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ANT-P'
8__~~~~~~~~~K
PKA
c-A-,MP
~~~ AC
~
PDE
C3
GC
1.
2.
3.
4.
Agents acting through
stimulating cAMP
phospholipase C; DAG=diacylglycerol; Ins P3= inositol trisphosphate; PIP2= inositol agonists, vasoactive intestinal peptide and
bisphosphate; G =guanosine nucleotide binding protein; AC= adenylate cyclase. prostaglandins.
896 Knox, Tattersfield
cGMP, have been shown to relax canine and and cGMP converting them to their inactive 5'-
bovine airway smooth muscle56"5 and, in the nucleotide metabolites 5'-AMP and 5'-GMP.
case of sodium nitroprusside, human airway Theophylline and other xanthine derivatives
smooth muscle.59 S-nitrosothiols, which consist cause airway smooth muscle relaxation in vitro
of nitric oxide linked to a thiol group and are and bronchodilatation in vivo, and although
found endogenously in airway secretions, relax they may have other mechanisms of action,
guinea pig and human airway smooth muscle.60 phosphodiesterase (PDE) inhibition appears to
Dissolved nitric oxide gas relaxed bovine trach- be important for smooth muscle relaxation.7'
ealis in one study.6' Endogenous nitric oxide Theophylline has been shown to relax smooth
and S-nitrosothiols are produced by cells such muscle from several species including man
as airway epithelium and non-adrenergic non- when contracted with a wide range of spas-
cholinergic nerves and may be involved in the mogens in vitro,72 although it is some 1000
regulation of bronchomotor tone (fig 5).62 This times less potent than isoprenaline in relaxing
effect might, however, be offset by pro- human bronchi contracted by moderate doses
inflammatory actions of nitric oxide.62 of carbachol.73 Theophylline is a rather non-
selective inhibitor of tissue phosphodiesterases
and this is one factor underlying its narrow
ATRIAL NATRIURETIC PEPTIDE therapeutic index.
Atrial natriuretic peptide (ANP) relaxes guinea Recent studies have identified at least seven
pig63 and bovine airway smooth muscle and classes of PDE isoenzymes, each of which has
this is associated with increased cGMP64 in several isoforms (table 2). These isoenzymes
bovine airway smooth muscle. ANP is degraded vary in their tissue distribution and their ability
rapidly by epithelial peptidases and the re- to break down cAMP and cGMP.7475 Airway
sponse to ANP is enhanced by removing epi- smooth muscle contains several PDE iso-
thelium or adding a peptidase inhibitor.65 The enzymes in most species and in human airway
effects of ANP appear to be less marked in smooth muscle types III, IV and, to a lesser
human airway smooth muscle.6S65 Two related extent, V are important for relaxation.76-79
peptides, brain natriuretic peptide (BNP) and Drugs which inhibit specific isoenzymes may
C-type natriuretic peptide (CNP), have been be relatively tissue selective in their effects and
shown to increase cGMP and relax guinea thus have advantages over theophylline. Studies
pig airway smooth muscle, but have not been of some of the more specific type IV inhibitors
studied in man.6970 are currently under investigation in man.
.s
...
........
.:
......
1..;
in human airways.97100 K+ channel openers are
s; ;
The large conductance K+ channels (n iaxi-K) through cGMP. Na+/K+ ATPase activity is
found in airway smooth muscle from several increased by protein kinase A but not protein
species including ma99 are activated by cal-
kinase G in canine airway smooth muscle mem-
cium and inhibited by charybdotoxin. Maxi-
brane particulates,29 and inhibition of Na+/
K+ channels may have a role in both CAMP K+ ATPase with ouabain inhibits the relaxant
and cGMP-mediated airway smooth muscle responses to drugs that act through cAMP such
relaxation. The channels are activa ted by as [ agonists, but not those that act through
cAMP-dependent protein kinase in rat)bit tra- cGMP such as nitroprusside.2829 Activators of
chea27 and directly by cAMP in porciine and Na+/K+ ATPase or Na+/Ca2'+ exchange would
ferret trachea30 and, when inhibited by charyb- therefore be expected to act as airway smooth
dotoxin, cAMP-mediated relaxation of' guinea muscle relaxants. No such agents are currently
pig and human airway smooth muscle 94 95 and available.
