Biomedical subjects

P Geppetti

Publications and source records attributed to P Geppetti.

At least 73 records · Page 4Linked to original sources

PubMed1995

Buspirone, but not sumatriptan, induces miosis in humans: relevance for a serotoninergic pupil control.

BACKGROUND AND OBJECTIVE: Drugs that act on the serotoninergic system have been shown to influence the pupil size. However, the 5-hydroxytryptamine (5-HT) receptor type or subtype that affects pupil diameter has not been defined in humans. With a placebo-controlled, double-blind randomized design, we investigated in healthy volunteers the effect on pupil size of buspirone and sumatriptan, which mainly act on 5-HT1A- and the 5-HT1-like receptors, respectively. METHODS: The pupil area was measured by means of a videopupillometer before and after a single oral administration of placebo or of three different doses of active drugs. Heart rate and arterial blood pressure were recorded after pupil area measurement. RESULTS: Buspirone (5, 10, and 20 mg) caused a dose-dependent miosis. Sumatriptan (50, 100, and 200 mg) did not affect the pupil size. Twenty milligrams of buspirone reduced the mydriasis induced by pretreatment with homatropine eyedrops. A 20 mg dose of buspirone reduced blood pressure without change in heart rate, whereas buspirone, at doses lower than 20 mg, and sumatriptan did not affect heart rate and blood pressure. CONCLUSIONS: This study suggests that buspirone, but not sumatriptan, the selective agonist of 5-HT1-like receptors, causes miosis in humans by activation of 5-HT1A receptors, possibly located in the central nervous system where they inhibit iris sympathetic pathways. Measurement of pupil size seems to provide a valuable and sensitive index of 5-HT1A receptor function in humans.

Administration, Oral↗

PubMed1995

Nedocromil sodium reduces allergen-induced plasma extravasation in the guinea pig nasal mucosa by inhibition of tachykinin release.

The effect of topically applied (10 microliters) nedocromil sodium (NS) and sodium cromoglycate (CS) on the plasma extravasation induced by local application of ovalbumin (5%, 10 microliters) into the respiratory nasal mucosa of sensitized guinea pigs pretreated with the neutral endopeptidase inhibitors, phosphoramidon, was studied. Topical NS (220 nmol, 10 microliters) reduced by 57% the Evans blue dye extravasation caused by local application of ovalbumin into the nasal mucosa, whereas CS (220 nmol, 10 microliters) was without effect. The tachykinin NK1 receptor antagonist CP-99994 (2 mumol/kg, i.v.) reduced by 45% the plasma extravasation induced by antigen challenge. The combination of NS and CP-99994 did not increase further the inhibition caused by NS alone. Plasma extravasation evoked by instillation of bradykinin (50 nmol), which causes this response by releasing tachykinins from sensory nerves, was markedly reduced by NS, but not by CS. Plasma extravasation evoked by installation of substance P, which acts directly on the endothelial cells, was not affected by NS. We conclude that the reduction by NS of the plasma extravasation induced by antigen challenge in the nasal mucosa of sensitized guinea pigs is due to the inhibition of tachykinin release from sensory nerve endings.

Allergens↗

PubMed1995

Inhibition of bradykinin-evoked trigeminal nerve stimulation by the non-peptide bradykinin B2 receptor antagonist WIN 64338 in vivo and in vitro.

