Does use or withdrawal of long-acting beta 2-adrenoceptor induce desensitisation?
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Adrenergic beta-2 Receptor Agonists↗
Biomedical subjects
M Molimard
Publications and source records attributed to M Molimard.
Muscarinic stimulation of airway smooth muscle cells.
1. Acetylcholine, the principal neurotransmitter of the parasympathetic nervous system, is released at both ganglionic synapses and postganglionic neuroeffector junctions and acts by activation of nicotinic and muscarinic cholinoceptors. This review focuses on the effects of postjunctional muscarinic stimulation of airway smooth muscle. 2. On pharmacological criteria, four distinct subtypes of muscarinic cholinoceptor, denoted M1, M2, M3 and M4 receptors, have been identified by use of selective antagonists. Cloned muscarinic cholinoceptors are members of the family of GTP-binding protein-coupled receptors, which are characterized by seven transmembrane (TM) regions connected by intra- and extracellular loops. Between the fifth and the sixth TM regions, muscarinic receptors possess a large intracytoplasmic loop that is considered to be responsible for G-protein-coupling selectivity and exhibits high divergence between the different subtypes. 3. At the site of the smooth muscle itself, both binding and Northern blot studies have demonstrated, in a variety of species, that muscarinic receptor subtypes present are M2 and M3. M2 receptors are coupled to Gi proteins and adenylyl cyclase inhibition and thus to cAMP signaling. M3 receptors are coupled to Gq/11 protein and phosphoinositide hydrolysis and thus to calcium signaling. 4. Muscarinic-induced contraction of airway smooth muscle is mediated by M3 receptors. M2-mediated inhibition of adenylyl cyclase contributes to the prevention of bronchodilation. Cross-talk between muscarinic and beta2 adrenoceptors is likely to be present in airway smooth muscle. The pathophysiological role of this cross-talk requires further investigation.
Cholinergic Agents↗
In vitro-induced human airway hyperresponsiveness to bradykinin.
Lipopolysaccharide (LPS) and interleukin (IL)-1beta have been reported to induce airway hyperresponsiveness in several animal models. This study investigated the effect of LPS or IL-1beta on bradykinin-induced human isolated bronchi contraction. LPS (100 ng x mL(-1) for 3-6 h) and IL-1beta (3x10(-10) and 3x10(-9) M for 20 min to 3 h) time-dependently potentiated bradykinin-induced contraction. This contraction was abolished, as in control experiments, by indomethacin (10(-6) M) or by the thromboxane (Tx) receptor antagonist GR 32191 but not by the cyclo-oxygenase-2 inhibitor, CGP28238. In contrast, the Tx mimetic U46619-induced contraction of human bronchi was not enhanced IL-1beta pretreatment. In the presence of GR 32191 (10(-6) M), bradykinin induced a prostanoid dependent relaxation that was not significantly modified by IL-1beta pretreatment. Determination of prostanoids in the organ bath fluid showed that bradykinin induced TxB2, the stable metabolite of TxA2, and 6-keto prostaglandin F1alpha, the stable metabolite of PGI2, release. Only TxA2 release was potentiated by IL-1beta. Taken together our results suggest that interleukin-1beta (1-3 h)-induced potentiation of the effect of bradykinin is linked to an increased activity of thromboxane synthase and, in turn, to increased thromboxane synthesis.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Long- and short-acting beta2 adrenoceptor agonists: interactions in human contracted bronchi.
