Regulation of Myocardial Contractility by a Downstream Mechanism

Correspondence to Masao Endoh, MD, Department of Pharmacology, Yamagata University School of Medicine, 2-2, 2-chome, Iida-nishi, Yamagata 990-9585, Japan.

Key Words: Ca²⁺ • myocardial contractility • myocardial cell • troponin C

Binding of intracellular Ca²⁺ ions to troponin C subsequent to membrane excitation triggers the interaction of actin with myosin molecules by displacing the inhibition induced by troponin I at diastolic levels of [Ca²⁺]_i. Therefore, in intact myocardial cells, the amplitude and rate of tension development and relaxation are primarily determined by the rate of Ca²⁺ mobilization and deprivation, by the crossbridge cycling rate, or by the contribution of both. From this perspective, there are 3 general types of mechanisms by which it should be possible to alter the contractile performance of cardiac muscle. Binding of Ca²⁺ to troponin C plays a key role and is considered to be the central mechanism of cardiac excitation-contraction coupling. The regulation of the Ca²⁺ mobilizing process is regarded as the upstream mechanism; the process subsequent to Ca²⁺ binding to troponin C (ie, an alteration of the response of the myofilaments to a given level of occupancy of Ca²⁺ binding sites on troponin C) is regarded as the downstream mechanism.¹

The mechanistic analysis of the role of Ca²⁺ ions in the cardiac contractile regulation in intact myocardial cells has progressed significantly since the introduction of methods to apply the Ca²⁺-sensitive photoprotein (aequorin) and fluorescent dyes (eg, fura-2, indo-1, and fluo-3) in intact myocardial cells.^{2 3 4} The majority of inotropic interventions alter the intracellular Ca²⁺ transient. The increase in frequency of contraction (force-frequency relationship) and cardiotonic agents, such as ß-adrenoceptor agonists, digitalis, and phosphodiesterase III inhibitors, act primarily through the upstream mechanism. By contrast, . . . [Full Text of this Article]

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