1. This study investigated the effect of the recently described non-peptide bradykinin B2 receptor antagonist, WIN 64338 ([[4-[[2- [[bis(cyclohexylamino)methylene]amino]-3-(2-naphthalenyl)-1-oxopropyl] amino]phenyl]methyl]tributylphosphoniumchloride monohydrochloride), in experimental models of bradykinin-evoked sensory nerve stimulation. 2. In the rabbit isolated iris sphincter in vitro, bradykinin-evoked contractile responses are mediated via tachykinins released from peripheral endings of the trigeminal sensory nerve. WIN 64338 (1-10 microM) competitively antagonised contractile responses to bradykinin with a pKB estimate of 6.6 +/- 0.1 (n = 11). The antagonism was selective since WIN 64338 (10 microM) did not significantly inhibit submaximal contractile responses to the direct-acting spasmogens substance P (10 nM), neurokinin A (3 nM), substance P methyl ester (10 nM) or senktide (100 nM); nor by sensory non-adrenergic non-cholinergic nerve stimulation evoked by capsaicin (10 microM), or electrical field-stimulation (3, 10, 30 Hz) (P > 0.05; n = 3-11). 3. Topical application of bradykinin to the conjunctiva and to the nasal mucosa of the guinea-pig in vivo causes plasma extravasation predominantly via the release of tachykinins from peripheral endings of the trigeminal nerve. The increases in plasma extravasation (measured by extravasation of Evans blue dye) induced by bradykinin in the guinea-pig conjunctiva (20 nmol) and nasal mucosa (50 nmol) were markedly reduced (by 81 +/- 3% and 69 +/- 5%, respectively) following pretreatment with WIN 64338 (30 nmol kg-1, i.v.) (n = 5-6; P < 0.05), with almost complete inhibition at a higher dose of WIN 64338 (300 nmol kg-1, i.v.; n = 5-6). This inhibition was selective since at 300 nmol kg-1, WIN 64338 did not inhibit plasma extravasation evoked by substance P in the conjunctiva (5 nmol; P > 0.05; n = 6) or in the nasal mucosa (50 nmol; P > 0.05; n = 5). 4. This study demonstrates that WIN 64338 is a selective and competitive bradykinin B2 receptor antagonist and can be useful for analysing bradykinin-evoked trigeminal nerve stimulation both in vitro and in vivo.

Animals↗

PubMed1995

Involvement of tachykinins in plasma extravasation induced by bradykinin and low pH medium in the guinea-pig conjunctiva.

1. The effect of bradykinin, capsaicin, substance P and low pH medium on plasma extravasation in the guinea-pig conjunctiva has been studied. Evans blue dye was measured in the conjunctiva after local instillation of the agents into the conjunctival sac. 2. Bradykinin (2-50 nmol), capsaicin (20-50 nmol) and substance P (0.5-5 nmol) caused a dose-dependent increase in plasma extravasation with the following order of potency: substance P > bradykinin = capsaicin. The effect of capsaicin (50 nmol) and substance P (5 nmol) was abolished by the tachykinin NK1 receptor antagonist, CP-99,994 (8 mumol kg-1, i.v.) (P < 0.01), whereas CP-100,263 (8 mumol kg-1, i.v.) the inactive enantiomer of CP-99,994 was without effect. CP-99,994 inhibited by 70% (P < 0.01) the effect of bradykinin. 3. The kinin B2 receptor antagonist, Hoe 140 (icatibant, 10 nmol kg-1, i.v.) abolished the response to bradykinin (50 nmol) (P < 0.01), but did not affect the responses to capsaicin (50 nmol) or substance P (5 nmol). Plasma extravasation induced by low pH medium (pH 1) was abolished by CP-99,994 (P < 0.01) and by Hoe 140 (P < 0.01). 4. The present findings suggest that: endogenous or exogenous tachykinins increase plasma extravasation in the guinea-pig conjunctiva by activation of NK1 receptors; bradykinin-induced plasma extravasation is mediated by tachykinin release from sensory nerve endings; low pH media cause plasma extravasation via release of kinins that by activation of B2 receptors release tachykinins from sensory nerve endings.

Animals↗

PubMed1995

New aspects on the role of kinins in neurogenic inflammation.

The inflammatory response to injury consists of the activation of several protective mechanisms involving different cellular systems. Among the mechanisms and systems that exert their effects rapidly, peptide transmitters released from peripheral endings of primary sensory neurons (evoking neurogenic inflammation) play a major role in the response to tissue injury. Noxious stimuli may directly activate sensory nerves to release proinflammatory neuropeptides. More recently, evidence has accumulated suggesting that indirect mechanisms leading to sensory neuropeptide release are also activated in relevant models of pathophysiological conditions. Tachykinin NK1 and NK2 receptor antagonists reduced the plasma extravasation in the trachea and nasal mucosa and the bronchoconstriction caused by antigen challenge in sensitized guinea-pigs. Blockage of kinin B2 receptors with the selective antagonist HOE-140 had a similar inhibitory effect. The magnitude of the inhibition observed with the kinin receptor antagonist alone was similar to that caused by a combination a tachykinin and kinin receptor antagonists. This suggests activation of a common final pathway by these two groups of mediators. Pharmacological and biochemical evidence suggests that in the airways of sensitized guinea-pigs, kinins released by the anaphylactic reaction stimulate the release of tachykinins from sensory nerves, thus contributing to their proinflammatory action.

