Caractérisation pharmacologique des récepteurs des kinines et des neurokinines chez la souris

Une étude systématique a été effectuée dans divers segments de l'intestin (duodénum, estomac, iléon, colon, caecum) et du tractus urogénital (vessie, vas deferens non stimulé) de souris dans le but d'identifier les tissus qui sont sensibles à divers peptides vasoactifs notamment les kinines et les neurokinines. L'estomac de souris possède des sites fonctionnels B[indice inférieur 1] et B[indice inférieur 2] des kinines et NK-1 et NK-2 des neurokinines. La vessie s'avère être un tissu plus sélectif ne contenant que les sites B[indice inférieur 2] des kinines et NK-2 des neurokinines. Les réponses myotropes véhiculées par les récepteurs B[indice inférieur 1]sont lentes et réversibles comparativement aux réponses induites par l'activation des récepteurs B[indice inférieur 2]. Afin de procéder à une caractérisation pharmacologique des récepteurs aux kinines et neurokinines, deux critères de Schild ont été utilisés, à savoir l'ordre de puissance des agonistes (pD[indice inférieur 2]) et les affinités apparentes des antagonistes (pA[indice inférieur 2])."--Résumé abrégé par UMI

Caractérisation pharmacologique des récepteurs des kinines et des neurokinines chez la souris

Une étude systématique a été effectuée dans divers segments de l'intestin (duodénum, estomac, iléon, colon, caecum) et du tractus urogénital (vessie, vas deferens non stimulé) de souris dans le but d'identifier les tissus qui sont sensibles à divers peptides vasoactifs notamment les kinines et les neurokinines. L'estomac de souris possède des sites fonctionnels B[indice inférieur 1] et B[indice inférieur 2] des kinines et NK-1 et NK-2 des neurokinines. La vessie s'avère être un tissu plus sélectif ne contenant que les sites B[indice inférieur 2] des kinines et NK-2 des neurokinines. Les réponses myotropes véhiculées par les récepteurs B[indice inférieur 1]sont lentes et réversibles comparativement aux réponses induites par l'activation des récepteurs B[indice inférieur 2]. Afin de procéder à une caractérisation pharmacologique des récepteurs aux kinines et neurokinines, deux critères de Schild ont été utilisés, à savoir l'ordre de puissance des agonistes (pD[indice inférieur 2]) et les affinités apparentes des antagonistes (pA[indice inférieur 2])."--Résumé abrégé par UMI

In vitro and in vivo effects of kinin B(1) and B(2) receptor agonists and antagonists in inbred control and cardiomyopathic hamsters

1. The aims of this study were to examine the possible alterations occurring in the effects of kinins on isolated aortae of inbred control (CHF 148) and cardiomyopathic (CHF 146) hamsters of 150–175 and 350–375 days of age. 2. Bradykinin (BK) and desArg(9)BK contracted isolated aortae (with or without endothelium) of hamsters of both strains and ages. After tissue equilibration (90 min), responses elicited by both kinin agonists were stable over the time of experiments. The patterns of isometric contractions of BK and desArg(9)BK were however found to be different; desArg(9)BK had a slower onset and a longer duration of action than BK. 3. Potencies (pEC(50) values) of BK in all groups of hamsters were significantly increased by preincubating the tissues with captopril (10(−5) M). 4. No differences in the pEC(50) values and the E(max) values for BK or desArg(9)BK were seen between isolated vessels from inbred control and cardiomyopathic hamsters. 5. The myotropic effect of BK was inhibited by the selective non peptide antagonist, FR 173657 (pIC(50) 7.25±0.12 at the bradykinin B(2) receptor subtype (B(2) receptor)). Those of desArg(9)BK, at the bradykinin B(1) receptor subtype (B(1) receptor) were abolished by either R 715 (pIC(50) of 7.55±0.05; α(E)=0), Lys[Leu(8)]desArg(9)BK (pIC(50) of 7.21±0.01; α(E)=0.22) or [Leu(8)]desArg(9)BK (pIC(50) of 7.25±0.02; α(E)=0.18). 6. FR 173657 had no agonistic activity, exerted a non competitive type of antagonism and was poorly reversible (lasting more than 5 h) from B(2) receptor. In vivo, FR 173657 (given per os at 1 and 5 mg kg(−1), 1 h before the experiment) antagonized the acute hypotensive effect of BK in anaesthetized hamsters. 7. It is concluded that aging and/or the presence of a congenital cardiovascular disorder in hamsters are not associated with changes in the in vitro aortic responses to either BK or desArg(9)BK