The aim of this study was to systematically compare the interaction of the long-acting beta2-adrenoceptor agonists formoterol and salmeterol with short-acting beta2-adrenoceptor agonists in contracted human bronchi. Human bronchi were obtained at thoracotomy from patients with lung cancer. Formoterol or salmeterol at concentrations inducing up to 92 and 94% of their maximal relaxant effect, respectively, were added to bronchial rings contracted with carbachol (10(-6) M). After a time period of 30 min, concentration-response curves for the short-acting beta2-adrenoceptor agonists, salbutamol, terbutaline, isoprenaline and fenoterol were recorded. Administration of equieffective concentrations of salmeterol and formoterol, resulted in only salmeterol inducing a shift to the right of isoprenaline, terbutaline, fenoterol and salbutamol concentration-response curves. The rank order of shift was salbutamol > fenoterol > terbutaline > isoprenaline. Formoterol, up to concentrations of 3x10(-9) M induced submaximal relaxation resulting in no shift in short-acting beta2-adrenoceptor agonist concentration-response curves. Salmeterol but not formoterol appears to antagonize the relaxation of human contracted bronchi induced by short-acting beta2-agonists. These results obtained in vitro cannot be translated in clinical terms. This study, however, highlights the need for clinical studies on the interaction of long-acting and short-acting beta2-adrenoceptor agonists in acute severe asthma.
Adrenergic beta-Agonists↗
Circulating immune complexes in human tuberculosis sera: demonstration of specific antibodies against Mycobacterium tuberculosis glycolipid (DAT, PGLTb1, LOS) antigens in isolated circulating immune complexes.
An enzyme-linked immunosorbent assay (ELISA) for IgG using three glycolipid antigens from Mycobacterium tuberculosis in 65 tuberculosis (TB) patients and 50 healthy control subjects was performed. The circulating immune complexes (CICs) were isolated by precipitation with polyethylene glycol 6000 (PEG). This method associated to ELISA measured the specific antibodies present in these CICs. PEG [optical density (OD) 280] was shown to be significantly elevated (P < 0.001) in tuberculous samples. The concentrations of IgG antibodies complexed to the three glycolipid antigens were shown to be higher in patient with tuberculosis than in normal control subjects (P < 0.001). No correlation was observed between levels of free and CIC-bound antibodies. These antibodies isolated from CICs were responsible for almost all of the false-negative serological results. However, great heterogeneity was noticed depending on the antigen used, showing a more positive ELISAs against DAT (77%) than against LOS (71%) or PGLTb1 (18.5%). No correlation was established between the presence of specific CIC-complexed IgG and the bacteriological load or the tuberculosis localization (pulmonary vs. extrapulmonary). The sensitivity of ELISA for CIC-complexed IgG to DAT and LOS was lower in HIV-infected TB patients. From these results, we conclude that detection of complexed IgG DAT and LOS glycolipid antigen will be useful as a complementary technique for the serodiagnosis of tuberculosis.
Adult↗
SR 140333 prevents potentiation by citric acid of plasma exudation induced by histamine in airways.
We here report a model of potentiation by citric acid of airway microvascular leakage induced by histamine and its modification by the tachykinin NK1 and NK2 receptor antagonists, SR 140333 ((S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)p iperidin- 3-yl]ethyl}-phenyl-1-azoniabicyclo[2.2.2]octane, chloride) and SR 48968 (S)-N-methyl-N-[4-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4- dichlorophenyl-butyl]benzamide. Guinea-pigs exposed to an acrosol of citric acid 0.4 M for 1 h developed 24 h later a hyperresponsiveness to histamine-induced microvascular leakage measured by Evans blue dye extravasation. SR 140333, but not SR 48968 (1 mg kg-1 given each once 30 min before citric acid exposure), prevented this potentiation. These results provide further evidence of the role of tachykinin and tachykinin NK1 receptor stimulation on airway hyperresponsiveness and its neurogenic inflammatory component.
Animals↗
The human bronchus model in vitro. Pharmacological approach of various components involved in the functional response.
