Calcium Channel Antagonists

Abstract

In 1883, Sidney Ringer described the importance of calcium in cardiac contraction (Ringer, 1883). Since that seminal observation, the importance of calcium as a transducer for coupling of biological signals has become evident. The signal transduction role of calcium is made possible by a large, inward-directed gradient of ionized calcium across the plasma membrane. Cytosolic concentrations of calcium in a resting, nonstimulated cell are some 10,000-fold lower than external concentrations (approximately 10⁻⁷ M vs 10⁻³ M) (Fozzard et al., 1985; Tsien et al., 1984). This extreme gradient is maintained by an intrinsic low permeability of the plasma membrane to calcium, active exchange mechanisms and pumps that remove calcium, sequestration of calcium by intracellular organelles such as mitochondria and the endoplasmic reticulum, and buffering by cytosolic calcium-binding proteins. Elevation of cytosolic calcium contractions to 1–10 μM initiates physiologic responses appropriate to the cell type. In muscle, interaction with troponin C or other calcium-binding regulatory proteins initiates contraction. In neuronal, exocrine, and endocrine tissue, secretion ensues. The diversity of responses initiated, the energy expenditure to maintain low cytosolic levels, and the multiplicity of ways to deplete cytosolic calcium all highlight the biologic importance of this messenger system.