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See detailIn Vitro Inhibitory Effect of SR 27417, a Potent Platelet-Activating Factor (PAF) Receptor Antagonist, on the PAF-Induced Bovine Platelet Aggregation
Bastos da Silva, Miriam; Delaunois, Annie ULg; Gustin, Pascal ULg et al

in Veterinary Research (2000), 31(2, Mar-Apr), 267-672

The in vitro inhibitory effect of SR 27417, an antagonist of the platelet-activating factor (PAF) receptor, on PAF-induced platelet aggregation was studied in blood collected from seven healthy Friesien ... [more ▼]

The in vitro inhibitory effect of SR 27417, an antagonist of the platelet-activating factor (PAF) receptor, on PAF-induced platelet aggregation was studied in blood collected from seven healthy Friesien calves. Inhibitory effects of SR 27417 were determined at thirteen different concentrations (0.1-400 nM) by using the dose-response curves of PAF on calf platelet aggregation. In the presence of SR 27417, the maximal slopes of aggregation (%/min) induced by low and high concentrations of PAF were significantly different from the control values obtained without an antagonist at p < or = 0.05 and p < or = 0.01 respectively. In vitro PAF-induced calf platelet aggregation was dose-dependently inhibited by SR 27417. The drug inhibited PAF-induced platelet aggregation in a competitive reversible manner (pA2 = 10.46 +/- 2.36 mol x L(-1)). In conclusion, the results of our study showed that addition of SR 27417 to bovine platelet in vitro inhibits PAF-induced platelet aggregation. [less ▲]

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See detailInflammatory Effect of Intratracheal Instillation of Ultrafine Particles in the Rabbit: Role of C-Fiber and Mast Cells
Nemmar, A.; Delaunois, Annie ULg; Nemery, B. et al

in Toxicology and Applied Pharmacology (1999), 160(3), 250-61

The effects of ultrafine polystyrene carboxylate-modified (fluorospheres) on inflammatory processes are being investigated in rabbit lungs. One milliliter of sterile NaCl (0.9%) containing 4 mg of ... [more ▼]

The effects of ultrafine polystyrene carboxylate-modified (fluorospheres) on inflammatory processes are being investigated in rabbit lungs. One milliliter of sterile NaCl (0.9%) containing 4 mg of ultrafine particles (UFP) was intratracheally instilled into anesthetized rabbits. The control animals were only instilled with sterile NaCl (0.9%). Twenty hours after being instilled, the rabbits were killed and their lungs were excised and then tracheally perfused with phosphate-buffered physiological solution (PBS). The lung effluents, collected from small holes made in the pleura, were analyzed for substance P (SP) and histamine content by radioimmunoassay (RIA) methods, after administration of drugs. In addition, in other groups of rabbits, the lung wet/dry (W/D) weight ratio was monitored, as were the cellular and protein contents in bronchoalveolar lavage (BAL). Electron microscopy examination was also performed. In tracheally superfused experiments, UFP induced a significant enhancement of both SP and histamine releases after administration of capsaicin (10(-4) M), to stimulate C-fiber, and carbachol (10(-4) M), a cholinergic agonist. A significant increase in histamine release was also recorded in the UFP-instilled group following the administration of both SP (10(-6) M) plus thiorphan (10(-5) M) and compound 48/80 (C48/80) (10(-3) M) to stimulate mast cells. In addition, the BAL fluid analysis of UFP groups showed an influx of neutrophils and an increase in total protein concentration. An increase in the lung WW/DW ratio was also recorded. Both epithelial and endothelial injuries were observed in the lungs of UFP-instilled rabbits. The pretreatment of rabbits in vivo with a mixture of either SR 140333 and SR 48368, a tachykinin NK(1) and NK(2) receptor antagonist, or a mixture of terfenadine and cimetidine, a histamine H(1) and H(2) receptor antagonist, prevented UFP- induced neutrophil influx and increased total proteins and lung WW/DW ratio. Therefore, it can be concluded that chemicaly inert, electrically charged UFP induce a pulmonary inflammatory process during which the release of SP and histamine from C-fibers and mast cells was enhanced after various stimuli. These latter mediators can also modulate the inflammatory process. [less ▲]

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See detailModulatory Effect of Imetit, a Histamine H3 Receptor Agonist, on C-Fibers, Cholinergic Fibers and Mast Cells in Rabbit Lungs in Vitro
Nemmar, A.; Delaunois, Annie ULg; Beckers, Jean-François ULg et al

in European Journal of Pharmacology (1999), 371(1), 23-30

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release ... [more ▼]

