦合中的作用单个肌细胞中的染料。 E-C偶联过程可分为3个过程：上游（Ca〜（2+）动员），中央（Ca〜（2+）与肌钙蛋白C结合）和下游机理（细丝调节和跨桥循环）。这些机制受到各种正性肌力干预的不同调节。正作用力频率关系和β-肾上腺素受体刺激，磷酸二酯酶3抑制剂和洋地黄的作用基本上是通过上游机制发挥的。 α-肾上腺素受体刺激，内皮素-1，血管紧张素II和临床上可用的Ca〜（2+）敏化剂，如左西孟旦和匹莫苯丹，是由上游和中枢/下游机制共同作用的。 Ca-（2+）敏化剂（如EMD 57033和Org 30029）的Frank-Starling机理和作用主要是通过中央/下游机理引起的。尽管在衰竭的心肌细胞中和在酸性条件下，上游和中枢机制被显着抑制，但是Ca〜（2+）敏化剂（例如EMD 57033和Org 30029）可以在这种条件下诱发强心作用。 Ca〜（2+）敏化剂具有充沛的优势，且Ca ~~（2+）超负荷的风险较小，并且可以在病理情况下保持有效性，因此具有治疗充血性心力衰竭和缺血性心脏病的收缩功能障碍的高治疗潜力。

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