Studying the human bronchi in vitro, and therefore sheltered from the toxicity problems inherent in human experiments, makes it possible to conduct a monofactorial analysis, disregarding the perturbations engendered by reflex phenomena, hemodynamic changes, etc. Analysing the effects of mediators on tissues may be less simple that it looks, due to the multiplicity of the cell types that are present. For example, in studying the effects of bradykinin we have shown that bradykinin is a potent contractile agent of small-diameter isolated bronchi, whereas it has no significant contractile effect on larger bronchi. The bradykinin-induced contraction results from a contractile component due to stimulation of the TP receptor, and of a relaxant component due to relaxant prostanoids. The two components of the bradykinin effects are produced by stimulation of B2 receptors. In vitro stimulation of bronchi by LPS or interleukin-1 beta permits us to obtain hyperreactivity to bradykinin due to induction of thromboxane synthetase or isomerase rather than to induction of B2 receptors or cyclooxygenase. Involvement of the nervous system may persist in the in vitro bronchial model, and indeed we have shown, for example, that pentamidine, well known for its tussigenic effect, is an indirect parasympathomimetic compound. Thus, study of the isolated bronchus permits an approach to the mechanisms of action of medicinal drugs. Despite the simplification provided compared to the in vivo study, analysis of bronchoreactivity on the isolated bronchus must take into account numerous parameters which interfere with the proper effects of the substances.
Bronchi↗
Influence of methoctramine on the acetylcholine-isoprenaline functional antagonism in the guinea pig isolated trachea.
It has been suggested that activation of muscarinic M2 receptors is one of the components of the functional antagonism between muscarinic and beta-adrenoceptor agonists in canine and guinea pig tracheal smooth muscle. The aim of the present study was to determine in the guinea pig trachea the importance of this component according to the magnitude of the acetylcholine-induced contraction. Cumulative concentration-response curves for isoprenaline were obtained in the absence or presence of the muscarinic M2 receptor antagonist methoctramine (3 x 10(-7) M) in tracheal rings under basal tension or precontracted by acetylcholine 2 x 10(-7), 3 x 10(-6) and 10(-4) M, giving contractions of 25, 50 Or 75%, respectively, of the maximal tension induced by acetylcholine 3 x 10(-3) M. In the absence of methoctramine, acetylcholine induced a concentration-dependent shift of the concentration-response curves of isoprenaline (-log EC50 of isoprenaline are 8.09 +/- 0.07, 7.85 +/- 0.08, 7.38 +/- 0.12 and 6.49 +/- 0.12, n = 6 for basal tension and for acetylcholine concentrations of 2 x 10(-7), 3 x 10(-6) and 10(-4) M, respectively). In the presence of methoctramine, the basal -log EC50 of isoprenaline was unmodified, whereas the acetylcholine induced shifts of concentration-response curves of isoprenaline were abolished for low levels of contraction (25%) and significantly reduced to 50 and 75% levels of contraction. Under similar conditions, acetylcholine-induced shifts of concentration-response curves of isoprenaline were unmodified by the muscarinic M1 receptor antagonist pirenzepine (10(-7) M). These results suggest that the inhibitory effect of M2 receptors on beta-adrenoceptor agonists effects is important for low contraction levels induced by acetylcholine, and that this effect becomes less important for higher concentrations of acetylcholine.
Acetylcholine↗
Indirect muscarinic receptor activation by pentamidine on airway smooth muscle.