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release of substance P and histamine in lung effluents. The amounts of substance P and histamine released in lung superfusates were measured by radioimmunoassay (RIA) after administration of capsaicin and carbachol. Capsaicin (10(-4) M) induced a simultaneous increase in substance P (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly, carbachol (10(-4) M) caused an increase in the release of both substance P (367 +/- 111%) and histamine (1379 +/- 351%). The effect of capsaicin was prevented by pretreating the lungs with the tachykinin NK1 receptor antagonist SR 140333 (10(-7) M), and atropine (10(-6) M). SR 140333 prevented the carbachol-induced release of substance P but not of histamine. Exogenous substance P induced an increase in histamine release (136 +/- 7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%). This effect was prevented by atropine (10(-6) M). Pretreatment of lungs with imetit (5 x 10(-8) M), a selective H3 receptor agonist, prevented the capsaicin-induced release of both mediators. Imetit also blocked the carbachol-induced release of substance P but not of histamine. Exogenous substance P-evoked histamine release was inhibited by imetit. Therefore, it can be concluded that substance P released through the action of capsaicin can activate cholinergic fibers, leading to cholinoceptor stimulation with subsequent activation of C-fibers and mast cells. While the presence of presynaptic H3 receptors modulating substance P-induced acetylcholine release was only surmised, the existence of modulating histamine H3 receptors on C-fibers was confirmed. [less ▲]

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See detailInteractions between cytochrome P-450 activities and ozone-induced modulatory effects on endothelial permeability in rabbit lungs: influence of gender.
Delaunois, Annie ULg; Florquin, Sandra ULg; Segura, P. et al

in Inhalation Toxicology (1999), 11(11), 999-1014

The effects of rabbit exposure to ozone (O(3)) (0.4 ppm for 4 h) on two different cytochrome P-450 (CYP450)-dependent activities were investigated. In turn, the role of CYP450 in the inhibitory effect of ... [more ▼]

The effects of rabbit exposure to ozone (O(3)) (0.4 ppm for 4 h) on two different cytochrome P-450 (CYP450)-dependent activities were investigated. In turn, the role of CYP450 in the inhibitory effect of O(3) on acetylcholine (ACh)-evoked increase in endothelial permeability was also assessed. Immediately after the period of exposure, rabbits of both sexes were sacrificed and their lungs were extracted. Some lungs were used for preparation of microsomes and measurement of 7-ethoxyresorufin O-deethylase (EROD) and parathion oxidase activities. Other rabbit lungs were isolated and recirculatingly blood-free perfused. Arterial, venous pressures, and lung weight were continuously recorded. Capillary pressure was measured by applying the double occlusion method. Capillary filtration coefficient (K(f,c)) was evaluated by measuring the amount of fluid filtering through the endothelium when vascular pressures were suddenly increased. Dose-response curves to ACh were constructed in air- or O(3)-exposed rabbits. Some animals were pretreated with piperonyl butoxide (PBO), a well-known inhibitor of CYP450. O(3) significantly reduced both EROD and parathion oxidase lung microsomal activities in females, while it had no effect in males. Exposure to O(3) strongly inhibited the ACh-induced increase in K(f,c). Pretreatment with PBO reversed the modulatory effect of O(3) on endothelial permeability in male rabbits, but not in females. It was concluded (1) that inhibition of 2 different CYP450-dependent activities after exposure to 0.4 ppm O(3) for 4 h appears to be a gender-dependent phenomenon, and (2) that CYP450 is probably involved in the O(3)-evoked inhibitory mechanism against ACh-induced increase in endothelial permeability, but only in males. [less ▲]

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See detailIdentification of mechanisms involved in the acute airway toxicity induced by parathion.
Segura, P.; Chavez, J.; Montano, L. M. et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (1999), 360(6), 699-710

Organophosphates are still widely used worldwide and cause thousands of intoxications every year. In this work we investigated the mechanisms of parathion (Pth) airway toxicity, using biochemical and ... [more ▼]

