Regulation of Myocardial Contractility by a Downstream Mechanism

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 β-adrenoceptor agonists, digitalis, and phosphodiesterase III inhibitors, act primarily through the upstream mechanism. By contrast, length-dependent regulation (Frank-Starling mechanism), activation of receptors coupled to the stimulation of phosphoinositide hydrolysis (α-adrenoceptors, endothelin, and angiotensin AT2 receptors), and actions of novel Ca2+ sensitizers (eg, EMD 57033 and Org 30029) are …