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Biomedical subjects

P Geppetti

Publications and source records attributed to P Geppetti.

At least 55 records · Page 3Linked to original sources
PubMed1998

Characterization of the endothelin receptor subtype mediating epithelium-derived relaxant nitric oxide release from guinea-pig trachea.

1. The endothelin (ET) receptor subtype that mediates niric oxide (NO)-dependent airway relaxation in tracheal tube preparations precontracted with carbachol and pretreated with indomethacin was investigated. The release of NO induced by ET from guinea-pig trachea using a recently developed porphyrinic microsensor was also measured. 2. ET-1 (1 pM-100 nM) contracted tracheal tube preparations pretreated with the NO-synthase inhibitor, L-NMMA, and relaxed, in an epithelium-dependent manner, preparations pretreated with the inactive enantiomer D-NMMA. The effect of L-NMMA was reversed by L-Arg, but not by D-Arg. 3. The selective ET(B) receptor agonists, IRL 1620 or sarafotoxin S6c, both (1 pM-100 nM) contracted tracheal tube preparations in a similar manner either after treatment with D-NMMA or with L-NMMA. In the presence of the ET(A) receptor antagonist, FR139317 (10 microM), ET-1 administration resulted in a contraction that was similar after either L-NMMA or D-NMMA. In the presence of the ET(B) receptor antagonist, BQ788 (1 microM), ET-1 relaxed and contracted tracheas pretreated with D-NMMA and L-NMMA, respectively. 4. Exposure of tracheal segments to ET-1 (1-1000 nM) caused a concentration-dependent increase in NO release that was reduced by L-NMMA. IRL1620 (1 microM) did not cause any significant NO release. FR139317 (10 microM), but not, BQ788 (1 microM), inhibited the NO release induced by ET-1. 5. These results demonstrate that in the isolated guinea-pig trachea activation of ET(B) receptors results in a contractile response, whereas activation of ET(A) receptors cause both a contraction, and an epithelium-dependent relaxation that is mediated by NO release.

Animals↗
PubMed1998

Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P.

The use of angiotensin-converting enzyme (ACE) has been associated with the occurrence of adverse effects, including cough and angioneurotic edema. Accumulation of kinins has been suggested to play a major role in these adverse effects of ACE inhibitor, although conclusive evidence for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of neurogenic inflammatory mechanisms. Intravenous captopril and enalapril increased the extravasation of Evans blue dye in all tissues examined (trachea, stomach, duodenum, and pancreas). This effect was evident 15 minutes after drug administration. The particulate dye Monastral blue identified the sites of captopril-induced leakage in the microvasculature. Pretreatment with the bradykinin B2 receptor antagonist Hoe 140 or with the tachykinin NK1 receptor antagonist SR 140333 inhibited captopril-evoked increase in plasma extravasation. In mice in which the gene encoding the bradykinin B2 receptor was disrupted by gene targeting, neither bradykinin nor captopril increased plasma extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive response induced by captopril. The present findings suggest that ACE inhibition increases kinin levels in tissues and/or plasma. These increased kinin levels increase microvascular leakage in mouse airways and digestive tract via the release of tachykinins from terminals of primary sensory neurons. Exaggerated kinin production and the subsequent stimulation of peptide release from sensory nerves may be involved in adverse effects of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Endogenous nitric oxide inhibits bronchoconstriction induced by cold-air inhalation in guinea pigs: role of kinins.

