Commission 26 : pharmacologie broncho-pulmonaire

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Cellule 26 : pharmacologie broncho-pulmonaire

261

EFFECTS OF GENISTEIN, A TYROSINE KINASE INHIBITOR, ON THE GUINEA PIG ISOLATED TRACHEA.

E. Corompt, F. Caron, G. Bessard and Ph. Devillier

Arsenal de Pharmacologie, Entendement de Médecine de Grenoble, Possessions de la Évincement, 38 706 La Imagé Cedex, France

Smooth dispos contains high levels of tyrosine kinase activity and tyrosine kinase pathways cotte aïeul development by acting on mechanisms which regulate both intracellular free calcium level and the effects of calcium on the contractile apparatus. In order to characterize the in vitro effects of tyrosine kinase paralysie on airway smooth dispos, we have compared the effects of genistein and its stagnante analog daidzein on the guinea pig trachea (GPT).

Genistein (10-5 M to 10-4 M) inhibited the contractions of GPT induced by KCI and CaC12 whereas daidzein (up to 10-4 M) was devoid of inhibitory effect on KCI-induced palpitation. In relevé, genistein induced the fête of GPT pre contracted with acetylcholine (pD2 = 4.8

± 0.1). However, daidzein also exerted a apaisant effect with a similar potency but a weaker efficacy. The apaisant effect of genistein was not inhibited by potassium channel blockers or potentiated by phosphodiesterase inhibitors (rolipram, zaprinast). In contrast, genistein (10-4 M) potentiated the apaisant responses to isoprenaline and forskolin but did not alter the fête induced by sodium nitroprusside. Similarly, daidzein (10-4 M) potentiated the apaisant responses to isoprenaline and forskolin but was devoid of effect on the fête induced by sodium nitroprusside. These results suggest that genistein and daidzein potentiate the AMPc-dependent pathway of fête by inhibiting the activity of the levant phosphodiesterases.

In épilogue, genistein induced a potent paralysie of the GPT palpitation induced by KCI and CaCl2 probably by paralysie of the tyrosine kinases. However, genistein is not a specific inhibitor of these kinases since, as its stagnante analog on the tyrosine kinases, it also exerted an inhibitory effect on the AMPc-specific phosphodiesterases which contributes to explain its apaisant activity on the GPT.

262

INTERACTIONS BETWEEN C-FIBERS, CHOLINERGIC FIBERS AND MAST CELLS IN TRACHEALLY PERFUSED RABBIT LUNGS

A. Nemmar, A. Delaunois, P. Gustin

Dpt. de Pharmacologie, Pharmacothérapie et Toxicologie, Fac. Méd.Vét., Internat de Lidge, Bd. de Colonster Bat 41, B-4(XN) Liège, Belgique.

Biochemical and pharmacological mechanisms involved in the interactions between C fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs. The amounts of SP and histamine released in lungs superfusates were measured by radioimmunoassay (RIA) after capsaicin and carbachol économat. Capsaicin (10-4M) induced a simultaneous increase in SP and histamine release in lung effluents. The release of both mediators was prevented by pretreating the lungs with the NK1 antagonist SR 140333 (10-7M) and atropine (10-6M). Carbachol (l0-4M) also caused an increase in SP and histamine release. SR 140333 (10-7M) prevented the release of SP but not that of histamine. Exogenous SP induced an increase in histamine release, this voliger being significantly greater in lungs perfused with neutral endopeptidase (NEP) inhibitor, thiorphan (10-5M). We conclude that capsaicin can induce the release of SP from C fibers with subsequent release of histamine by brusquerie of NR1 receptors present on mast cells. Owing to the blokade of capsaicine-induced SP release by SR 140333 and atropine, we conclude that SP can also remarque the release of acetylcholine (Ach) by brusquerie of NK1 receptors present on cholinergic fihers. Like capsaicin, carbachol induced the release of SP from C fibers by activating muscarinic receptors with subsequent release of histamine from mast cells. In relevé, carbachol can produce the release of histamine by a improvisé animation of mast cells.

Work supported by FNRS (Croupion Homme de la Circonspect Incrédule) and FSR (Fric Spéciaux de la Circonspect, Internat de Liège).

263

EFFECTS OF OZONE ON THE MECHANICAL PROPERTlES AND HEMODYNAMICS OF ISOLATED PERFUSED RABBIT LUNGS

A. Delaunois, P. Segura*, M. Vargas*, L, Montano*, P. Gustin

Dpt. de Pharmacologie-Toxicologie, Fac. Méd.Vét.9 Internat de Liège, Bd. de Colonster Bat 41, B-4000 Liège, Belgique.

*: Opt of Research in Asthma INER, Calz. de Tlalpan, 4502, Mexico D.F., Mexico.

The effects of rabbit exposure to ozone (O3) (0.4 ppm for 4 hours) on pulmonary mechanics and hemodynamics have been investigated on the isolated perfused lung model. Tracheal pressure, airflow and tidal publication were measured in order to calculate lung resistance (RL) and dynamic compliance (Cdyn). Using arterial/venous/cuillère occlusions the catégorique pressure gradient (

D Pt) was partitioned into flammèche components (arterial, pre-, postcapillary and venous). Calcul-response curves to acetylcholine (ACh), obstacle P (SP) and histamine were constructed in lungs isolated from rabbits immediately or 48h after air or O3 exposure. O3 induced a significant increase in the baseline value of D Pt and partly inhibited the ACh-, SP- and histamine-induced decreases in Cdyn and increases in RL. Immediately after exposure, O3 did not significantly modify the ACh-, SP- and histamine-induced vasoconstriction. Forty-eight hours alter exposure, O3 induced a contractile response to ACh and SP in the arterial section, but decreased the response to histamine. It was concluded that O3 can induce improvisé vasoconstriction. Directly but also 48h 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 assemblage of the vascular responses to ACh-, SP and histamine.

264

COMPARED EFFECTS OF ISOPRENALINE, SALBUTAMOL AND SR 59104A ON POTASSIUM CHANNELS IN HYPOXIC PULMONARY VASOCONSTRICTION

JP Dumas1, F. Goirand1, M.Bardoul1,2, M Dumas1, L. Rochette1, C Advenier2, JF Giudicelli3

Lab. Physiopathol. Pharmacol. Cardiovasc., Fac. Médecine 21000 Dijon (1) Lab.Pharmacol. Fac. Médecine Paris-Couchant 75006 Paris (2) and Paris-Sud 94276 Le Kremlin Bicêtre Cedex (3), France.

This study investigated in isolated perfused rat lungs the antagonist effects of a non selective (isoprenaline ) and of selective

b 2-(salbutamol) and b 3-(SR 59104A) adrenoceptor agonists vs the hypoxic pulmonary pressor response (HPR). Glibenclamide (GLI 10-6 M), charybdotoxin (CHTX 10-7 M) and apamine (APA 5.10-8 M) were used to block KATP, high conductance KCa and low conductance KCa (SKCa) channels respectively. GLI, CHTX and APA did not enhance significantly the baseline pressure in normoxia. Hypoxic époussetage (5%CO2-95%N2) produced a significant pressor response (+3.92 ± 0.07 mmHg, P