Calcium ions play an important role in the regulation of many cellular processes, such as synaptic transmission and muscle contraction. The role of calcium in these cellular functions is as a second messenger, for example, regulating enzymes and ion channels. The entry of extracellular Ca2+ in the cytosol of myocardial cells and the release of Ca2+ from intracellular storage sites is important for initiating contractions of the myocardium. Normally, the concentration of Ca2+ in the extracellular fluid is in the millimolar range, whereas the intracellular concentration of free Ca2+ is less than 10"7 M, even though the total cellular concentration may be 10"3 M or higher. Most of the Ca2+ is stored within intracellular organelles or tightly bound to intracellular proteins. The free Ca2+ needed to satisfy the requirements of a contraction resulting from a stimulus may result from activation of calcium channels on the cell membrane and/or the release of calcium from bound internal stores. Each of these methods of increasing free cytosolic Ca2+ involves channels that are selective for the calcium ion. Calcium channel blockers reduce or prevent the increase of free cytosolic calcium ions by interfering with the transport of calcium ions through these pores.
Calcium is one of the most common elements on earth. Most calcium involved in biological systems occurs as hy-droxyapatite, a static, stabilizing structure like that found in bone. The remaining calcium is ionic (Ca2+). Ionic calcium functions as a biochemical regulator, more often within the cell. The importance of calcium ions to physiological functions was realized first by Ringer, who observed in 1883 the role of Ca2+ in cardiac contractility.
The ionic composition of the cytosol in excitable cells, including cardiac and smooth muscle cells, is controlled to a large extent by the plasma membrane, which prevents the free movement of ions across this barrier. Present in the membranes are ion-carrying channels that open in response to either a change in membrane potential or binding of a li-gand. Calcium-sensitive channels include (a) Na+ to Ca2+ exchanger, which transports three Na+ ions in return for one Ca2+; (b) a voltage-dependent Ca2+ channel, which provides the route for entry of Ca2+ for excitation and contraction in cardiac and smooth muscle cells and is the focus of the channel-blocking agents used in medicine; and (c) receptor-operated Ca2+ channels mediated by ligand binding to membrane receptors such as in the action of epinephrine on the ^-adrenergic receptor. The membrane of the sar-colemma within the cell also has ion-conducting channels that facilitate movement of Ca2+ ions from storage loci in the sarcoplasmic reticulum.
Four types of calcium channels, differing in location and function, have been identified: (a) L type, located in skeletal, cardiac, and smooth muscles, causing contraction of muscle cells; (b) T type, found in pacemaker cells, causing Ca2+ entry, inactivated at more negative potentials and more rapidly than the L type; (c) N type, found in neurons and acting in transmitter release; and (d) P type, located in Purkinje cells but whose function is unknown at this time.
Calcium antagonists act only on the L-type channel to produce their pharmacological effects. The L channels are so called because once the membrane has been depolarized, their action is long lasting. Once the membrane has been depolarized, L channels must be phosphorylated to open.
Although there are similarities between L-type calcium channels that exist in cardiac and smooth muscle, there are distinct differences between the two. Cardiac L channels are activated through ^-adrenergic stimulation via a cAMP-dependent phosphorylation process,11 whereas L channels in smooth muscle may be regulated by the inositol phosphate system linked to G-protein-coupled, receptor-linked phospholipase C activation.12
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