Anaphylaxis↗

PubMed1995

NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea.

In neurogenic inflammation, tachykinins trigger the adhesion of neutrophils and eosinophils to leaky venules. The goals of the present study were to determine whether this leukocyte adhesion is mediated by neurokinin type 1 (NK1) receptors and to determine whether the amount of leukocyte adhesion corresponds to the amount of plasma leakage. Anesthetized rats were injected intravenously with substance P, the NK1 receptor agonist [Sar9, Met(O2)11]-substance P, or the NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10). Five minutes later, the adherent neutrophils and eosinophils in blood vessels of the tracheal mucosa were stained histochemically and plasma leakage was quantified, as assessed by the extravasation of Monastral blue. Substance P and the NK1 agonist caused similar amounts of leukocyte adhesion, but the NK2 agonist had no effect. Pretreatment with the NK1 receptor antagonist CP-96,345 (4 mg/kg iv), before challenge with substance P, capsaicin, or aerosol hypertonic saline, reduced the amount of neutrophil adhesion by 56%, 93%, and 57% and reduced the amount of eosinophil adhesion by 70%, 83%, and 65%, respectively. Plasma extravasation was decreased by 89%, 95%, and 94%. The number of adherent neutrophils in the trachea was strongly correlated with the number of adherent eosinophils (r2 = 0.61). The greatest amount of leukocyte adhesion occurred in larger diameter venules than did the maximal amount of Monastral blue leakage. We conclude that NK1 receptors mediate the adhesion of neutrophils and eosinophils as well as the plasma leakage triggered by substance P, capsaicin, or hypertonic saline. This leukocyte adhesion evidently does not occur at exactly the same sites as the plasma leakage.

Animals↗

PubMed1995

Viral infection potentiates the increase in airway blood flow produced by substance P.

We examined the effect of respiratory tract infection with Sendai virus on the responsiveness of airway blood flow to substance P (SP) in rats. Pathogen-free rats were inoculated with either Sendai virus suspension or sterile viral growth medium into each nostril. Five days later, we measured airway and esophageal blood flows before and immediately after injection of SP or histamine into the left ventricle of rats in both groups using a modification of the reference-sample microsphere technique. Viral infection potentiated the increase in airway blood flow evoked by SP but not by histamine. We also examined the effect of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) on the SP-induced increase in airway blood flow. Both phosphoramidon (NEP inhibitor) and captopril (ACE inhibitor) potentiated the increase in airway blood flow produced by SP in pathogen-free rats. In the presence of both peptidase inhibitors, a submaximal dose of SP increased blood flow to a similar level in infected and pathogen-free rats. Thus decreased activity of both ACE and NEP may be involved in the exaggerated increase in airway blood flow evoked by SP in virus-infected rats.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects.

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.

Adult↗

PubMed1995

Plasma extravasation in the rat trachea induced by cold air is mediated by tachykinin release from sensory nerves.

