38 results on '"Pruneau, D"'
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2. HyperHaesTM verstärkt den postiven Effekt von LF16-0687 auf das posttraumatische Hirnödem nach CCI bei der Ratte
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Thomale, UW, Griebenow, M, Pruneau, D, Kroppenstedt, SN, Unterberg, AW, and Stover, JF
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ddc: 610 - Published
- 2004
3. HyperHaesTM enhances the effect of LF16-0687 on post traumatic edema formation following CCI in rats
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Thomale, UW, Griebenow, M, Pruneau, D, Kroppenstedt, SN, Unterberg, AW, Stover, JF, Thomale, UW, Griebenow, M, Pruneau, D, Kroppenstedt, SN, Unterberg, AW, and Stover, JF
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- 2004
4. Detrimental Role of Bradykinin B2 Receptor in a Murine Model of Diffuse Brain Injury
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Hellal, F., primary, Pruneau, D., additional, Palmier, B., additional, Faye, P., additional, Croci, N., additional, Plotkine, M., additional, and Marchand-Verrecchia, C., additional
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- 2003
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5. Pharmacological and functional characterization of the guinea-pig B2bradykinin receptor stably expressed in CHO-K1 cell line
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Robert, C, primary, Pruneau, D, additional, and Paquet, J -L, additional
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- 2002
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6. Pharmacological and molecular evidence for kinin B1 receptor expression in urinary bladder of cyclophosphamide-treated rats
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Belichard, P, primary, Luccarini, J M, additional, Defrêne, E, additional, Faye, P, additional, Franck, R M, additional, Duclos, H, additional, Paquet, J L, additional, and Pruneau, D, additional
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- 1999
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7. Pharmacological characterization of the bradykinin B2receptor: inter-species variability and dissociation between binding and functional responses
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Paquet, J -L, primary, Luccarini, J -M, additional, Fouchet, C, additional, Defrêne, E, additional, Loillier, B, additional, Robert, C, additional, Bélichard, P, additional, Cremers, B, additional, and Pruneau, D, additional
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- 1999
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8. Stable expression of human kinin B1receptor in 293 cells: pharmacological and functional characterization
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Bastian, S., primary, Loillier, B., additional, Paquet, J. L., additional, and Pruneau, D., additional
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- 1997
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9. Pharmacological evidence for a single bradykinin B2 receptor in the guinea-pig
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Pruneau, D., primary, Luccarini, J.M., additional, Defrêne, E., additional, Paquet, J.L., additional, and Bélichard, P., additional
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- 1995
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10. The kinin B1 receptor antagonist des-Arg9-[Leu8]bradykinin: an antagonist of the angiotensin AT1 receptor which also binds to the AT2 receptor
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Pruneau, D., primary, Duvoid, A., additional, Luccarini, J.M., additional, Bélichard, P., additional, and Bonnafous, J.C., additional
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- 1995
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11. Induction of kinin B1 receptor-dependent vasoconstriction following balloon catheter injury to the rabbit carotid artery
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Pruneau, D., primary, Luccarini, J.M., additional, Robert, C., additional, and Bélichard, P., additional
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- 1994
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12. Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619
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Cocks, T.M., primary, Kemp, B.K., additional, Pruneau, D., additional, and Angus, J.A., additional
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- 1993
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13. ω-Conotoxin GVIA is a potent inhibitor of sympathetic neurogenic responses in rat small mesenteric arteries
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Pruneau, D., primary and Angus, J.A., additional
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- 1990
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14. Pharmacological and functional characterization of the guinea-pig B[sub2] bradykinin receptor stably expressed in CHO-K1 cell line.
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Robert, C., Pruneau, D., and Paquet, J.-L.
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BRADYKININ , *PHARMACOLOGY - Abstract
1 In the present study, pharmacological properties of a bradykinin B[sub 2] receptor amplified either from guinea-pig ileum or lung and homologous to the previously reported sequence except two amino-acid changes L[sup 124] → P and N[sup 227] → Y in the receptor protein were characterized. 2 Tritiated bradykinin ([³H]-BK) specifically bound to the cloned guinea-pig B[sub 2] bradykinin receptor stably expressed in Chinese hamster ovary cells (CHO-K1) with a K[sub D] value of 0.29 ± 0.07 nM. In competition experiments, bradykinin (BK) affinity constant value was 0.21 ± 0.05 nM while the two specific kinin B[sub 1] ligands, des-Arg[sup 9]-bradykinin (DBK) and des-Arg[sup 9]-Leu[sup 8]-bradykinin (DLBK) were unable to compete with [³H]-BK. As the specific peptide antagonist D-Arg-[Hyp³,Thi[sup 5],D-Tic[sup 7],Oic[sup 8]]bradykinin (HOE140), (E)-3-(6-acetamido-3-pyridil)-N-[-N-[2,4-dichloro-3-[(2-methyl-8-quinolin y1)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657) and 1-[[3-[2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-phenyl]sulfonyl] -2(S)-[[4-[4-(aminoiminomethyl)-phenylcarbonyl]piperazin-1-yl]carbonyl]py rrolidine (LF16-0335C) exhibited a high affinity for this receptor with K[sub i] values of 7.34 ± 2.45 nM and 8.54 ± 1.55 nM respectively. 3 BK and kallidin (KD) increased inositol phosphates (IPs) levels with EC[sub 50] values of 0.44 ± 0.12 nM and 6.88 ± 0.28 nM, respectively. Neither DLBK nor DBK (0.01 nM to 10 µM) stimulated or inhibited IPs turnover and as expected HOE140 did not raise IPs production. HOE140 (0.1 µM) and LF 16-0335c (1 µM) right shifted the BK response curve with pK[sub B], values of 9.2 ± 0.4 and 8.4 ± 0.3, respectively. 4 The results indicate that this cloned guinea-pig receptor displayed typical pharmacological properties of a bradykinin B[sub 2] receptor and support the existence of a single B[sub 2] receptor in... [ABSTRACT FROM AUTHOR]
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- 2002
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15. Pharmacological and molecular evidence for kinin B1 receptor expression in urinary bladder of cyclophosphamide-treated rats.
