Cardiac Ca^<2+> Signaling and Ca^<2+> Sensitizers
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概要
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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 β-adrenoceptor stimulation, phosphodiesterase 3 inhibitors and digitalis are essentially exerted via upstream mechanism. Alpha-adrenoceptor stimulation, endothelin-I, 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 as EMD 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.
- 2008-11-20
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