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Eur Respir J
1993, 6, 130- 134
SHORT REVIEW
Inhaled loop diuretics as potential new anti-asthmatic drugs
S. Bianco*, M.G. Pieroni*", R.M . Refini**, M. Robuschi+, A. Vaghi++, P. Sestini**
Inhaled loop diuretics as potential new anti-asthmatic drugs. S. Bianco, M.G.
Pieroni, R.M. Refini, M. Robuschi, A. Vaghi, P. Sestini .
ABSTRACT: The observation that changes in bronchial osmolari ty can induce
bronchoconstriction in asthma ins pired the experimental studies which, unexpectedly, revealed that fr usemide is an effective bronchoprotective agent against
a variety of osmotic and non osmotic stimuli. Although the mechanism of this
protective effect is not fully understood, studies in vivo and iiZ vitro s uggest that
frusemide may inhibit tbe activation of different cell types induced by bronchoconstrictor stimuli. Other loop diu retics also exert bronchoprotective acti vity, but frusemide appears to be the mor e effective bronchoprotective agent of
this family, r egardless of their diuretic potency and lipid solubility. Despite the
relati vely large amoun t of experimental evidence, there is currently little information on the clinical effecti veness of frusemide in asth ma and a long-term
con trolled study is currently in progress. T he observations that treatment with
a combination of inhaled acetylsalicylate and frusemide results in a markedly
increased bronchop rotective effect compared to either drug a lone, opens a new
pers pecti ve in the possible clinical use of these drugs. Prelimina ry studies sug·
gest that the association of these drugs is well tolerated and may result in a
remarkable steroid sparing effect in patients with steroid dependent asth ma, for
whom a convenient alternative to long-term steroid therapy is not cur rently
availa ble.
Eur Respir J., 1993, 6, 130- 134.
Introduction
The physicochemical characteristics of the fluid
lining the airways affect bronchial reactivity in asthmatic patients, as indicated by the bronchoconstriction
induced in these patients by a variety of stimuli that
affect the osmolarity of the bronchial environment [I].
The liquid and ion composition of the bronchial
lining fluid is largely regulated by ion transport pathways in the epithelial cells of the airways [2, 3]. The
original idea behind the series of acute studies on the
effect of frusemide on bronchial reactivity was that,
since loop diuretics inhibit the basolateral Na+/l(+/Cl·
eo-transport in epithel.ial cells [4, 5], this effect
could change the bronchial response to osmolar
stimuli. Unexpectedly, these experiments demonstrated
that inhaled frusemide is a very effective bronchoprotective agent and, hence, a potential anti-asthmatic
drug.
The aim of this paper is to summarize the results
obtained using inhaled frusemide and other loop diuretics against a variety of bronchoconstrictor stimuli in
asthmatic patients, to examine the possible mechanism
of action of the bronchial protective effect of these
drugs, and to consider the possible future application
of these drugs in the therapy of asthma.
*
Institute of Respiratory and Cardiovascular Diseases, Ospedale S. Raffaele,
Milan, Italy. ** Institute of Respiratory
Diseases, University of Siena, Italy.
• Institute of Respirato ry Diseases,
University of Milan, Italy. ++ Ospedale
di Garbagnate, Milan, ftaly.
Correspondence: S. Bianco
Institute of Respiratory and Cardiovascular Diseases
Ospedale S. Raffaele
Milan
Italy
Keywords: Asthma
bronchial hyperreactivity
frusemide
loop d iuretics
Received: June 25, 1992
Accepted after revision October 4, 1992
Effect of inhaled frusemide on experimentallyinduced bronchoconstriction
Osmolar stimulants were the first bronchoconstrictor agents against which the effect of inhaled frusemide was tested. In a series of controlled studies we
found that inhalation of 40 mg frusemide inhibited the
bronchoconstrictor response to ultrasonically nebulized
water [6, 7], exercise [8], and hypertonic solutions of
NaCl [9]. Under the same experimental conditions, oral
frusemide was ineffective, suggesting that the protective effect was due to direct action of inhaled frusemide on the bronchial mucosa. More recently, inhaled
frusemide has also been shown to protect asthmatic
patients against cold air and hypertonic KCJ-induced
bronchoconstriction [ 10, 11], and against blood gas
changes induced by ultrasonically nebulized distilled
water [12]. The nature of the osmotic changes induced in these models varies considerably, depending
on the stimulus: hypotonic aerosols, such as distilled
water, are presumed to reduce bronchial osmolarity,
whereas hypertonic solutions, exercise and cold air
hyperventilation are presumed to have the opposite
effect. The fact that significant protection has been
observed against all of these stimuli suggests that inhaled frusemide does not counteract the osmotic
INHALED LOOP DIURETICS IN ASTHMA
changes directly, but probably interferes with mechanisms triggered by these changes, such as stimulation
of sensory receptors and/or release of mediators from
superficial airway mast cells [13].