Cold air was delivered to anesthetized, artificially ventilated, pathogen-free F344 rats via a tracheal cannula. Inhalation of cold air increased Evans blue dye extravasation in the trachea in a time-dependent (1 to 10 min) manner. Plasma extravasation increased after 3 min exposure to cold air and reached a maximum after 10 min exposure. The neutral endopeptidase inhibitor, phosphoramidon (2.5 mg/kg, intravenously), increased by 84% the plasma extravasation induced by inhalation of cold air for 1 min. The plasma extravasation evoked by 5 min exposure to cold air was abolished by the NK1 tachykinin receptor antagonist, CP-99,994 (4 mg/kg, intravenously); was reduced 30% by the B2 bradykinin receptor antagonist, HOE140 (0.1 mumol/kg, intravenously); and was not affected by H1 (pyrilamine, 10 mg/kg, intraperitoneally) or H2 (cimetidine, 10 mg/kg, intraperitoneally) histamine receptor antagonists or the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenously). In rats infected with Sendai virus, plasma extravasation evoked by inhalation of cold air was greater than in pathogen-free rats. Pretreatment with CP-99,994 (4 mg/kg, intravenously) inhibited completely the plasma extravasation induced by cold air in virus-infected rats. These findings indicate that cold air increases plasma extravasation in the rat trachea by a neurogenic mechanism that involves the release of tachykinins from sensory nerves. Kinin release may also play a role in this neurogenic inflammatory response.

Air↗

PubMed1994

Tachykinins and kinins in antigen-evoked plasma extravasation in guinea-pig nasal mucosa.

The plasma extravasation evoked by instillation of 5% ovalbumin in the nasal mucosa of sensitized guinea-pigs was potentiated by the neutral endopeptidase inhibitor, phosphoramidon, and was reduced by the tachykinin NK1 receptor antagonist, CP-96,345. The bradykinin B2 receptor antagonist, HOE 140, also reduced the plasma extravasation evoked by the antigen. The combination of HOE 140 and CP-96,345 did not increase further the inhibition caused by HOE 140 alone. Plasma extravasation evoked by instillation of capsaicin was abolished by CP-96,345. HOE 140 blocked and CP-96,345 markedly reduced plasma extravasation caused by instillation of bradykinin. Plasma extravasation evoked by instillation of substance P was not affected by HOE 140. We conclude that antigen challenge causes plasma extravasation in the nasal mucosa of sensitized guinea-pigs, an effect that is due in part to the release of tachykinins from sensory nerve endings. Our evidence suggests that tachykinin release in response to antigen is provoked mainly by the release of kinins.

Animals↗

PubMed1994

Modulation of calcitonin gene-related peptide release evoked by bradykinin and electrical field stimulation in guinea-pig atria.

Electrical field stimulation (EFS) and bradykinin (BK) are able to activate capsaicin-sensitive sensory neurons of guinea-pig atria in a omega-conotoxin (CTX)-sensitive and Ruthenium Red (RR)-insensitive manner. The aim of this work was to study EFS and BK-induced release of calcitonin gene-related peptide (CGRP) from guinea-pig atria and in particular the action of morphine and neuropeptide Y (NPY) on this release. EFS-induced CGRP release was frequency-dependent and tetrodotoxin (TTX)-sensitive, while BK-evoked CGRP release was TTX-insensitive. On the other hand, CGRP outflow induced by either EFS or BK was similarly reduced in the presence of morphine and NPY. It is therefore hypothesized that NPY and opioids exert their inhibitory action by acting on the very terminal region of the nerve fibre. Moreover, our results show that dermorphine but not dynorphin reduced BK-evoked CGRP release, suggesting that mu opioid receptors are responsible for morphine action. Studying the action of peptide YY and NPY(16-36) on BK-evoked CGRP release, we demonstrated that both had similar inhibitory effects, supporting the presence of Y2 receptors on the nerve terminal region.

Animals↗

PubMed1994

Protons: small stimulants of capsaicin-sensitive sensory nerves.

The data reviewed in this article suggest that protons should no longer be considered simply as an unwanted by-product of anaerobic respiration that results from either an accumulation of inflammatory cells or a reduced oxygenated blood supply during ischaemia. A fall in extracellular pH can stimulate a subpopulation of sensory nerves by activation of ion channels. The available evidence indicates that most, if not all, of the activated neurones are also stimulated by capsaicin, and that protons and capsaicin share a common mechanism of neuronal activation. A proton should be viewed as a mediator that elicits a protective response with reflex cardiovascular and respiratory responses, which modulate systemic blood flow, and with the local release of sensory neuropeptides, which vasodilates the microvasculature and stimulates extravasation.

Animals↗

PubMed1994

Role of kinins in anaphylactic-induced bronchoconstriction mediated by tachykinins in guinea-pigs.

