Thorax: first published as 10.1136/thx.38.7.481 on 1 July 1983. Downloaded from 83/210 Thorax 1983;38:481-485 Editorial Calcium-channel blockers and asthma The concentration of free calcium ions (Ca++) in the which selectively permit Call to enter the cell cytoplasm regulates many aspects of cell function, down its concentration gradient. There are at least including muscle contraction and the secretion of two types of calcium channel, one opening in mediators, neurotransmitters and hormones. Con- response to cellular depolarisation (voltage- traction of airway smooth muscle, secretion of mast dependent) and one in response to activation of a cell mediators and mucus, and vagal neurotransmis- specific receptor, such as an a-adrenoceptor sion, all of which may be increased in asthma, are (receptor-operated).6 It has been calculated that dependent on movement of Ca++ into the cell. This there are up to 10 000 voltage-dependent calcium raises the possibility that an increase in Ca++ flux channels in each cardiac cell.3 may be a fundamental abnormality in asthma and The interrelationships between Ca++ and cyclic might be an explanation for bronchial hyperreactiv- nucleotides are complex. In smooth muscle cyclic ity.' The development of drugs that interfere with AMP accelerates Call removal from the cytoplasm the entry of Ca++ into cells has now made it possible and prevents the influx of Ca++, thus reversing the to study the role of Ca++ in disease, and these drugs effects of activation.7 Ca++ also inhibits adenylate are widely used in the treatment of cardiovascular cyclase and stimulates guanylate cyclase.8 Many of disease. There has recently been increasing interest the drugs used in treating asthma may reduce in the use of calcium-channel blockers in asthma, intracellular Ca' I Thus ,8-adrenoceptor agonists not because of their therapeutic potential but bring about relaxation by increasing cyclic AMP and because of what they may reveal about underlying cholinergic antagonists by directly reducing Ca++ mechanisms. influx by reducing Ca++ in the smooth muscle cell. http://thorax.bmj.com/ Theophyllines and cromoglycate may also have their CALCIUM IONS AND CELL FUNCTION primary actions on Ca++ influx. The concentration of free intracellular Ca++ in rest- ing cells is approximately 0-1 ,moIIl, whereas that in extracellular fluid is 1 mmo0l/;2 3 and recent studies CALCIUM-CHANNEL BLOCKERS using bioluminescent indicators of free intracellular Voltage-dependent calcium channels are specific to Ca++ have found that the Ca++ concentration calcium, although cations of similar size such as increases 100-fold after cell activation.45 When barium may also enter. Larger cations, such as man- intracellular Ca++ rises to a critical concentration ganese and lanthanum, block the channel. Recently on October 1, 2021 by guest. Protected copyright. (about 1 ,umol/l) it binds to a specific binding protein organic compounds that specifically block these called calmodulin, which then activates the specific channels have been developed; they include ver- kinase and enzyme system that brings about the apamil, nifedipine, and diltiazem, which have no response, such as contraction or secretion. This apparent structural similarities.89 Binding studies increase in cytoplasmic Ca++ is derived from using labelled derivatives indicate that these drugs extracellular Ca`+ or intracellular stores (mainly bind with high affinity to different sites on the sarcoplasmic reticulum), or both. Indeed, the entry calcium channel9a10 but there may be complex allo- of Ca++ into the cell may trigger the release of Ca++ steric interactions between the different classes of from intracellular stores. The source of Ca++ calcium-channel blocker.'0a Their precise mode of required for the cellular response may differ action at a molecular level is still debated. from tissue to tissue. The cell membrane Calcium-channel blockers are now extensively itself is impermeable to Ca++ and Ca++ moves into used in cardiac disease, and appear to be safe and the cell through specific channels. These are macro- without troublesome side effects.891' These drugs molecular structures traversing the membrane appear to be relatively specific for voltage- Address for reprint requests: Dr P J Barnes, Department of dependent calcium channels, and have little action Medicine (Respiratory Division), Royal Postgraduate Medical on receptor-operated channels. At higher doses they School, Hammersniith Hospital, London W12 OHS. may have other effects, such as a-adrenoceptor 481 Thorax: first published as 10.1136/thx.38.7.481 on 1 July 1983. Downloaded from 482 Barnes blockade, phosphodiesterase inhibition, and inhibi- tively resistant to blockade.'3 In the same prepara- tion of Na-K ATPase, and