Physiological and pathophysiological modulation of calcium signaling in myocardial cells.

The relationship between changes in intracellular Ca2+ transients and isometric contractions has been assessed in intact cardiac muscle preparations, superficial cells of which have been microinjected with the Ca(2+)-sensitive bioluminescent protein aequorin. Regulation of myocardial contractility by physiological and pathophysiological intervention is achieved by either (1) modulation of intracellular Ca2+ mobilization, or (2) modulation of Ca2+ sensitivity of myofibrils, or both. Regulation of contractility by changes in heart rate a well established frequency-force relationship that plays an important role in the cardiac pumping function in situ is mainly achieved by mechanism (1), other mechanisms becoming involved depending on the range of frequency of stimulation. The length-dependent regulation of contractility (length-tension relationship in vitro or Frank-Starling's law, or ventricular function curve in situ) is achieved essentially by mechanism (2). Catecholamines promote mechanism (1) through activation of beta- and/or alpha-adrenoceptors, alpha-adrenoceptor stimulation being much less effective than beta-stimulation in this respect. beta-Adrenoceptor stimulation decreases, while alpha-stimulation may increase the Ca(2+)-sensitivity of contractile proteins. Subsequent to exposure of muscle preparations to Ca2+ free solution, a prominent and reversible dissociation of force of contraction from Ca2+ transients was produced when the [Ca2+]0 was gradually returned to the level of the normal Krebs-Henseleit solution [( Ca2+]0 = 2.5 mM). The aequorin-injected multicellular intact myocardial cell preparation provides an excellent experimental paradigm through which to address the physiological, pharmacological and pathophysiological modulation of E-C coupling in mammalian cardiac muscle. The subcellular mechanism involved, especially in the pathophysiological modulation of Ca2+ signaling process in myocardial cells, awaits further study.