Inhalation of cold air in guinea pigs increases total pulmonary resistance (RL), an effect that is mediated by kinins and tachykinins. Bronchoconstriction induced by bradykinin (BK) inhalation in guinea pigs is markedly inhibited by nitric oxide (NO) release from the airway epithelium. We investigated whether endogenous NO modulates the increase in RL induced by inhalation of cold air. In anesthetized and artificially ventilated guinea pigs pretreated with atropine, cold-air inhalation (13 degrees C in the trachea) for 5 min did not increase RL. Pretreatment with intravenous N(G)-nitro-L-arginine methyl ester (L-NAME) (but not with its inactive enantiomer, D-NAME) increased RL, an effect reversed by L-Arg. The increase in RL induced by cold air after L-NAME was abolished by the tachykinin NK2-receptor antagonist SR 48968 or the kinin B2-receptor antagonist, HOE 140. After administration of SR 48968, inhalation of cold air reduced baseline airway tone. However, after HOE 140, cold-air inhalation did not affect baseline airway tone. L-NAME exaggerated the bronchoconstriction induced by BK. However, L-NAME did not affect capsaicin-induced bronchoconstriction. BK increased cyclic guanosine monophosphate (cGMP) levels in strips of guinea pig trachealis muscle in vitro, whereas the selective tachykinin NK2-receptor agonist [betaAla8]neurokinin A (4-10) was without effect. The present data suggest that bronchoconstriction induced by cold-air inhalation and mediated by kinin and tachykinin release is inhibited by endogenous NO, and that kinins, but not tachykinins or cold air alone, release bronchorelaxant NO.

Air↗
PubMed1998

Regulation of airway neurogenic inflammation by neutral endopeptidase.

Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

Animals↗
PubMed1997

The control of microvascular permeability and blood pressure by neutral endopeptidase.

Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides. Thus, absence of NEP may predispose development of inflammation and hypotension. We examined these possibilities in mice in which the NEP gene was deleted by homologous recombination. There was widespread basal plasma extravasation in postcapillary venular endothelia in NEP-/- mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B2) receptors. Mean arterial blood pressure was 20% lower in NEP-/- animals, but this was unaffected by reintroduction of recombinant NEP and the kinin receptor antagonists. The hypotension was also independent of nitric oxide (NO), because NEP-/- mice treated with a NO synthase inhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by degrading SP and BK, and may regulate blood pressure set point through a mechanism that is independent of SP, BK and NO. The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.

Animals↗
PubMed1997

Differential activation of the epithelial and smooth muscle NK1 receptors by synthetic tachykinin agonists in guinea-pig trachea.

1. The presence of tachykinin NK1 receptors have been shown in the epithelium and smooth muscle of guinea-pig airways. Previous data showed that substance P (SP), and the NK1 receptor agonist, [Sar9, Met (O2)11]-SP, relax guinea-pig tracheal tube preparations by stimulation of epithelial NK1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK1 receptor agonist, septide, was unable to produce this effect. The aim of the present study was to investigate the ability of a series of SP analogues to stimulate NK1 receptors of guinea-pig airway epithelium. 2. Isometric tension was recorded in isolated tracheal tube preparations in which compounds were administered intraluminally in the presence of phosphoramidon, indomethacin (both 1 microM) and the tachykinin NK2 receptor antagonist, SR 48,968 ((S)-N-methyl N-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzam ide) (0.1 microM). Cumulative concentration-response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 microM). 3. Contractile responses to low concentrations (0.1-10 nM) of substance P (SP) and the selective agonist of NK1 receptors, [Pro9]-SP. in non precontracted tracheae were higher in preparations pretreated with the NO-synthase inhibitor, NG-monomethyl L-arginine (L-NMMA, 100 microM) than in preparations pretreated with its inactive enantiomer D-NMMA (100 microM). Tracheal tube preparations precontracted with ACh and pretreated with D-NMMA were relaxed by low concentrations of SP and [Pro9]-SP (0.1-10 nM). In contrast, after pretreatment with L-NMMA, SP and [Pro9]-SP contracted tracheae at all the concentrations tested. 4. Concentration-response curves to the NK1 receptor agonists, SP methyl ester, [Apa9-10]-SP and [pGlu6] SP (6-11) obtained in non-precontracted tracheae were similar in the presence of either D-NMMA or L-NMMA. SP methyl ester, [Apa9-10]-SP and [pGlu6] SP (6-11) did not produce any relaxation, but instead, cause contractions in tracheal tube preparations precontracted with ACh and pretreated with D-NMMA. Concentration-response curves produced by all these agonists were similar in preparations precontracted with ACh and pretreated with L-NMMA or D-NMMA. 5. In guinea-pig tracheal tube preparations two groups of NK1 receptor agonists can be distinguished: one group, including [Pro9]-SP, stimulator epithelial NK1 receptors, the other group, including SP methyl ester, [Apa9-10]-SP and [pGlu6] SP (6-11), does not. One possible explanation for these findings and for the existence of compounds with a peculiar 'septide-like' pharmacological profile in the guinea-pig trachea could be the recently proposed phenomenon referred to as 'agonist-directed receptor trafficking'.