may not be as selective as tion it was found that verapamil inhibited contrac- previously believed.'2 tion due to low concentrations of acetylcholine but not contraction due to high concentrations.'4 Similar AIRWAY SMOOTH MUSCLE results have been reported with guinea-pig The source of calcium for muscle contraction differs trachea,'5 suggesting that the relative contribution of between muscle types, and even between the same intracellular and extracellular Call may depend not muscle type in different tissues. Skeletal muscle is only on the stimulus but also on its magnitude. In dependent only on intracellular calcium stores and vitro nifedipine inhibits contraction induced by his- contraction is therefore unaffected by calcium- tamine and by antigen in guinea-pig tracheal6 17 and channel blockers, whereas vascular smooth muscle is human airway smooth muscle.'8 '9 Since nifedipine is dependent on extracellular Ca++ and is therefore equally potent in guinea-pig lung strip preparations, susceptible to blockade. The dependency of smooth this suggests that small airways may behave in the muscle on extracellular Call may vary between dif- same way.'6 Animal studies in vivo have shown that ferent sites since smooth muscle in arterioles is much nifedipine given intravenously or by inhalation has more sensitive to calcium-channel blockers than is no effect on resting bronchomotor tone,'6202' but that from veins.'2 gives appreciable protection against bronchoconstr- Airway smooth muscle has been less extensively iction induced by histamine, prostaglandin F2., and studied and appears to be dependent on both exter- citric acid in dogs,20 21 and against constriction nal and internal sources of Call, but this may vary induced by histamine and carbachol in guinea-pigs.'6 with the contractile stimulus (fig). Serotonin- Similar findings have been reported in patients induced contraction of canine tracheal strips is with asthma. Neither nifedipine given sublingually strongly inhibited by lanthanum and by verapamil, nor verapamil given by inhalation had any whereas acetylcholine-induced contraction is rela- significant effect on resting airway function.22 25 voltage dependent receptor-operated calcium channel calcium channel INHIBITED by: nifedipine ++ Ca" http://thorax.bmj.com/ Ca EXTRACEELLULAR verapamil a-adrenoceptor.ETA INTRACEIlLULAR Ca Calcium ion (Ca++) fluxes in an airway internal stor t[Ca ] smooth muscle cell. The rise in intracellular Ca++ causes contraction and on October 1, 2021 by guest. Protected copyright. may be due to entry ofCa++ from outside inactive calmodulin active calmodulin via voltage-dependent or receptor-operated calcium channels or from internal stores. Only the activation of myosin kinase voltage-dependent calcium channel is effectively inhibited by calcium-channel blockers, such as nifedipine and verapamil. Ca++ is removed from the cell by an Na+ - Ca++ exchange pump or by a cyclic-AMP-dependent mechanism. CONTRACT ION Ca +.+ cMP `1r.~ 3-adrenoceptor Na Thorax: first published as 10.1136/thx.38.7.481 on 1 July 1983. Downloaded from Calcium-channel blockers and asthma 483 There was, however, significant protection against (SP Skov et al, paper presented to Eleventh Interna- bronchoconstriction induced by exercise,222' tional Congress of Allergology and Clinical hyperventilation,26 26histamine,~~23 2527 methacholine,272 Immunology, 1982). In vivo, nifedipine reduces deep inspiration,28 and antigen,'8 although in one plasma histamine concentrations and prevents the study no protection against histamine-induced rise in plasma histamine with exercise in individuals bronchoconstriction was found.29 In only one study with asthma,23 although this is likely to reflect was protection completely effective,22 the others mediator release from circulating basophils rather showing partial protection with considerable inter- than from pulmonary mast cells. subject variability. Perhaps the dose of calcium- channel blocker used in these studies was too low, OTHER PULMONARY EFFECTS but the dose of sublingual nifedipine is limited by Neurotransmission is similarly dependent on cardiovascular side effects and possibly administra- external Call and it is possible that Ca++ channel tion by aerosol (as in some of the animal studies) blockers have an inhibitory effect on reflex vagal would be more effective. It is also possible that bronchoconstriction, although this has not been induced bronchoconstriction in asthma is regulated studied systematically. The secretory activity of air- by receptor-operated rather than voltage-dependent way submucosal glands and transport of ion and calcium channels, and it may be more dependent on water across the airway epithelium are also depen- internal calcium stores. Further studies on