Organophosphates are still widely used worldwide and cause thousands of intoxications every year. In this work we investigated the mechanisms of parathion (Pth) airway toxicity, using biochemical and functional approaches. A plethysmographic technique for unrestrained guinea pigs was used to analyze Pth-induced modifications of airway mechanics and responsiveness to acetylcholine (ACh: 0.1-3.2 mg/ml, 2-min inhalation each dose). The isolated perfused rabbit lung preparation was used to study the acute effects of Pth on airway responsiveness to ACh (10(-8)-10(-3) M), histamine (10(-8)-10(-3) M) and substance P (10(-10)-10(-6) M), pulmonary acetylcholinesterase inhibition and cytochrome P450 (P450) activity, and their modifications with previous administration of Pth (1 mg/kg s.c. daily, 7 days). We found that: (1) In guinea pigs Pth (3.2-17 mg/kg i.p.) produced a dose-dependent increase in a lung resistance index (iRL), which was greatly reverted (approximately 50%) by salbutamol (2 mg/ml, 2-min inhalation, or 10 microg/kg i.p.). This salbutamol effect was transient (5-10 min), suggesting that this bronchodilator triggered additional obstructive mechanisms. (2) Pth increased the water content in lung parenchyma samples, but not in trachea or bronchi, and augmented the respiratory secretions measured through monosaccharide content in bronchoalveolar lavage. (3) The increase in iRL was greater in female animals, probably due to a higher P450 basal activity, and completely blocked by pharmacological inhibition of P450 with piperonyl butoxide (500 mg/kg i.p.). (4) In male guinea pigs a subclinical dose of Pth (10 mg/kg i.p.) induced airway hyperresponsiveness to ACh. In isolated perfused rabbit lung Pth (10(-6) M) produced airway hyperresponsiveness to ACh and histamine, the latter prevented by atropine (10(-5) M). (5) Repetitive exposure to subclinical doses (1 mg/kg s.c.) of Pth during 1 week caused approximately 80% inhibition of P450 activity in rabbits, which was not enough, however, to prevent the functional manifestation of Pth toxicity in the airways. [less ▲]

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See detailRadioimmunoassay of Substance P in Lung Perfusate
Nemmar, A.; Gustin, Pascal ULg; Delaunois, Annie ULg et al

in Journal of Pharmacological & Toxicological Methods (1998), 39(2), 109-115

A radioimmunoassay of the undecapeptide substance P (SP) and its application in rabbit lung superfusate has been developed. The assay was based on the use of a radioactive tracer, 125I-SP-Tyr8, which ... [more ▼]

A radioimmunoassay of the undecapeptide substance P (SP) and its application in rabbit lung superfusate has been developed. The assay was based on the use of a radioactive tracer, 125I-SP-Tyr8, which showed, with an excess of antibodies, a specific binding greater than 90% and a nonspecific binding lower than 2%. This tracer was stable for 4 weeks at -20 degrees C. Its specific radioactivity was 384 Ci/mmol. The assay's lower limit of detection was 10 pg/ml (0.7 fmol). The determination of SP in rabbit lung perfusate required extraction and concentration using octadecylsilane cartridges. Under these conditions, the recovery of SP from experiments on lung perfusates (n=4) was 75.0+/-4.5%, and the intraassay and interassay coefficients of variation were 7.3+/-1.9% and 10.7+/-1.3%, respectively. Amounts of SP released in rabbit lung perfusates were determined following stimulation of pulmonary C fibers with capsaicin (10(-4) M). During the stimulation period, the values of SP from lung perfusates (n=6) increased significantly when compared with baseline values. [less ▲]

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See detailComparison of ozone-induced effects on lung mechanics and hemodynamics in the rabbit.
Delaunois, Annie ULg; Segura, P.; Montano, L. M. et al

in Toxicology and Applied Pharmacology (1998), 150(1), 58-67

The effects of rabbit exposure to ozone (O3)(0.4 ppm for 4 h) on pulmonary mechanical properties and hemodynamics have been investigated on the isolated perfused lung model. Tracheal pressure, airflow ... [more ▼]