Animals↗
PubMed1997

Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas.

Neurogenic inflammation is mediated by release of tachykinins from sensory nerves, which stimulate plasma extravasation from postcapillary venules. Because there are conflicting results regarding the importance of neurogenic inflammation in the gastrointestinal tract, we quantified plasma extravasation using Evans blue and identified sites of the leak using Monastral blue in the mouse. Substance P and bradykinin stimulated extravasation from postcapillary venules in the stomach, small and large intestine, pancreas, urinary bladder, trachea, and skin by two- to sevenfold by interacting with NK1 and B2 receptors, respectively. Stimulation of sensory nerves with capsaicin also induced extravasation. Capsaicin- and bradykinin-stimulated extravasation was attenuated by an NK1-receptor antagonist and is thus mediated by release of tachykinins and activation of the NK1 receptor. We conclude that 1) substance P stimulates extravasation in the gastrointestinal tract and pancreas of mice by interacting with the NK1 receptors, and 2) capsaicin and bradykinin induce plasma extravasation by stimulating tachykinin release from sensory nerves. Thus neurogenic mechanisms mediate inflammation in the gastrointestinal tract and pancreas of the mouse.

Animals↗
PubMed1996

Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma.

BACKGROUND: Bronchoconstriction induced by bradykinin is reduced by the release of nitric oxide (NO) in the airways of guinea pigs. Inhaled NO is known to cause bronchodilatation in asthmatic patients. To find out the role of endogenous NO in airway response to bradykinin in asthma, we examined the effect of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on broncho-constriction after bradykinin challenge in ten patients with mild asthma. METHODS: The study had a randomised, double-blind, placebo-controlled, cross-over design. Participants were studied during two phases, each consisting of 2 study days. After baseline measurements of forced expiratory volume in 1 s (FEV1) participants inhaled an aerosol of L-NMMA or saline (placebo). After 5 min, saline and doubling doses of bradykinin (from 0.25 nmol) were inhaled until FEV1 fell by at least 20% of the post-saline value. The effect of L-NMMA and placebo on airway response to doubling concentrations of methacholine (from 0.03 mg/mL) was then examined. We also assessed the effect of the inactive enantiomer of L-NMMA, D-NMMA, and placebo on bronchoconstriction after bradykinin or methacholine challenge in six of the participants. FINDINGS: The geometric mean of the provocative dose producing a 20% fall in FEV1 to bradykinin was 138.0 nmol (range 48.2-475.2 nmol) after placebo and 11.2 nmol (range 0.9-51.3 nmol) after L-NMMA (p < 0.01). L-NMMA also caused a decrease in the provocative concentration of methacholine producing a 20% fall in FEV1 from 0.93 mg/mL (range 0.12-2.55 mg/mL) to 0.38 mg/mL (range 0.06-0.92 mg/mL; p < 0.01). In contrast, D-NMMA did not affect airway response to bradykinin or methacholine. INTERPRETATION: The results suggest that bronchoconstriction after bradykinin inhalation is greatly inhibited by the formation of NO in airways of asthmatic patients and that NO could have a bronchoprotective role in asthma.

Adult↗
PubMed1996

Increased liposome extravasation in selected tissues: effect of substance P.