cGMP-mediated relaxation in bovine airway Amiloride, a non-specific inhibitor of sodium
smooth muscle58 are inhibited. Friactional channels and transport processes including
antagonism could be responsible fo r these Na+ entry channels, Na+/H+ and Na+/Ca2+
inhibitory effects, however. Charyb dotoxin exchange, relaxes airway smooth muscle tone
can cause calcium influx through ivoltage- and inhibits receptor-operated contraction in
dependent calcium channels, and the inhibit- canine and bovine trachealis and the *.response
I AA-1nA
ory effect of charybdotoxin on isoprcenaline- to antigen in guinea pig airways in vitro.l_
induced relaxation in guinea pig tra,chea is Further studies suggest that this effect may be
inhibited by nifedipine.96 due to inhibition of Na+ entry channels'06 or
protein kinase C'07 rather than inhibition of
Na+/H+ exchange or Na+/Ca2" exchange. In-
METABOLICALLY CONTROLLED CHANNEL s haled amiloride caused no bronchodilatation,
ATP-sensitive K+ channels open in resp)onse to however, in one study of normal and asthmatic
a reduction in ATP and K+ channel ac tivators subjects.'08
Ainvay smooth muscle relaxation 899
induced contractions of the guinea-pig trachea and lung Taylor SG, et al. Relaxant effects of the potassium channel
parenchyma. Jf Pharmacol Exp Ther 1983;225:310-5. activators BRL 38227 and pinacidol on guinea pig and
84 Advenier C, Cerrina J, Duroux P, Floch A, Renier A. Effects human airway smooth muscle, and blockade of their
of five different calcium antagonists on guinea pig isolated effects by glibenclamide and BRL 31660. Pulmonol Phar-
trachea. Br Jf Pharmacol 1984;82:727-33. macol 1993;6:77-86.
85 Burka JF. Effects of calcium channel blockers and a cal- 101 Cortijo J, Sarria B, Pedros C, Perpina M, Paris F, Morcillo
modulin antagonist on contractions of guinea pig airways. E. The relaxant effects of cromakalim (BRL 34915) on
Eur J7 Pharmacol 1984;99:257-68. human isolated smooth muscle. Naunyn Schmiedebergs
86 Henderson AF, Heaton RW, Dunlop LS, Costello JF. Effects Arch Pharmacol 1992;346:462-8.
of nifedipine on antigen-induced bronchoconstriction. 102 Black JL, Barnes PJ. Potassium channels and airway
Am Rev Respir Dis 1983;127:549-53. function: new therapeutic prospects. Thorax 1990;
87 Murray MA, Kotlikoff MI. Receptor-activated calcium in- 45:213-8.
flux in human airway smooth muscle cells. Jf Physiol 199 1; 103 Krampetz IK, Bose R. Relaxant effect of amiloride on
435:123-44. canine tracheal smooth muscle. J Pharmacol Exp Ther
88 Kirkpatrick CT. Excitation and contraction in bovine trach- 1988;246:641-8.
eal smooth muscle. Jf Physiol 1975;244:263-8 1. 104 Knox AJ, Ajao P, Britton JR, Tattersfield AE. The effect
89 Stephens NL, Kroeger EA, Kromer U. Induction of a of sodium transport inhibitors on airway smooth muscle
myogenic response in tonic airway smooth muscle by contractility in vitro. Clin Sci 1990;79:315-23.
tetraethylammonium. Am Jf Physiol 1975;228:628-32. 105 Souhrada M, Souhrada MH, Souhrada JF. The inhibition
90 McCann JD, Welsh MJ. Calcium-activated potassium chan- of sodium influx attenuates airway response to a specific
nels in canine airway smooth muscle. J Physiol 1986;372: antigen challenge. Br _7 Pharmacol 1988;93:884-92.
113-27. 106 Yu J, Guia A, Minks S, Kepron W, Cragoe EJ Jr, Sharma
91 Kotlikoff MI. Potassium currents in canine airway smooth S, et al. Role of sodium in antigen-induced contraction
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3):L394-5. 11-124.
92 Marthan R, Martin C, Thierry A, Mironnuea J. Calcium 107 Knox AJ, Ajao P. The effect of inhibitors of Na+/H+
channels in isolated smooth muscle cells from human exchange on airway smooth muscle contractility. Pulmonol
bronchus. Y Appl Physiol 1989;66:1706-14. Pharmacol 1994;7:99-102.
93 Hisada T, Yoshihisa K, Tsuneaki S. Properties of membrane 108 Knox AJ, Britton JR, Tattersfield AE. Effect of sodium-
current from guinea-pig trachea. Pflugers Arch 1990;416: transport inhibitors on bronchial reactivity in vivo. Clin
151-61. Sci 1990;79:325-30.
94 Murray MA, Berry JL, Cook SJ, Foster RW, Green KA, 109 Nagai H, Yamada H, Goto S, Inagaki N, Koda A. Re-
Small RC. Guinea-pig isolated trachealis: the effects of duction of antigen-induced contraction of sensitised
charybdotoxin on mechanical activity, membrane po- guinea-pig tracheal smooth muscle in vitro by calmodulin
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Role of potassium channels in bronchodilator responses in in sensitisation and antigen response of airway smooth
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96 Huang JC, Garcia ML, Reuben JP, Kacsorowski GJ. In- 111 Venugopalan CS, O'Rourke YM, Tucker TA. Broncho-
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Pharmacol 1993;235:37-43. 112 Knox AJ, Higgins BG, Hall IP, Tattersfield AE. The effect
97 Taylor SG, Bumstead J, Morris JEJ, Shaw DJ, Taylor JF. of lithium on bronchial reactivity in asthma. Clin Sci
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Br J' Pharmacol 1988;96:795P. azepam, flurazepam and midazolam on airway smooth
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