The effects of rabbit exposure to ozone (O3)(0.4 ppm for 4 h) on pulmonary mechanical properties and hemodynamics have been investigated on the isolated perfused lung model. Tracheal pressure, airflow, and tidal volume were measured in order to calculate lung resistance (RL) and dynamic compliance (Cdyn). Using the arterial/venous/double occlusion method, the total pressure gradient (deltaPT) was partitioned into four components (arterial, pre-, postcapillary and venous). Dose-response curves to acetylcholine (ACh), substance P (SP), and histamine were constructed in lungs isolated from rabbits immediately or 48 h after air or O3 exposure O3 induced a significant increase in the baseline value of deltaPt, more markedly 48 h after the exposure. Immediately after the exposure, O3 partly inhibited the ACh-, SP-, and histamine-induced decreases in Cdyn and increases in RL. This inhibitory effect was still in part present 48 h after O3 treatment. In the groups studied immediately after exposure, O3 did not significantly modify the ACh-, SP-, and histamine-induced vasoconstriction. Forty-eight hours after exposure, O3 induced a contractile response to ACh and SP in the arterial segment but decreased the response to histamine. We conclude that O3 can induce direct vascular constriction. Directly, but also 48 h after exposure, O3 can inhibit the ACh-, SP-, and histamine-induced changes in lung mechanical properties. Ozone can also induce some changes in the intensity and in the location of the vascular responses to ACh, SP, and histamine. [less ▲]

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See detailOzone-Induced Stimulation of Pulmonary Sympathetic Fibers: A Protective Mechanism against Edema
Delaunois, Annie ULg; Segura, P.; Dessy, Cécile ULg et al

in Toxicology and Applied Pharmacology (1997), 147(1), 71-82

Tropospheric ozone exerts well-described toxic effects on the respiratory tract. Less documented, by contrast, is the ability of ozone to induce protective mechanisms against agents that are toxic to the ... [more ▼]

Tropospheric ozone exerts well-described toxic effects on the respiratory tract. Less documented, by contrast, is the ability of ozone to induce protective mechanisms against agents that are toxic to the lungs. In particular, interactions between ozone and the sympathetic nervous system have never been considered. Using a model of permeability edema in isolated perfused rabbit lungs, we report here that, immediately after exposure of rabbits to 0.4 ppm ozone for 4 hr, the pulmonary microvascular responses to acetylcholine and substance P are completely blocked. Several lines of evidence, including partial inhibition of the ozone-induced protective effect by several drugs (alpha2- and beta-adrenergic antagonists, neuropeptide Y antagonist, guanethidine), measured levels of released catecholamines in blood and urine and the in vitro response of isolated lungs exposed to 0.4 ppm ozone all seem to suggest that ozone can stimulate pulmonary adrenergic fibers and induce the local release of catecholamines and neuropeptide Y, this resulting in transient protection against pulmonary edema. We also showed that, 48 hr after the exposure, ozone increased the baseline microvascular permeability and the response to low concentrations of acetylcholine [less ▲]

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See detailInteractions between acetylcholine and substance P effects on lung mechanics in the rabbit.
Delaunois, Annie ULg; Gustin, Pascal ULg; Segura, P. et al

in Fundamental & Clinical Pharmacology (1996), 10(3), 278-88

The pharmacological mechanisms involved in the acetylcholine (ACh)- and substance P (SP)-induced changes in pulmonary mechanics were studied in isolated perfused rabbit lungs. Tracheal pressure (Ptr) and ... [more ▼]

The pharmacological mechanisms involved in the acetylcholine (ACh)- and substance P (SP)-induced changes in pulmonary mechanics were studied in isolated perfused rabbit lungs. Tracheal pressure (Ptr) and airflow were measured by a Fleisch pneumotachograph and pressure transducers. Air volume, lung resistance (RL) and dynamic compliance (Cdyn) were calculated. ACh induced a dose-dependent increase in Ptr and RL, and a decrease in Cdyn. These effects were strongly prevented by atropine, and partly by SR140333, a neurokinin NK1 receptor antagonist; SR48968, a neurokinin NK2 receptor antagonist; indomethacin and antihistaminics. Ketanserin had no significant protective effect against ACh. SP also induced concentration-dependent increases in RL and decreases in Cdyn. SR140333 and atropine strongly inhibited the effects of SP, while ketanserin, SR48968, antihistaminics and indomethacin did not protect the lungs against this drug. 5-hydroxytryptamine induced no significant change in lung mechanic parameters. Cumulative concentrations of histamine increased RL and decreased Cdyn. We conclude that ACh-induced changes in lung resistance and compliance are in part mediated by a direct effect on airway smooth muscle and in part by the stimulation of C fibers, by the release of histamine from mast cells and by the synthesis of arachidonic acid metabolites. In turn, the effects of SP on lung mechanics are partly due to cholinergic activation. [less ▲]

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See detailEndogenous nitric oxide modulates acetylcholine-induced edema and vasoconstriction in isolated perfused rabbit lungs.
Delaunois, Annie ULg; Gustin, Pascal ULg; Ansay, Michel ULg

in Journal of Pharmacology and Experimental Therapeutics (The) (1995), 274(2), 559-97