The release of preformed and newly generated mediators from superficial bronchial mast cells is very
relevant to the bronchial response to allergens [14].
We speculated that if the protective activity of frusemide was, at least partially, mediated by a stabiHzing
effect on these cells, then frusemide could also inhibit
the immediate bronchoconstrictor response to allergens.
In controlled studies, inhaled frusemide protected
asthmatic subjects from the early and late responses
to allergen challenge [15-19], but not from the
increase in bronchial reactivity following the late reaction [ 18]. Inhaled frusemide was also found to
reverse the early response, when administered after
allergen chaHenge [18]. The protective effect observed
on the late response [19] was also of interest, because
the time of its occurrence, 4-8 h after the challenge,
frusemide is beyond the estimated duration of action
of inhaled frusemide. According to preliminary studies on the distilled water-induced airway response,
furosemide is most active in the first hour after administration [20]. Tn a single study, no further protection against the late response was afforded by a
second dose of frusemide administered two hours after challenge (unpublished results). Frusemide presumably exerts its protective activity during the early
phase of the reaction, by inhibiting the release of inflammatory mediators necessary for the development
of the late response.
In patients with allergic rhinitis, premedication with
frusemide has also been shown to prevent the increase
in bronchial responsiveness to methacholine that
follows the early asthmatic response [I 7], a finding
which we were unable to confirm in a subsequent
study in asthmatic patients [2 I]. Actively sensitized
guinea-pigs [16J, and dogs [22], were also protected
by inhaled frusemide against bronchoconstricrion induced by antigen inhalation but not by nonspecific
stimuli. An intravenous infusion of frusemide fai led
to protect guinea-pigs from the anaphylactic response,
suggesting that in this model the drug also acts via a
local mechanism [I6].
Frusemide also gives significant protection against
challenge with sodium metabisulphite and adenosine
[23- 25]. The mechanism of action of these bronchoconstrictor agents is still unknown, but is considered to be, at least partially, mediated by nerve and
mast cell activation. In contrast, the bronchoconstrictor activity of methacholine, histamine and prostaglandin F 2a (PGF2 a) is considered to be mostly due to
the direct activation of specific receptors on bronchial
smooth muscle. In controlled studies, inhaled frusemide did not protect against methacholine in asthmatic
patients [10, 23, 26], whereas, a reduction of sensitivity was observed in two studies on normal subjects
[27, 28]. Similarly, frusemide caused minimal [29],
or no [24, 30], protection against histamine-induced
bronchoconstriction, and has had no effect on the
131
bronchial response to PGF2t, [3 1[. ll did. however.
cause s ignificam pro tectio n against thl! bronchoconstriction induced by leukotriene D~ (LTD4 ) [30].
The protective activity o r frusemide on the respi ratOry tract is not limited to bronchoconstriction. as it
also protects agains t the tu ssive response to low
chloride solutions [32. 33 ]. and to PGF~,. [3Jj. In
contrast, it was ineffective on cough induced by citric
acid [34j. capsaicin ]32), ami metabisulphite LJSj.
Interesting ly. the bronchoconstrictor effect o f metabi!.ulphite is inhi bited by frusemide ]23. 24, 35j. but
no t that o f PG F~u f3 I] , in contrast to the results
obtaiued on coug h induced by the same stimuli .