We have used a pharmacologic mediator to open intercellular connections in selected vessels to allow liposomes to escape from the blood stream and to extravasate into tissues that have appropriate receptors. We have examined the effects of substance P (SP), a peptide known to increase vascular permeability in selected tissues, such as trachea, esophagus, and urinary bladder in rats. We used quantitative fluorescence analysis of tissues to measure two fluorescent markers, one attached to the lipid (rhodamine-phosphatidylethanolamine) and another, doxorubicin (an anti-tumor drug), encapsulated within the aqueous interior. We have also examined the deposition of liposomes microscopically by the use of encapsulated colloidal gold and silver enhancement. Analysis of the biochemical and morphological observations indicate the following: (i) Injection of SP produces a striking increase in both liposome labels, but only in tissues that possess receptors for SP in postcapillary venules; (ii) liposome material in these tissues has extravasated and is found extracellularly near a variety of cells beyond the endothelial layer over the first few hours; (iii) 24 h following injection of liposomes and SP, liposome material is found in these tissues, localized intracellularly in both endothelial cells and macrophages. We propose that appropriate application of tissue-specific mediators can result in liposome extravasation deep within tissues that normally do not take up significant amounts of liposomes from the blood. Such liposomes are able to carry a variety of pharmacological agents that can be released locally within selected target tissues for therapeutic purposes.

Animals↗
PubMed1996

Cold air-induced bronchoconstriction is mediated by tachykinin and kinin release in guinea pigs.

In the present study, we investigated the role of acetylcholine, tachykinins and kinins in the bronchoconstriction induced by cold air inhalation. Cold air was delivered to anaesthetised, artificially ventilated guinea pigs through a tracheal cannula. Inhalation of cold air increased the maximum total pulmonary resistance (RL) in a time-dependent manner, reaching a maximum after 15 min of exposure. The increase in RL induced by exposure to cold air for 10 min was not affected by pretreatment with atropine (1.4 mu mol/kg, i.v.); it was abolished by the tachykinin NK2 receptor antagonist, SR 48968 (0.3 mu mol/kg, i.v.) and was reduced by 58% by the kinin B2 receptor antagonist, HOE 140 (0.1 mu mol/kg, i.v.). These findings suggest that cold air induces bronchoconstriction in guinea pigs via a cascade that involves the release of kinins and tachykinins.

Animals↗
PubMed1996

Tachykinin and kinin receptor antagonists: therapeutic perspectives in allergic airway disease.

The morbidity of allergic airway disease and the number of deaths resulting from it have not declined in the past ten years. The multiplicity of mediators released in the acute allergic reaction and our limited knowledge of the basic mechanisms that drive chronic inflammation have hampered the design of effective therapeutic regimens for this type of disease. In this article, Claude Bertrand and Pierangelo Geppetti summarize recent studies in which new, potent and selective tachykinin and kinin receptor antagonists demonstrate the involvement of tachykinins and kinins in airway anaphylaxis, and review how these antagonists might be of use in treating allergic asthma and rhinitis.

Animals↗
PubMed1996

Tachykinins mediate the potentiation of antigen-induced bronchoconstriction by cold air in guinea pigs.

The role of tachykinins in the potentiation of antigen-evoked bronchoconstriction induced by inhalation of cold air was studied in guinea pigs. Cold air was delivered through a tracheal cannula to anesthetized, artificially ventilated guinea pigs sensitized with ovalbumin and pretreated with atropine (1.4 micromol/kg). Inhalation of cold air increased total pulmonary resistance (RL) in a time-dependent manner; inhalation of cold air for 10 or 15 minutes, but not for 5 minutes, produced a significant increase in RL. Aerosolized ovalbumin (5 breaths) increased RL in a dose-dependent manner (0.5% to 5%). Inhalation of cold air for 5 minutes significantly enhanced both the peak and the duration of the increase in RL induced by 0.5% ovalbumin. The tachykinin neurokinin 2-receptor antagonist, SR 48968 (0.3 micromol/kg intravenously) inhibited both the peak and the duration of the bronchoconstriction induced by 5-minute inhalation of cold air and ovalbumin (0.5%), whereas it did not affect the response to ovalbumin (0.5%) alone. These findings suggest that exposure to cold air potentiates the bronchoconstriction response to antigen and that this potentiation is mediated by tachykinin release from sensory nerves.