1. Pentamidine is routinely used to reduce the incidence of Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus, but it has been described as inducing pulmonary adverse effects, such as cough and bronchospasm. 2. In this paper we have investigated the effects of pentamidine on guinea-pig isolated main bronchi and human isolated bronchi. Pentamidine induced a concentration-dependent contraction in both preparations with pD2 values of 9.64 +/- 0.07 (n = 8) and 9.73 +/- 0.06 (n = 8) and a maximal effect (Emax) of 40 +/- 4% and 34 +/- 5% of the response to acetylcholine (1 mM) in guinea-pig and human bronchi respectively. Atropine (0.01 to 0.1 microM) and the muscarinic M3 receptor antagonist, hexahydro-siladiphenidol (0.1 and 1 microM) inhibited pentamidine-induced concentration-responses in both preparations in a non-competitive manner, whereas only high concentrations of the M1 receptor antagonist pirenzipine (1 microM) inhibited pentamidine concentration-response curves. 3. The cholinesterase inhibitor, tacrine (1 microM), potentiated the effect of pentamidine; in contrast, morphine inhibited pentamidine-induced responses. 4. The bronchoconstrictor effect of pentamidine on guinea-pig and human isolated bronchi was not modified by the H1 histamine receptor antagonist, mepyramine, by indomethacin or by the neurokinin NK1 and NK2 receptor antagonists, CP-96,345 and SR 48969 respectively, suggesting that neither histamine receptor stimulation, arachidonic acid derivative formation, nor tachykinin release are involved in pentamidine-induced contraction of human and guinea-pig airways. 5. Our overall results suggest that pentamidine induces contraction of guinea-pig and human isolated bronchi through prejunctional cholinergic nerve stimulation.
Adult↗
Evidence for functional tachykinin NK1 receptors on human isolated small bronchi.
On human small isolated bronchi (diameter < 1 mm), but not on larger bronchi (diameter 3-5 mm), substance P (SP) and specific tachykinin SP-preferring neurokinin (NK1) receptor agonists {[beta Ala4, Sar9, Met(O2)11]SP-(4-11), [Sar9, Met(O2)11]SP, [Arg6,Sar9,Met(O2)11]SP-(6-11), and septide; 10(-10) to 10(-6) M} produced a concentration-dependent contraction that occurred at low concentrations (pD2 values of 7.79-8.33) and was characterized by a low intrinsic activity [maximal effect (Emax) of 38-45% of Emax induced by 3 mM acetylcholine, in a noncumulative manner]. Comparison of cumulative and noncumulative concentration-response curves to SP and NK1 receptor agonists suggest rapid receptor desensitization. The SP (10(-8) M)-induced contraction was inhibited by tachykinin NK1 receptor antagonists (rank order of potency: SR-140333 > CP-96,345 > RP-67580) but not by the tachykinin NK2 receptor antagonist SR-48968. Indomethacin (10(-6) M) abolished the SP-induced contraction. Our results suggest that tachykinin NK1 receptors are present on human small bronchi and that their stimulation induces a prostanoid-dependent contraction. The small isolated bronchus is an interesting model of human tissue to test NK1 receptor antagonists.
Benzamides↗
Furosemide inhibits bradykinin-induced contraction of human bronchi: role of thromboxane A2 receptor antagonism.
Bradykinin contracts human isolated small bronchi through prostanoid release and subsequent TP receptor stimulation. Furosemide 10(-4) to 10(-3) M concentration dependently inhibited bradykinin- and the stable TP receptor agonist U-46619-induced contraction of human isolated small airways. The inhibitory effect of furosemide on U-46619-induced contraction involves competitive antagonism at TP receptors. Such an inhibition of TP receptors could a least partly explain the inhibitory effect of furosemide on bradykinin-induced contraction, and could be one of the mechanisms of the protective effect of furosemide in asthma.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Role of thromboxane A2 in bradykinin-induced human isolated small bronchi contraction.
We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
In vitro effects of HOE 140 in human bronchial and vascular tissue.
Bradykinin is a potent inflammatory mediator which may be involved in various airway diseases. A selective and potent antagonist of the bradykinin B2 receptor has recently been discovered (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin). The purpose of this study was to evaluate the potency of this compound in isolated human tissue (bronchus, pulmonary artery endothelium, umbilical artery and vein smooth muscle). Bradykinin induced contractions of the isolated human bronchus and umbilical artery and vein (the umbilical vessels were pretreated with indomethacin and L-nitro-arginine to inhibit prostaglandin and nitric oxide synthesis). It provoked an endothelium-dependent relaxation in the human pulmonary artery. HOE 140 was a non-competitive antagonist in human bronchial tissue (pKB: 8.19 +/- 0.30) and a competitive one in vascular tissue (pA2: 7.97 +/- 0.12, 8.16 +/- 0.16 and 8.00 +/- 0.11 in human pulmonary artery, umbilical artery and vein respectively). The effect of HOE 140 was selective as it did not influence the umbilical vein contractile response to serotonin and histamine. HOE 140 up to 3 x 10(-6) M was devoid of residual agonistic activity in the various human preparations studied. Furthermore, although the effects of HOE 140 were fully reversible, in isolated bronchial airways and umbilical veins, HOE 140 (10(-6) M) still possessed activity 1 h after being washed out in both tissues. Our results indicate that HOE 140 is a potent and potentially long-acting antagonist of the human bradykinin B2 receptor.