Possible mechanism of action
A number of Olher drugs affecting ion transpon have
been investig<lled tO provide further information on the
mechanism of ac t io n o f fru semi de in asthma.
Bumeranide and piretanide are k1op diuretics or higher
potency th~m fmsemide . as far as inhibition o f Na?/K '/
Cl eo-transport and on mllriuretic activity are concerned 1361. They are also more pote nt than frusemide in inhibiting ion transport in the clog tracheal
epithe lium 14 1, and electrically -induced conlracLion o f
guinea-pig bronchial su·ips in l'ilro [37] . However,
when :tdministercd. by inhalation. to asthmatic.: subjects
at doses with equi vale nt diuretk activity. bumetanide
provided significanlly lower protect-io n than frusemide
agains t exerc ise- [38 ] and udenosine-i nduced f24j
bronchoconstriction. and it had no effect against sodium merabisulphite 124 1.
Unde r the same experimental cond itio ns, pirc tanide
showed little protection againsl distilled wate r- IJ9l
nnd metabisulphite-induccd bronchoconstriction [40 ].
Higher doses of pircwnide, however, caused significant. dose-related pr<>tection agaillst distilled water. and
the drug was ro ughly equivalent t<> frusemide on an
equimo lar dose 139j. A newer loop diuretic, torasemide, a lso had liule effect against distilled Wilierinduced bronchoconsrriction f41] . The reason for thilt
dissociation between tl1e diuretic a nd the bro nc hoprotective activities of loop diure Lics is not clear. The
bronchoprotective activi ty may be mediated by a
mechanism differe nt from the Na../ K'/Cl cO-lransport
inhibition. responsible for the diuretic acti vity. Alte rnatively, the kinetics of frusemide in the airways might
be different from other diuretics. resulting in stronger
or longer local activity. The phannacok inetic propertics of frusemide and orhe r loor diuretics after inhalatio n have not been investigated. Their protective
e ffect. however, does not appear to depend on lipid
solubilit y, as bumetanide and torasemide are hig hly
lipo philic, whereas frusemide and pirctanide have low
lipid solubi lity [361.
lncre;~ :; ing infonnation is available on the bronchial
effects of drugs active o n differen t ion tra nsport
mechanisms. Inhalation of the Na'/K~ adenosine triphosphatase (ATPase) blocke r. ouabain. does not alter
the bronchial responses to exerc ise Il l. or histamine
132
S. BlANCO ET AL.
(42], in asthmatic patients. The Na+ channeL blocker,
amiloride, has been reported to slightly reduce
bronchoconsniction, but not cough, induced by distilled
water, and to have no significant effect on exercise,
metabisulphite, methacholine and cold air-induced
bronchoconstriction [43, 45]. The carbonic anhydrase
inhibitor, acetazolamide, has been shown to reduce the
bronchial response to cold air and metabisulphite [45].
Finally, it is interesting to note that sodium cromoglycate, an anti-asthmatic drug with a spectrum of
actjvities very similar to frusemide, has recently been
shown to be a potent Cl· channel inhibitor in a mast
cell derived tumour line [46].
These findings suggest that ion transport mechanisms
participate in the control of bronchial reactivity in
asthma, but they do not provide sufficient infonnation
to detennine the exact mechanism(s) involved. As ion
transport pathways are present in virtually every cell
type, all cells suspected to be involved in the pathogenesis of bronchial hyperreactivity in asthma are potential targets for the action of frusemide. However,
since frusemide has little protective activity on bronchoconstrictor stimuli acting directly on smooth
muscle, an effect on these cells appears unlikely. The
effects of loop diuretics [4, 5], and allergen challenge
[47, 48], on ion transport in the airways have mostly
been investigated on the tracheal epithelium of experimental animals. Conflicting results have been reported on the effect of frusemide on human nasal
epitheHum in vivo [23, 49]. The response of nasal
epithelium, however, might not be representative of the
action of frusemide at bronchial level, as we failed to
observe consistent protection for nasal allergen challenge following frusemide inhalation in patients with
allergic rhinitis (unpublished results). Frusemide has
been shown to inhibit allergen-induced histamine release from rat peritoneal mast cells [50], and human
blood cells [51], and to inhibit the release of histamine
and leukotrienes from human lung fragments sensitized
in vitro [52]. Other cells, which have been reported
to be affected by frusemide, include guinea-pig eosinophils [53], as well as human neutrophils [54, 55], alveolar macrophages [56, 57], and bronchial epithelial
cells [57]. No infonnation is available on the effect
of loop diuretics on human airway neurotransmission.