1. In the present study, we have investigated the role of kinins in allergen-induced bronchoconstriction. 2. Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 mumol kg-1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 mumol kg-1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 mumol kg-1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10 microM, 40 breaths). On the other hand, a combination of the NK1 (CP-96,345, 2 mumol kg-1, i.v.) and NK2 (SR 48968, 0.3 mumol kg-1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea-pig airways. 3. Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with atropine (1.4 mmol kg-1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 mumol kg-1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4. Pretreatment with a combination of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen-induced bronchoconstriction.5. These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response.

Adrenergic beta-Antagonists↗

PubMed1994

Evidence for reduction of bradykinin-induced bronchoconstriction in guinea-pigs by release of nitric oxide.

1. In this study the influence of nitric oxide (NO) on the bronchoconstriction induced by bradykinin in anaesthetized and artifically ventilated guinea-pigs pretreated with atropine was investigated. 2. Aerosol administration of bradykinin (0.1-1 mM, 40 breaths) caused a dose-dependent increase in lung resistance (RL): maximum increase in RL was 2.5 fold the baseline value. Pretreatment with aerosolized NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) (1 mM, 10 breaths every 5 min for 30 min), NO synthase inhibitors, markedly increased the bronchoconstrictor response to bradykinin. L-Arginine, but not D-arginine, (3 mM, 10 breaths every 5 min for 30 min) reversed the hyperresponsiveness to aerosolized bradykinin caused by L-NAME and L-NMMA. 3. L-NAME (1 mM, 10 breaths every 5 min for 30 min) increased the bronchoconstriction induced by intravenous bradykinin (1-10 nmol kg-1). L-Arginine, but not D-arginine, (10 breaths every 5 min for 30 min) reversed the hyperresponsiveness to intravenous bradykinin caused by L-NAME. 4. The increase in RL induced by capsaicin, either aerosol (10 microM, 10 breaths) or i.v. (20 nmol kg-1) was not affected by L-NAME (1 mM, 10 breaths every 5 min for 30 min). Acute resection of the vagi did not affect the bronchoconstriction evoked by bradykinin in guinea-pigs, either in the absence or presence of L-NAME (1 mM, 10 breaths every 5 min for 30 min). 4. These results suggest that, irrespective of the route of administration, bradykinin releases NO or a related molecule which exerts a bronchodilator action that opposes the bronchoconstrictor mechanisms activated by bradykinin itself.

Aerosols↗

PubMed1994

Airway vasodilation by bradykinin is mediated via B2 receptors and modulated by peptidase inhibitors.

We studied the effect of exogenous bradykinin on blood flow in the airway microcirculation of anesthetized F344 rats in vivo. We made three successive determinations of airway blood flow and cardiac output using a modification of the reference sample microsphere technique. Injection of bradykinin into the left ventricle increased airway blood flow in a dose-related manner. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, completely abolished bradykinin-, but not histamine-induced vasodilation. A bradykinin B1 receptor agonist, [des-Arg9]bradykinin, did not affect airway blood flow. We also studied the effect of inhibitors of angiotensin-converting enzyme (captopril) and neutral endopeptidase (phosphoramidon) on bradykinin-induced vasodilation. Pretreatment with captopril, but not phosphoramidon, potentiated the bradykinin-induced vasodilation. However, the addition of phosphoramidon further potentiated the effect of captopril. We conclude that injection of bradykinin into the left ventricle produces a dose-related vasodilation in the airway microcirculation mediated via B2 receptors, an effect that is modulated primarily by angiotensin-converting enzyme and, to a lesser extent, by neutral endopeptidase.

Animals↗

PubMed1994

Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.