Up-regulation of kinin B(1) receptor in the lung of streptozotocin-diabetic rat: autoradiographic and functional evidence

1. The function and autoradiographic binding expression of kinin B(1) receptors were evaluated in the lungs of Streptozotocin (STZ)-diabetic rats. 2. The intrapleural injection (i.pl.) of des-Arg(9)-bradykinin (des-Arg(9)-BK) (50 and 100 nmol per site), a selective B(1) receptor agonist, increased time-dependently the mononuclear and neutrophil cells influx in the pleural cavity of rats treated with STZ (65 mg kg(−1), i.p., 4 days earlier). This effect was significantly less in control rats. 3. The influx of mononuclear and polymorphonuclear neutrophil cells induced by des-Arg(9)-BK was significantly inhibited by two B(1) receptor antagonists (des-Arg(10)-Hoe140 or R-715, 100 nmol per site, 5 min earlier), but not by two B(2) receptor antagonists (Hoe140, 10 nmol or NPC 18884, 100 nmol per site, 5 min earlier). However, Hoe140 prevented the higher basal leukocyte influx seen in STZ-diabetic rats. 4. Leukocyte infiltration induced by des-Arg(9)-BK in STZ-diabetic rats was significantly reduced after treatment with insulin (2 U per day, s.c. over 4 days) or with an anti-PMN antibody (0.1 ml of a 1 : 20 dilution, i.pl. 5 min earlier). 5. Specific B(1) receptor binding sites were seen in lung sections from both control and STZ-diabetic rats, yet the density of labelling was much greater in diabetic rats and particularly after intrapleural injection of des-Arg(9)-BK. Treatment with insulin or with the anti-PMN antibody markedly reduced B(1) receptor binding sites occurring after the injection of des-Arg(9)-BK in STZ-diabetic rats. 6. Data suggest that the B(1) receptor is up-regulated in the lungs of STZ-diabetic rats, and its activation increases leukocyte infiltration into the pleural cavity. The overexpression of B(1) receptors seems to depend on neutrophils influx and appears to be associated with hyperglycaemia

Evidence for in vitro expression of B(1) receptor in the mouse trachea and urinary bladder

1. Motor responses to des-Arg(9)-bradykinin and bradykinin were studied in the isolated mouse trachea (precontracted with carbachol, 10 μM) and the urinary bladder of either Swiss, C57Bl/6J or bradykinin B(2) receptor knockout (Bk2r(−/−)) mice after 1–6 h in vitro. The expression of mRNA for the mouse B(1) receptor in tracheal and urinary bladder tissues was also studied by using Northern blot analysis. 2. In isolated tracheae, des-Arg(9)-bradykinin produced a relaxant response that increased over time: no response was observed after 1 h of incubation, whereas after 6 h the maximum response (1 μM) was 68–84% of the relaxation produced by isoproterenol (1 μM) in the three mouse strains. The relaxant response to bradykinin (1 μM) observed at 1 h (38–51% of isoproterenol) was increased (62–65% of isoproterenol) after 6 h in Swiss and C57Bl/6J mice, but was absent in Bk2r(−/−) mice. In the presence of cycloheximide, des-Arg(9)-bradykinin did not cause any response at 6 h. 3. Similar findings were obtained in the urinary bladder: at 1 h des-Arg(9)-bradykinin (1 μM) did not cause any motor effect, whereas at 6 h it caused a contraction that was 28–59% of that produced by carbachol (1 μM) in the three mouse strains. Cycloheximide blocked the response to des-Arg(9)-bradykinin. Bradykinin (1 μM) contracted urinary bladders at 1 h (34–35% of carbachol), as well as at 6 h (66–77% of carbachol) in Swiss and C57Bl/6J strains, but was without effect in Bk2r(−/−) mice. 4. Northern blot hybridization with a specific cDNA probe against mouse B(1) receptor mRNA using total RNA extracted from tracheae and urinary bladders freshly removed from Swiss and Bk2r(−/−) mice revealed minimal expression. However, marked hybridization was detected 150 min after in vitro exposure in both tissues. 5. Evidence is provided that in vitro exposure of mouse trachea and urinary bladder causes a time-dependent induction of B(1) receptors that cause relaxation and contraction, respectively