In the guinea-pig, frusemide and bumetanide inhibit
both cholinergic and non-cholinergic neurallymediated bronchoconstriction in vitro, through a
mechanism not influenced by the presence of the
epithelium, and which appears to be mediated by
inhibition of Na+fK+fCl· eo-transport [37].
The possibility that the protective activity of frusemide on bronchial reactions is mediated by prostaglandins has been investigated using cyclooxygenase
inhibitors. Oral treatment with indomethacin and
flurbiprofen failed to affect the protective activity of
frusemide on the response to distilled water and
metabisulphite, respectively, [58, 59]. The effect of
frusemide on exercise-induced bronchoconstriction was
reversed by oral indomethacin treatment [60]. We
have recently observed that inhalation of lysine
acetylsalicylate (LASA) strongly potentiates the protective activity of frusemide against distilled waterinduced responses [61], and that it has an additive effect against a llergen-induced bronchoconstriction [21].
Inhaled sodium salicylate does not potentiate the activity of frusemide, suggesting that the effect of LASA
is due to prostaglandin inhibition [62]. Surprisingly,
the protective effect of frusemide on exercise-induced
reactions also appears to be potentiated by inhaled
LASA [63]. Thus, the effect of non-steroidal, antiinflammatory agents on the protective activity of frusemide appears to depend on the route of administration
and possibly on the stimuli and the drugs used.
Therapeutic perspectives
Taken together, these experimental studies indicate
that frusemide has a wide spectrum of activity not
confined to epithelial cells but extending to other cell
types, including neutrophils, eosinophils, macrophages
and nerve fibres, all of which are involved in the
pathogenesis of asthma. These observations suggest
that frusemide might provide a novel approach to the
treatment of asthma, or might constitute a starting
point for the development of new anti-asthma drugs.
Frusemide has not caused bronchodilatation in any of
the studies detailed above, or in a controlled study in
which specific airway resistance and forced expiratory
volume in one second were monitored for 5 h in a
group of asthmatic patients with airway obstruction
highly reversible after inhalation of fenoterol [64]. In
a more recent study, frusemide did not interact with
salbutamol-induced bronchodilatation, and the two
drugs had an additive protective effect against distilled
water-induced bronchoconstriction [65]. A beneficial
effect of inhaled frusemide, however, can be expected
in patients with bronchial hyperreactivity, due to the
prevention of bronchoconstriction. This possibility is
speculative at present, and controlled clinical studies
to verify the hypothesis are currently being perfonned.
Preliminary results from short-term clinical studies,
showing a small beneficial effect of inhaled frusemide
in patients with severe asthma [66-69], also need
confirmation by ongoing clinical trials. Treatment
with inhaled frusemide should, therefore, not be prescribed outside controlled studies until it has been
formally validated.
The recent observation that the protective activity of
frusemide is greatly potentiated by inhaled LASA and
by other prostaglandin inhibitors [60, 62] raises the
possibility that the association of the two drugs might
provide increased therapeutic activity. Preliminary
results from an open study indicate that combined
treatment with inhaled frusemide and LASA had a
significant steroid-sparing effect in a group of patients
with severe, steroid-dependent asthma [70]. Appropriate controlled studies are needed to confirm this
observation, and to provide more information on the
relative contribution of the two drugs. If confinned,
these results might open new therapeutic perspectives,
particularly for patients with severe asthma, for whom
INHALED LOOP DIURETICS IN ASTHMA
a satisfactory alternative to long-tenn therapy with systemic steroids is not currently available.
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