The modulatory role of endogenous nitric oxide (NO) on pulmonary edema induced by acetylcholine (ACh), capsaicin, substance P (SP) and 5-hydroxytryptamine (5-HT) was investigated by using an inhibitor of ... [more ▼]

The modulatory role of endogenous nitric oxide (NO) on pulmonary edema induced by acetylcholine (ACh), capsaicin, substance P (SP) and 5-hydroxytryptamine (5-HT) was investigated by using an inhibitor of NO synthase, N-omega-nitro-L-arginine (L-NNA). The effects of endogenous NO on the hemodynamic response to ACh, 5-HT and SP were also investigated. The capillary filtration coefficient (Kf,c), the total pressure gradient (delta Pt) and its four components [arterial (delta Pa), pre- (delta Pa') and post-capillary (delta Pv'), and venous gradient (delta Pv)] were evaluated on isolated, ventilated, perfused rabbit lungs. ACh (10(-8) to 10(-4) M) and SP (10(-10) to 10(-6) M) induced a concentration-dependent increase in the Kf,c. Capsaicin (10(-4) M) and 5-HT (10(-4) M) also increased this parameter. L-NNA (10(-4) M) completely inhibited the effects of ACh and capsaicin on the Kf,c, without preventing the effects of SP and 5-HT. ACh induced a concentration-dependent vasoconstriction in the precapillary segment. Pretreatment with L-NNA enhanced this increase in delta Pa' but also increased delta Pv' and delta Pv. 5-HT increased delta Pt and delta Pa proportionally to the concentration. This effect was enhanced by L-NNA, which also increased delta Pa'. SP had no significant hemodynamic effect. Pretreatment with L-NNA did not modify the response to SP. Sodium nitroprusside (10(-5) M) induced a left shift of the concentration-response curve to ACh on the Kf,c, although it did not change the response to SP. Sodium nitroprusside also inhibited the hemodynamic effect of ACh. It was concluded that endogenous NO is involved in ACh-and capsaicin-induced edema via a prejunctional stimulatory effect on the C-fibers. Endogenous NO can also modulate ACh- and 5-HT-induced vasoconstriction by exerting a vasodilator action on the whole pulmonary vascular bed. [less ▲]

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See detailModulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs.
Delaunois, Annie ULg; Gustin, Pascal ULg; Garbarg, M. et al

in European Journal of Pharmacology (1995), 277(2-3), 243-50

The modulatory role of histamine H3 receptors in pulmonary oedema induced by acetylcholine, capsaicin and by exogenous substance P was investigated in isolated, ventilated rabbit lungs. Endothelial ... [more ▼]

The modulatory role of histamine H3 receptors in pulmonary oedema induced by acetylcholine, capsaicin and by exogenous substance P was investigated in isolated, ventilated rabbit lungs. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Acetylcholine (10(-8) to 10(-4) M), substance P (10(-10) to 10(-6) M), capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) induced an increase in the Kf,c. Carboperamide, a novel histamine H3 receptor antagonist, induced a significant leftward shift of the concentration-response curve to acetylcholine and also enhanced the effect of capsaicin on the Kf,c, while it had no significant effect on the response to substance P and 5-HT. Imetit, a new histamine H3 receptor agonist, strongly inhibited the effects of acetylcholine and capsaicin. Imetit also strongly protected the lung against substance P effects but did not prevent the 5-HT-induced increase in the Kf,c. Carboperamide completely blocked the inhibitory effect of Imetit on the acetylcholine response. (R)-alpha-Methylhistamine, an other histamine H3 receptor agonist, had the same protective effect against acetylcholine response as Imetit. We conclude that histamine H3 receptors could protect the lung against acetylcholine- and capsaicin-induced oedema via a prejunctional modulatory effect on the C-fibres. However, since the response to exogenous substance P was also inhibited by histamine H3 receptor stimulation, the presence of such receptors at a postsynaptic level, probably on mast cells, was also suggested. [less ▲]

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See detailMechanisms of substance P-induced pulmonary oedema in the rabbit: interactions between parasympathetic and excitatory NANC nerves.
Delaunois, Annie ULg; Gustin, Pascal ULg; Ansay, Michel ULg

in Fundamental & Clinical Pharmacology (1995), 9(5), 450-7

The pharmacological mechanisms involved in the substance P (SP)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. Substance P induced a dose-dependent increase in the capillary ... [more ▼]

