Calcium-channel blockers andasthma

Theconcentration offree calcium ions(Ca++) inthe cytoplasm regulates manyaspects ofcell function, including muscle contraction andthesecretion of mediators, neurotransmitters andhormones. Contraction ofairway smooth muscle, secretion ofmast cell mediators andmucus, andvagal neurotransmission, allofwhichmaybeincreased inasthma, are dependent onmovementofCa++into thecell. This raises thepossibility thatanincrease inCa++flux maybeafundamental abnormality inasthma and might beanexplanation forbronchial hyperreactivity.' Thedevelopment ofdrugs thatinterfere with theentry ofCa++into cells hasnowmadeitpossible tostudy therole ofCa++indisease, andthese drugs arewidely usedinthetreatment ofcardiovascular disease. Therehasrecently beenincreasing interest intheuseofcalcium-channel blockers inasthma, notbecause oftheirtherapeutic potential but because ofwhattheymayreveal aboutunderlying mechanisms. CALCIUM IONSAND CELL FUNCTION Theconcentration offree intracellular Ca++inrestingcells isapproximately 0-1,moIIl, whereas that in extracellular fluid is1mmo0l/;2 3andrecent studies using bioluminescent indicators offree intracellular Ca++havefoundthattheCa++concentration increases 100-fold after cellactivation.45 When intracellular Ca++rises toacritical concentration (about 1,umol/l) itbinds toaspecific binding protein called calmodulin, whichthenactivates thespecific kinase andenzymesystemthatbrings aboutthe response, suchascontraction orsecretion. This increase incytoplasmic Ca++isderived from extracellular Ca`+orintracellular stores (mainly sarcoplasmic reticulum), orboth. Indeed, theentry ofCa++into thecell maytrigger therelease ofCa++ fromintracellular stores. The sourceofCa++ required forthecellular response may differ from tissue to tissue. The cellmembrane itself isimpermeable toCa++andCa++movesinto thecell through specific channels. Thesearemacromolecular structures traversing themembrane