Binding Sites↗
Analysis of the immunological humoral response to Mycobacterium tuberculosis glycolipid antigens (DAT, PGLTb1) for diagnosis of tuberculosis in HIV-seropositive and -seronegative patients.
Using an enzyme immunoassay (EIA) test, the concentrations of IgG antibodies against 2,3 diacyl trehalose (DAT) and phenolic glycolipid Tb1 (PGLTb1) were measured in the sera of 153 patients with active tuberculosis, 50 of whom were coinfected with HIV, and in the sera of 152 healthy blood donors, 149 asymptomatic HIV-seropositive patients, 12 HIV-seronegative patients with conditions simulating tuberculosis, 23 HIV-seropositive patients with disseminated infection caused by mycobacteria other than tuberculosis and 24 HIV-seropositive patients with pulmonary disease from whom mycobacteria was not isolated in culture. A slightly lower percentage (74%) of the HIV-seropositive than the HIV-seronegative (77%) tuberculosis patients were positive for anti-DAT and anti-PGLTb1 IgG antibodies, with a specificity ranging from 91 to 95%. There was no significant difference between EIA sensitivity in smear-positive and smear-negative patients with pulmonary tuberculosis for all HIV immune statuses and sites of disease (pulmonary vs. extrapulmonary). In HIV-seropositive patients, however, sensitivity was always lower for disseminated tuberculosis than for localized tuberculosis. Combining data for both the smear test and the EIA maximized sensitivity. The main value of the EIA test could be to provide early complementary information by antibody detection in patients with tuberculosis, particularly those with a negative smear test.
Adult↗
Contractile effects of bradykinin on the isolated human small bronchus.
Bradykinin (Bk) induced a contraction in all small bronchi samples (diameter, 0.5 to 1 mm) from 20 patients. pD2 was 7.7 +/- 0.1 (pD2 = -log EC50) and maximal effect (Emax) was 36.2 +/- 4.7% of the maximal response to acetylcholine. The B2 agonist [Hyp3TyrMe8]Bk contracted airway smooth muscle with a pD2 of 7.8 +/- 0.2 and an Emax of 39 +/- 9%. The B1 agonist [Sar1dPhe8desArg9]Bk induced only a weak contraction at 10(-6) M. The effect of Bk was abolished by the B2 (Hoe 140) but not by the B1 [Leu8desArg9]Bk receptor antagonist. Indomethacin 10(-6) M abolished Bk-induced contraction, suggesting that cyclooxygenase products are involved in Bk action. Capsaicin 10(-5) M, which selectively depletes C fibers from airway mediators through the ruthenium red pathway, and ruthenium red 10(-5) M significantly inhibited the concentration-response curves to Bk. However, tetrodotoxin (+/-)-CP-96,345, SR 48968, and atropine did not significantly affect Bk concentration-response curves, suggesting that nerve conduction, substance P (SP), neurokinin A (NKA), and acetylcholine release are not involved in Bk action. Our data indicate that Bk contracts human distal airway smooth muscle through the Bk B2 receptor and a cyclooxygenase pathway. This effect appears to involve capsaicin and ruthenium red pathways but neither acetylcholine nor NKA and SP release.