The pharmacological mechanisms involved in the substance P (SP)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. Substance P induced a dose-dependent increase in the capillary filtration coefficient (Kf,c), responsible for oedema. Atropine, hemicholinium-3 and ruthenium red pretreatment partly protected the lungs against SP effects, while tetrodotoxin and hexamethonium did not significantly modify them. (+/-)CP96,345, a NK1 receptor antagonist, completely inhibited the SP-induced increase in the Kf,c. Like SP, acetylcholine (ACh) and capsaicin also increased the Kf,c. Atropine and (+/-)CP96,345 completely blocked the oedema induced by both drugs. Tetrodotoxin and ruthenium red strongly inhibited the response to capsaicin and acetylcholine. It was concluded that SP-induced pulmonary oedema is in part mediated by a stimulating action on cholinergic efferent nerves, with subsequent release of endogenous acetylcholine. Acetylcholine can, in turn, stimulate the release of SP from excitatory non adrenergic, non cholinergic nerves. The effects induced by capsaicin and exogenous acetylcholine, thus endogenous SP, involve tetrodotoxin-sensitive mechanisms, while those produced by exogenous SP are tetrodotoxin-resistant. [less ▲]

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See detailProtective Effect of Various Antagonists of Inflammatory Mediators against Paraoxon-Induced Pulmonary Edema in the Rabbit
Delaunois, Annie ULg; Gustin, Pascal ULg; Vargas, M. et al

in Toxicology and Applied Pharmacology (1995), 132(2), 343-345

The protective effect of some antagonists of various inflammatory mediators against paraoxon-induced increases in endothelial permeability has been investigated in isolated perfused rabbit lungs. The ... [more ▼]

The protective effect of some antagonists of various inflammatory mediators against paraoxon-induced increases in endothelial permeability has been investigated in isolated perfused rabbit lungs. The edema induced by paraoxon has been previously related to a chain reaction mediated by acetylcholine. Lungs were ventilated and blood-free perfused with a constant flow. Arterial and venous pressures and lung weight were continuously recorded. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Paraoxon (4 x 10(-4) M) was injected in the perfusion circuit, in lungs with or without pretreatment with atropine, ketanserin, clonidine, morphine, indomethacin, and terfenadine plus cimetidine. Paraoxon induced a time-dependent increase in the Kf,c, a maximal effect being recorded 60 min after the injection. All the antagonists used as pretreatment significantly reduced the maximal effect recorded after paraoxon. These results show that muscarinic receptor antagonists, inhibitors of neuropeptides release, cyclooxygenase inhibitors, and 5-hydroxytryptamine and histamine receptor antagonists can protect the lung against the edema induced by paraoxon. This protective effect is due to inhibition of the chain reaction triggered by acetylcholine. [less ▲]

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See detailModulation of the acetylcholine- and substance P-induced pulmonary edema by calcitonin gene-related peptide in the rabbit.
Delaunois, Annie ULg; Gustin, Pascal ULg; Ansay, Michel ULg

in Journal of Pharmacology and Experimental Therapeutics (The) (1994), 270(1), 30-6

The effects of calcitonin gene-related peptide (CGRP) (6 x 10(-8) M) on hemodynamics and on pulmonary microvascular permeability were investigated in isolated, perfused rabbit lungs by measuring the ... [more ▼]

The effects of calcitonin gene-related peptide (CGRP) (6 x 10(-8) M) on hemodynamics and on pulmonary microvascular permeability were investigated in isolated, perfused rabbit lungs by measuring the arterial, capillary and venous pressures and the capillary filtration coefficient (Kf,c). CGRP was administered alone or in combination with capsaicin (10(-4) M), acetylcholine (ACh) (10(-11) M to 10(-7) M), substance P (SP) (10(-10) M to 10(-6) M) and serotonin (10(-4) M). The influence of a specific antagonist of CGRP receptors, CGRP8-37 (10(-8) M), on the pulmonary edema induced by these mediators was also considered. CGRP had no direct effect on the vascular pressures or on Kf,c. Capsaicin and serotonin induced an increase in Kf,c of 271 +/- 49% and 676 +/- 147% of base line, respectively. ACh and SP also increased the microvascular permeability, in proportion to the concentration. The effects of capsaicin, ACh and SP have been related to the activation of neurokinin NK1 receptors. Co-administration of CGRP with capsaicin and ACh enhanced the increase in Kf,c induced by these two drugs. By contrast, when co-injected with SP, CGRP inhibited the Kf,c increase induced by 10(-8) M and 10(-7) M of SP (P < .05) and significantly decreased the arterial and capillary pressures. CGRP also partly prevented the pulmonary edema induced by serotonin (P < .05). Pretreatment with CGRP8-37 partly prevented the effects of capsaicin and ACh on Kf,c but bestowed no protection against SP-induced pulmonary edema. These data suggest that CGRP is co-released with SP from the C-fibers upon the action of capsaicin and ACh in the rabbit lung. Because CGRP potentiated the pulmonary edema induced in capsaicin and ACh, but decreased the effects of SP, we hypothesize that CGRP exerts a positive retro-control on the release of neuropeptides by these fibers but can attenuate their effects on the target cells. [less ▲]