We evaluated the effects of nitric oxide (NO) generators and endogenous production of NO elicited by substance P (SP) in the angiogenesis process. Angiogenesis was monitored in the rabbit cornea in vivo and in vitro by measuring the growth and migration of endothelial cells isolated from coronary postcapillary venules. The angiogenesis promoted in the rabbit cornea by [Sar9]-SP-sulfone, a stable and selective agonist for the tachykinin NK1 receptor, and by prostaglandin E1 (PGE1), was potentiated by sodium nitroprusside (SNP). Conversely, the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), given systemically, inhibited angiogenesis elicited by [Sar9]-SP-sulfone and by PGE1. Endothelial cells exposed to SNP exhibited an increase in thymidine incorporation and in total cell number. Exposure of the cells to NO generating drugs, such as SNP, isosorbide dinitrate, and glyceryl trinitrate, produced a dose-dependent increase in endothelial cell migration. Capillary endothelial cell proliferation and migration produced by SP were abolished by pretreatment with the NO synthase inhibitors N omega-mono-methyl-L-arginine (L-NMMA), N omega-nitro-L-arginine (L-NNA), and L-NAME. Exposure of the cells to SP activated the calcium-dependent NO synthase. Angiogenesis and endothelial cell growth and migration induced by basic fibroblast growth factor were not affected by NO synthase inhibitors. These data indicate that NO production induced by vasoactive agents, such as SP, functions as an autocrine regulator of the microvascular events necessary for neovascularization and mediates angiogenesis.

Amino Acid Oxidoreductases↗

PubMed1993

Budesonide inhibits plasma extravasation induced by capsaicin and by substance P in the rat nasal mucosa.

We studied the effect of the locally administered glucocorticoid budesonide on plasma extravasation induced by capsaicin and by substance P (SP) in the nasal mucosa of pathogen-free rats. Using Evans blue dye as a tracer, we measured plasma extravasation induced by capsaicin (150 micrograms kg-1 i.v.) or SP (0.5 and 2.5 micrograms kg-1 i.v.) in the rat naso- and maxilloturbinates after pretreatment with budesonide (0.1-50 micrograms twice/day for 2 days in the right nostril; 50 micrograms only for SP) or its vehicle. We found that budesonide inhibits plasma extravasation induced by capsaicin in a dose-dependent fashion in the nasal cavity. After the highest dose (50 micrograms) of budesonide, the values of Evans blue in the nasal mucosa were not different from the values observed after capsaicin vehicle alone. Budesonide also reduced plasma extravasation induced by capsaicin in the trachea and the urinary bladder of the rats in a dose-dependent fashion. Budesonide (50 micrograms) delivered to the nose inhibited the plasma extravasation caused by 0.5 but not by 2.5 micrograms SP kg-1 in the nasal mucosa. We conclude that the postjunctional part of the neurogenic pathway is a target for glucocorticoid antiinflammatory action in the nasal mucosa, at least of the rat. Budesonide's effect on organs other than the nose can be explained by systemic absorption.

Administration, Topical↗

PubMed1993

Role of kinins in the vascular extravasation evoked by antigen and mediated by tachykinins in guinea pig trachea.

Tachykinins released from sensory nerves mediate, at least in part, the plasma extravasation induced by allergen challenge to the airways of sensitized guinea pigs. We investigated the role of kinins in this activation of sensory nerves. We found that the increase in Evans blue dye extravasation evoked by aerosol of bradykinin (100 microM, 2 min) in the presence of phosphoramidon (2.5 mg/kg, i.v.) was abolished completely by the selective B2 bradykinin antagonist, HOE 140 (0.1 mumol/kg, i.v.), and was inhibited (60%) by the selective NK1 tachykinin receptor antagonist, CP-96,345 (2 mumol/kg, i.v.). Plasma extravasation evoked by aerosolized substance P (10 microM/kg, 2 min) in presence of phosphoramidon was abolished by CP-96,345, but was not affected by HOE 140. The extravasation of the Evans blue dye evoked by OVA (5%, 2 min) in sensitized guinea pigs was reduced by HOE 140 (45%) when the animals were perfused after 5 min and by 39% when perfusion was performed at 10 min. In the presence of phosphoramidon, the response to OVA at 10 min was reduced by 57% by HOE 140 and by 72% by CP-96,345. The combination of CP-96,345 and HOE 140 did not further increase the inhibition obtained with CP-96,345 alone. The results provide evidence that the activation of sensory nerves that contribute to Ag-evoked plasma extravasation is due to kinin release. The contribution of this cascade of events may be exaggerated in pathophysiologic conditions in which neutral endopeptidase is down-regulated.

Animals↗