Acetylcholine↗
Effect of furosemide on prostaglandin synthesis by human nasal and bronchial epithelial cells in culture.
Inhaled furosemide protects asthmatic subjects against bronchial obstruction caused by indirect provocants. We have attempted to correlate the protective effect of furosemide with its ability to alter prostaglandin (PG) synthesis by the airway epithelium. Human epithelial cells from nasal polyps and bronchi were cultured in DME-Ham's F12 medium with 10% fetal calf serum. Confluent cells (days 6 through 8) were incubated for 30 min in fresh medium, and the PGs in the supernatant were measured by radioimmunoassay. Spontaneous output (ng.ml-1.mg-1 cell protein) was as follows (mean +/- SEM): PGE2 = 7.74 +/- 2.10 (n = 12), PGF2 alpha = 1.66 +/- 0.12 (n = 15), 6-keto-PGF1 alpha = 4.32 +/- 1.37 (n = 11), PGD2 = 0.73 +/- 0.16 (n = 11) for bronchial cells and PGE2 = 7.24 +/- 0.80 (n = 32), PGF2 alpha = 1.38 +/- 0.12 (n = 17), 6-keto-PGF1 alpha = 6.79 +/- 2.50 (n = 15), PGD2 = 0.42 +/- 0.07 (n = 17) for nasal cells. Incubation with arachidonic acid (25 micrograms/ml) for 30 min significantly increased the amounts of the four PGs. Incubation with furosemide (10(-4) M) for 30 min caused a marked reduction in both basal and arachidonic acid-stimulated production of PGE2 and PGF2 alpha but did not reduce production of 6-keto-PGF1 alpha and PGD2. Incubation with bumetanide (10(-4) M) for 30 min did not modify the PGE2 synthesis by nasal epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
6-Ketoprostaglandin F1 alpha↗
Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neurotransmission in guinea-pig bronchi.
Theophylline has been reported to inhibit excitatory noncholinergic but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might exert this effect through an inhibition of phosphodiesterases (PDE), and since many types of PDE have now been described, the aim of this study was to investigate the effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazodan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, respectively. Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin 10(-6) M and propranolol 10(-6) M. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. Rolipram (10(-9) to 10(-6) M) but not siguazodan or zaprinast, inhibited the peptidergic contraction in a concentration-dependent manner. Conversely, the cholinergic response was unaffected. Contractile responses induced by exogenous acetylcholine (10(-8) to 10(-3) M) or [Nle10]NKA(4-10) (10(-10) to 10(-6) M) were also unaffected by rolipram, siguazodan and zaprinast (10(-7) M). These results demonstrate that concentrations of rolipram, similar to those which inhibit PDE, reduce the release of sensory neuropeptides from C-fibre endings, and suggest that the cyclic adenosine monophosphate (AMP) PDE type IV is specifically involved in this effect, as in other anti-inflammatory effects.
Animals↗
Effect of frusemide on bradykinin- and capsaicin-induced contraction of the guinea-pig trachea.
Frusemide, a loop diuretic, inhibits the bronchial response to various bronchoconstrictor stimuli in asthmatic subjects. The underlying mechanisms remain unclear. In order to determine whether frusemide inhibits pharmacologically induced C-fibre stimulation, we investigated the effect of frusemide on bradykinin-, capsaicin-, neurokinin A-, and substance P-induced contraction of the guinea-pig isolated trachea. Frusemide 10(-5) and 10(-4) M produced a significant inhibition of concentration-response curves to bradykinin, which was markedly reduced by indomethacin 10(-6) M. Frusemide significantly reduced capsaicin-induced contraction only in the presence of indomethacin 10(-6) M. Neurokinin A- and substance P-induced contractions were not affected by frusemide and/or indomethacin. Our data suggest that a cyclo-oxygenase pathway is involved in the inhibition by frusemide of the bradykinin-induced contraction, but not in the inhibition of the capsaicin-induced contraction.
Animals↗