Airway Resistance↗
PubMed1996

The effects of repeated dermal application of capsaicin to the human skin on pain and vasodilatation induced by intradermal injection of acid and hypertonic solutions.

1. The effect of repeated capsaicin application on the skin of the volar surface of the forearm on the pain sensation and on the increase in blood flow induced by intradermal injection of low pH media or hypertonic solutions was investigated in 13 healthy volunteers. 2. Low pH media (4, and 2.5) were obtained by adding HCl to 0.9% saline. Hypertonic solutions (300 and 600 mM) were obtained by adding NaCl to pH 7.4, 0.9% saline. Capsaicin (1% in 50% ethanol) was painted on the volar skin of one forearm, chosen at random, for 7 days. The contralateral forearm was treated with the capsaicin vehicle. Pain was assessed by a visual analogue scale and skin blood flow by a laser doppler flowmeter. 3. Pain sensation and increase in blood flow (both peak and area under the curve) induced by low pH media were markedly reduced in the capsaicin pretreated side. Capsaicin pretreatment also reduced the increase in blood flow, but did not affect the pain response induced by hypertonic saline solutions. 4. Repeated application of capsaicin to the human skin inhibits both the sensory (pain) and 'efferent' (vasodilatation) responses induced by low pH media, whereas it reduces the vasodilatation, but not the pain caused by hypertonic media. 5. Repeated application of capsaicin to the human skin, a therapy used in various diseases, discriminates between sensory, but not 'efferent' responses induced by different stimuli.

Acids↗
PubMed1996

Evidence that tachykinins relax the guinea-pig trachea via nitric oxide release and by stimulation of a septide-insensitive NK1 receptor.

1. This study investigated the possibility that tachykinins relax the guinea-pig isolated trachea by releasing nitric oxide (NO) from the epithelium. The types of tachykinin receptor mediating both relaxation and contraction of the trachea were also studied. Isometric tension was recorded in isolated tracheal tube preparations precontracted with acetylcholine (10 microM) in which compounds were administered intraluminally in the presence of phosphoramidon and indomethacin (both 1 microM) and the tachykinin NK2 receptor antagonist, SR 48,968 ((S)-N-methyl-N[4-(4-acetyl amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), 0.1 microM). 2. In the presence of the inactive enantiomer of an NO-synthase inhibitor, NG-monomethyl-D-arginine (D-NMMA, 100 microM), substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and the selective NK1 receptor agonist, [Sar9, Met(O2)11]-SP, (0.1-10 nM) relaxed tracheal tube preparations. This relaxation was changed into a contraction by pretreatment with the NO-synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA, 100 microM). The effect of L-NMMA on SP- and [Sar9, Met(O2)11]-SP-induced responses was reversed by L-arginine (L-Arg, 1 mM), but not by D-Arg (1 mM). After removal of the epithelium SP, NKA and NKB and [Sar9, Met(O2)11]-SP (0.1-10 nM) evoked contractile responses in the presence of either L-NMMA (100 microM) or D-NMMA (100 microM). The effects of SP and [Sar9, Met(O2)11]-SP obtained in the presence of another NO-synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) or its inactive enantiomer, NG-nitro-D-arginine methyl ester (D-NAME, 100 microM) were similar to those observed with L-NMMA or D-NMMA, respectively. 3. The selective NK1 receptor agonist, [pGlu6, Pro9]-SP(6-11) (septide, 0.1-10 nM) evoked contractile responses of tracheal tube preparations in the presence of either D-NMMA (100 microM) or L-NMMA (100 microM). The log concentration-response curve to septide obtained in the presence of L-NMMA was similar to that obtained in the presence of D-NMMA. [Sar9, Met(O2)11]-SP (0.1-10 nM) relaxed tracheal tube preparations precontracted with septide (1 microM), whereas septide (0.1 nM-1 microM) further contracted tracheal tube preparations precontracted with [Sar9, Met(O2)11]-SP (1 microM). 4. Relaxant and contractile responses evoked by SP, NKA, NKB and by [Sar9, Met(O2)11]-SP (0.1-10 nM) were not affected by a combination of the histamine H1 (pyrilamine, 1 microM) and H2 (cimetidine, 1 microM) receptor antagonists, but were abolished by the tachykinin NK1 receptor antagonist, CP-99,994 ((2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine, 1 microM), though not by its inactive enantiomer CP-100,263 (1 microM). Contractile responses evoked by septide (10 nM and 1 microM) were also abolished by CP-99,994 (1 microM) but not by CP-100,263 (1 microM). 5. These results demonstrate that tachykinins relax guinea-pig tracheal tube preparations by releasing NO via the stimulation of epithelial NK1 receptors by a mechanism independent of histamine release. The NK1 receptor type involved is sensitive to SP, NKA, NKB and [Sar9, Met(O2)11]-SP but not to septide, and is pharmacologically distinct from the NK1 receptor that mediates contraction, which is stimulated by all the agonists, including septide.

