A growth of ideas: role of calcium as activator of cardiac contraction.

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A role for calcium as activator of cardiac contraction was first suggested in 1883, when Ringer observed that hearts placed in a calcium-free solution ceased to beat [1]. This was an accidental discovery that occurred when Ringer’s technician used distilled water, rather than the water supplied by the New River Water Company, in studies of isolated frog hearts. Ringer analyzed the ‘pipe water’, and found that it contained ‘minute traces of various inorganic substances’. When he tested the ability of different salts to support cardiac contraction, Ringer not only identified the ability of calcium to restore cardiac contraction, but also found that this effect was antagonized by potassium [2]. As described below, the negative inotropic effect of potassium was to confuse investigators more than a half century later. It took almost 80 years before the major systems responsible for the activating effect of calcium on the heart came into focus. This brief history provides a personal view of several of the discoveries between 1883 and the 1960s that made it possible to explain Ringer’s seminal observation. The slow pace at which science moved in the early 20th century is seen in the fact that 30 years elapsed between Ringer’s first report and the next logical experiment. This experiment, reported by Mines in 1913, showed that although the heart cannot contract in a calcium-free solution, it does generate an electrical signal [3]. Mines’ study, by demonstrating that calcium is not essential for electrical signaling at the cell surface, suggested instead that this ion might serve as a direct activator of the contractile process within the cell. However, another 30 years were to pass before methods were developed that could test this hypothesis directly. Demonstration of the ability of increased cytosolic calcium to activate the contractile machinery required methods … * Address for correspondence: 1592 New Boston Road, P.O. Box 1048, Norwich, VT 05055-1048, USA. Tel.: +1-802-649-3947; fax: +1-802-649-1746