Calcium-channel blocking agents, which include nifedipine, verapamil, and diltiazem, have recently been licensed for use in this country. Calcium antagonists are a heterogeneous group of agents with dissimilar structural, electrophysiologic, and pharmacologic properties. The chemical structures of the most commonly used calcium blocking agents (nifedipine, verapamil, and diltiazem) differ and the molecular basis of their action remains unknown. These agents not only have established beneficial effects in the treatment of cardiovascular diseases, but also serve as valuable research tools to elucidate the role of calcium flux in health and disease. Since many pathophysiologic events that underlie bronchial asthma and hyperreactive airway disease are calcium-dependent phenomena, it is possible that calcium antagonists may prove useful in both the therapy and prophylaxis of these conditions.
Pathophysiologic Role of Calcium
The physiologic role of calcium in the airway functions is summarized in Table 1. Several sources of calcium appear to be involved in such processes including extracellular, membrane-bound, bound, and stored intracellular calcium. Principal pathogenetic features of allergic bronchial asthma are derived from the release of chemical mediators from sensitized mast cells in an IgE-mediated reaction. This leads to construction of airway smooth muscle and mucous hypersecretion, either directly or through cholinergic reflex mechanisms. The release of mediators from mast cells (stimulus-secretion coupling), contraction of airway smooth muscle (excitadon-contraction coupling), and nerve impulse conduction are all dependent on the availability of free calcium and the flux of calcium ions; however, the concept of a calcium-modulating defect in bronchial asthma remains highly speculative. Obstructive Airway Disease may be a chronic and More info about diseases and hot news – Canadian health&care Mall – .
IgE-mediated histamine release from mast cells depends on the presence of extracellular calcium. Bridging of IgE receptors on mast cells by divalent antireceptor antibodies was found to induce Ca++ uptake, indicating that cross-linking of IgE receptors increases the membrane permeability of the mast cell toward calcium. Nonimmunologic stimulation of mast cells by compound 48/80, a substance known to be a potent histamine-releasing agent, however, circumvents this gating mechanism by mobilizing intracellular stores of calcium. Calcium may also play an important role in the synthesis of some of the mediators, since it has recently been shown that 5-lipoxygenase, the initial enzyme in the leukotriene pathway, is markedly stimulated by calcium. Thus, calcium not only acts as an important trigger in the release of mast-cell mediators initiated by both immunologic and nonimmunologic stimuli, but may also be involved in the synthesis of these mediators.
Calcium has an important influence on the secretion of both glycoproteins and electrolytes in many different secretory tissues. Stimulation of mucous glycoprotein secretion in rabbit tracheal explants by either the calcium ionophore A23187 or cystic fibrosis serum and of mucous secretion in canine and chicken airways indicates that calcium ions are an essential requirement for stimulus-secretion coupling in mucous and serous cells of the submucosal glands. However, secretion of tracheal mucous glycoproteins is stimulated by both an increased extracellular calcium and by a decreased extracellular calcium. This is surprising, since the secretogogue responses in other systems are abolished by low or zero extracellular calcium. Perhaps low extracellular calcium increases membrane permeability, producing a nonspecific leakage of molecules out of secretory cells. Changes in extra- and intra-cellular calcium also affect the ion transport and electrical properties of tracheal epithelium.
Bronchomotor tone is ultimately regulated by the availability of intracellular calcium to the contractile apparatus of the respiratory smooth muscle cell. Calcium may be mobilized from both extracellular and intracellular sources, and the relative contribution of each source is highly dependent on the tissue, the stimulus, and the response. Calcium flux through the smooth muscle cell membrane can occur in a number of ways. In vascular and respiratory smooth muscle, electrical depolarization of the cell membrane can lead to opening of “voltage… dependent” channels for transmembrane calcium flux (ie, electromechanical coupling). Pharmacologic agents such as serotonin in vascular smooth muscle and methacholine in tracheal smooth muscle open “receptor-operated” calcium channels independent of membrane depolarization (ie, “pharmacomechanicaT coupling). It was shown that “pharmacomechanical” coupling in canine tracheal muscle plays a greater role in acetylcholine-induced contraction than does “electromechanical” coupling and that the type of coupling mechanism involved depends on the dose. At low concentrations (10“M) acetylcholine causes voltage-dependent calcium influx; at high concentrations (10~M) voltage-independent calcium entry takes place. Available data on excitation-contraction coupling in respiratory smooth muscle is limited. Most comprehensive studies are available for canine, bovine, and guinea-pig tissues. For these tissues there is good evidence for multiple, stimulus-dependent routes of calcium mobilization.
Table 1—Role of Calcium in Airway Functions
|Release of chemical mediators|
|Immunologic release (antigen mediated): influx of extracellular|
|Nonimmunologic release (48/80-mediated): mobilization of in|
|tracellular Ca+ +|
|Synthesis of mediators: Ca++ stimulates 5-lipoxygenase, the|
|initial enzyme in the leukotriene pathway|
|Increased extracellular Increased secretion|
|Increased intracellular Ca+ + Increased secretion|
|Decreased extracellular Increased secretion?|
|Decreased extracellular Decreased electrical resistance;|
|Ca+ + decreased responsiveness of|
|short circuit current to|
|Increased intracellular Ca+ + Increased chloride secretion|
|(Ca+ + inophore A23187) and abolished sodium|
|Airway smooth muscle|
|Increased intracellular Ca+ + Contraction (electromechanical|
|(cytoplasmic) or pharmacomechanical|
|Decreased intracellular Relaxation|
|Ca+ + (cytoplasmic)|