Animals↗
PubMed1996

Evidence that epithelium-derived relaxing factor released by bradykinin in the guinea pig trachea is nitric oxide.

Bradykinin, applied locally to the airways, is a weak bronchoconstrictor agent in guinea pigs in vivo and it may cause constriction or dilatation of guinea pig airways smooth muscle in vitro. We examined the motor effect of bradykinin perfused through the lumen of isolated guinea pig tracheal tubes with or without nitric oxide (NO) synthase inhibitors. In the presence of NG-nitro-D-arginine methyl ester (D-NAME) or NG-monomethyl-D-arginine (D-NMMA) intraluminal bradykinin caused a moderate concentration-dependent relaxation. In contrast, in the presence of NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) tracheas developed a sustained increase in tone, and bradykinin caused a marked, concentration-dependent contraction, both effects being reversible by pretreatment with L-arginine, but not with D-arginine. The ability of bradykinin to relax (in the presence of D-NAME) or contract (in the presence of L-NAME) guinea pig tracheal tubes was not affected by indomethacin. Bradykinin contracted epithelium-denuded tracheas in the presence of either L-NAME or D-NAME. Both contraction and relaxation by bradykinin were blocked by the kinin B2 receptor antagonist, HOE 140. Baseline production of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in strips of guinea pig trachealis in vitro was markedly reduced by L-NAME, but not by D-NAME. Bradykinin increased baseline cyclic GMP concentration. These results indicate that bradykinin releases NO or a NO-related molecule, which, possibly by increasing cyclic GMP concentrations, mediates relaxation and opposes contraction induced by bradykinin itself, and further, that bradykinin releases NO from the tracheal epithelium.

Adrenergic beta-Antagonists↗
PubMed1995

Corticotropin-releasing factor inhibits antigen-induced plasma extravasation in airways.

We investigated the potential of corticotropin-releasing factor (CRF) to reduce neurogenic plasma extravasation in sensitised guinea pig airways evoked by antigen challenge. Inhalation of 5% ovalbumin for 2 min in the presence of phosphoramidon (2.5 mg/kg, i.v.) increased extravasation of Evans blue dye in the trachea and main bronchi. The increase in plasma extravasation induced by antigen challenge was significantly reduced by pretreatment with CRF (30 nmol/kg, i.v.) (73% in the trachea and 42% in the main bronchi). The inhibition of plasma extravasation by CRF (30 nmol/kg, i.v.) alone was not different from the inhibition induced by the combination of CRF and the tachykinin NK1 receptor antagonist, CP-99,994 (4 mg/kg, i.v.) (73% in the trachea and 38% in the main bronchi). CRF (30 nmol/kg, i.v.) inhibited by 32% in the trachea and by 43% in the main bronchi plasma extravasation induced by aerosolised bradykinin but did not reduce the plasma extravasation caused by aerosolised substance P in the presence of phosphoramidon. These findings suggest that CRF reduces ovalbumin-induced plasma extravasation in guinea pig airways by inhibiting the release of tachykinins from primary sensory nerves.

Animals↗