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See detailMultiple muscarinic receptor subtypes mediating pulmonary oedema in the rabbit.
Delaunois, Annie ULg; Gustin, Pascal ULg; Ansay, Michel ULg

in Pulmonary Pharmacology (1994), 7(3), 185-93

The effects of various muscarinic antagonists on acetylcholine (ACh)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. ACh induced a dose-dependent increase in the capillary ... [more ▼]

The effects of various muscarinic antagonists on acetylcholine (ACh)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. ACh induced a dose-dependent increase in the capillary filtration coefficient (Kf,c). This effect has been previously related to the activation of the capsaicin-sensitive nerve fibres and the release of substance P. Atropine, pirenzepine (M1-selective antagonist) and 4-DAMP (M3-selective antagonist) altered this response, producing a dose-dependent shift to the right of the ACh concentration-Kf,c response curve. By contrast, the M2-selective antagonist AFDX-116 shifted the ACh concentration-response curve to the left. Atropine, pirenzepine and 4-DAMP also significantly reduced the capsaicin-induced increase in the Kf,c, while AFDX-116 enhanced it. We conclude that multiple muscarinic receptor subtypes are present in the rabbit lung, located on the C-fibres, and are involved in the ACh-induced pulmonary oedema. M1 and M3 receptors seem to stimulate the release of neuropeptides from C-fibres, whereas M2 receptors have an inhibitory effect on these fibers. [less ▲]

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See detailModulatory Effect of Neuropeptide Y on Acetylcholine-Induced Oedema and Vasoconstriction in Isolated Perfused Lungs of Rabbit
Delaunois, Annie ULg; Gustin, Pascal ULg; Dessy-Doize, C. et al

in British Journal of Pharmacology (1994), 113(3), 973-81

1. The modulatory role of neuropeptide Y (NPY) on pulmonary oedema induced by acetylcholine and capsaicin was investigated. The effects of NPY on the haemodynamic response to acetylcholine, phenylephrine ... [more ▼]

1. The modulatory role of neuropeptide Y (NPY) on pulmonary oedema induced by acetylcholine and capsaicin was investigated. The effects of NPY on the haemodynamic response to acetylcholine, phenylephrine and substance P were also investigated. 2. Isolated, ventilated, exsanguinated lungs of the rabbit were perfused with a constant flow of recirculating blood-free perfusate. The double/arterial/venous occlusion method was used to partition the total pressure gradient (delta Pt) into four components: the arterial gradient (delta Pa), the pre- and post-capillary gradients (respectively delta Pa' and delta Pv') and the venous pressure gradient (delta Pv). Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). 3. Acetylcholine (10(-8) M to 10(-4) M) and substance P (SP, 10(-10) M to 10(-6) M) induced a concentration-dependent increase in the Kf,c. Capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) also increased this parameter. NPY (10(-8) M) completely inhibited the effects of acetylcholine and capsaicin on the Kf,c, without preventing the effects of substance P and 5-HT. 4. Acetylcholine induced concentration-dependent vasoconstriction in the precapillary segment. The effect was inhibited by NPY and aspirin, an inhibitor of cyclo-oxygenase, while ketanserin, a 5-HT2 receptor antagonist, and SR140333, a new NK1 antagonist, had no protective effect. Phenylephrine increased delta Pa at high concentration, an effect also inhibited by NPY and aspirin. Substance P had no significant haemodynamic effect. When injected together with NPY, substance P (10(-6) M) induced a significant increase in the total pressure gradient.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

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See detailRole of Neuropeptides in Acetylcholine-Induced Edema in Isolated and Perfused Rabbit Lungs
Delaunois, Annie ULg; Gustin, Pascal ULg; Ansay, Michel ULg

in Journal of Pharmacology and Experimental Therapeutics (The) (1993), 266(2), 483-491

Changes in pulmonary endothelial permeability and in microvascular hemodynamics in response to cumulative concentrations of acetylcholine (ACh) (10(-8) M to 10(-5) M) were investigated in isolated ... [more ▼]

Changes in pulmonary endothelial permeability and in microvascular hemodynamics in response to cumulative concentrations of acetylcholine (ACh) (10(-8) M to 10(-5) M) were investigated in isolated, perfused rabbit lungs. The total pressure gradient was partitioned into four components: arterial, pre- and postcapillary and venous. The capillary filtration coefficient (Kf, c) also was evaluated. ACh caused a significant increase in arterial and precapillary pressures at concentrations higher than 3 x 10(-6) M. The total pressure gradient and precapillary were significantly increased whereas arterial, postcapillary and venous pressure gradient remained unchanged. In papaverine (3 x 10(-4) M)-pretreated lungs, the vasoconstriction was abolished and a concentration-dependent increase in Kf,c was recorded from 10(-8) to 10(-5) M ACh. This reaction was accompanied by pulmonary edema. Atropine, indomethacin, aspirin, ketanserin, clonidine, morphine and (+/-)-CP 96-345, an antagonist of neurokinin NK1 receptors, completely prevented the effects of ACh on Kf,c. In contrast, cromolyn sodium and SR48968, a neurokinin NK2 antagonist, did not inhibit the response to ACh. Terfenadine together with cimetidine had a partially inhibitory effect. Changes in the Kf, c similar to those observed with ACh were induced by capsaicin (10(-4) M) by exogenous substance P (10(-7) M) and by 5-hydroxytryptamine (5-HT) (10(-4) M). The effects of SP were inhibited by aspirin, (+/-)-CP 96,345 and ketanserin, but not by atropine and antihistaminics. 5-HT effects were prevented by aspirin and not by (+/-)-CP 96,345. It was concluded that ACh-induced pulmonary edema was due to an increase in the capillary filtration coefficient.(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]

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See detailEffects of Capsaicin on the Endothelial Permeability in Isolated and Perfused Rabbit Lungs
Delaunois, Annie ULg; Gustin, Pascal ULg; Ansay, Michel ULg

in Fundamental & Clinical Pharmacology (1993), 7(2), 81-91

Changes in pulmonary endothelial permeability and in microvascular hemodynamics in response to capsaicin (10(-4) M) were investigated in isolated, perfused rabbit lungs. Blood-free perfusate was ... [more ▼]

Changes in pulmonary endothelial permeability and in microvascular hemodynamics in response to capsaicin (10(-4) M) were investigated in isolated, perfused rabbit lungs. Blood-free perfusate was recirculated through ventilated lungs in an isogravimetric state, under zone III conditions with a constant flow. Using the occlusions method, the total pressure gradient between the arterial and the venous levels (delta Pt) was partitioned into four components: arterial (delta Pa), pre-(delta Pa') and post-(delta Pv') capillary, and venous (delta Pv). The capillary filtration coefficient (Kf,c) was evaluated by measuring the amount of fluid filtering through the endothelium when arterial and venous pressures were suddenly increased. Capsaicin caused no changes in the vascular pressures at any level of the pulmonary circulation but induced a significant 3-fold increase in the Kf,c (P < 0.05). This reaction was accompanied by pulmonary oedema. The mechanisms involved in the permeability changes were investigated by testing the capacity of different drugs to block the response to capsaicin. Clonidine (10(-7) M to 10(-5) M), morphine (10(-6) M), aspirin (10(-3) M), ketanserin (10(-8) M) and (+/)- CP 96,345 (10(-6) M), an antagonist of neurokinin NK1 receptor, completely prevented the effects of capsaicin on the Kf,c. In contrast, terfenadine (10(-7)) together with cimetidine (10(-5) M) had no protective effect against capsaicin. It was concluded that capsaicin-induced pulmonary oedema was due to an increase in the capillary filtration coefficient and not to hemodynamic changes. This alteration in the endothelium permeability is mediated by the release of endogenous peptides from C-fibers upon the action of capsaicin and subsequent activation of NK1 receptors, probably by substance P. Moreover, 5-hydroxytryptamine receptors and arachidonic acid derivates are also involved in this reaction [less ▲]

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