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Belichard, P, Luccarini, J M, Defrêne, E, Faye, P, Franck, R M, Duclos, H, Paquet, J L, and Pruneau, D
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- 1999
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16. Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses.
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Paquet, J -L, Luccarini, J -M, Fouchet, C, Defrêne, E, Loillier, B, Robert, C, Bélichard, P, Cremers, B, and Pruneau, D
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- 1999
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17. Stable expression of human kinin B1 receptor in 293 cells: pharmacological and functional characterization.
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Bastian, S., Loillier, B., Paquet, J. L., and Pruneau, D.
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- 1997
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18. Identification of a key region of kinin B(1) receptor for high affinity binding of peptide antagonists.
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Bastian, S, Pruneau, D, Loillier, B, Robert, C, Bonnafous, J C, and Paquet, J L
- Abstract
To investigate the molecular basis for the specificity of ligand recognition in human kinin B(1) (B(1)R) and B(2) (B(2)R) receptors, we constructed a series of chimeric receptors by progressively replacing, from the N to the C terminus, the human B(2)R domains by their B(1) counterparts. The chimeric construct possessing the C-terminal tail and the transmembrane domain VII (TM VII) of the B(2)R (construct 6) displayed 7- and 20- fold decreased affinities for the B(1) agonist [(3)H]desArg(10)-kallidin (desArg(10)-KD) and the B(1) antagonist [(3)H]desArg(10)-[Leu(9)]-KD respectively, as compared with the wild-type B(1)R. Moreover, the substitution of the B(1) TM VII by its B(2) homologue TM increased the affinity for the pseudopeptide antagonists, Hoe140 and NPC 567. High affinity for desArg(10)-KD binding was fully regained when the B(2) residue Thr(287) was replaced in construct 6 by the corresponding B(1) Leu(294) residue. When the B(2) residue Tyr(295) was exchanged with the corresponding B(1) Phe(302), high affinity binding for both agonist and antagonist was recovered. Moreover, the L294T and F302Y mutant B(1)R exhibited 69- and 6.5-fold increases, respectively, in their affinities for the B(2) receptor antagonist, Hoe140. Therefore we proposed that Leu(294) and Phe(302) residues, which may not be directly involved in the binding of B(1)R ligands and, hence, their Thr(287) and Tyr(295) B(2) counterparts, are localized in a receptor region, which plays a pivotal role in the binding selectivity of the peptide or pseudopeptide kinin ligands.
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- 2000
19. Pharmacological and molecular evidence for kinin B1receptor expression in urinary bladder of cyclophosphamide‐treated rats
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Belichard, P, Luccarini, J M, Defrêne, E, Faye, P, Franck, R M, Duclos, H, Paquet, J L, and Pruneau, D
- Abstract
In the present study, we developed an experimental model of cystitis induced by cyclophosphamide (CYP). In order to characterize des‐Arg9‐BK‐induced contraction on the urinary bladder (UB) during the development of inflammation and to quantify kinin B1receptor gene expression using a quantitative RT–PCR technique.In the presence of peptidase inhibitors captopril (10 μM), DL‐thiorphan (1 μM) and DL‐2‐mercaptomethyl‐3‐guanidino‐ethylthiopropanoic acid (MERGEPTA 5 μM), bradykinin (BK) (0.3–3,000 nM) evoked a concentration‐dependent contraction of rat UB which was not different between the CYP‐ and vehicle‐treated groups. Unlike BK, des‐Arg9‐BK (0.3–100,000 nM) did not contract UB from vehicle‐treated rats but contracted vigorously bladder strips from CYP‐treated rats 14, 24 and 168 h after treatment. In UB of 24 h treated rat, the pD2value of des‐Arg9‐BK was 7.3±0.1.The cyclo‐oxygenase inhibitor indomethacin (3 μM) reduced by 30% the maximal response of des‐Arg9‐BK. Both the kinin B1receptor antagonists des‐Arg9‐[Leu8]BK (10 μM) and des‐Arg10‐Hoe 140 (10 μM) produced a rightward shift of the concentration‐response curve to des‐Arg9‐BK yielding pKBvalues of 6.8±0.2 and 7.2±0.1, respectively, whilst the kinin B2receptor antagonist Hoe 140 (1 μM) had no effect.After CYP treatment, mRNA coding for the kinin B1receptor appeared predominantly in UB. In this organ, the induction was progressive, reaching a maximum 48 h after CYP treatment.In conclusion, the present study provides strong evidence for an induction of kinin B1receptors in UB of CYP‐treated rats. This was associated at a molecular level with an increase in mRNA expression of the gene coding for the kinin B1receptor. This kinin receptor displayed the whole features of a classical rat kinin B1receptor.
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- 1999
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20. Pharmacological evidence for a single bradykinin B2receptor in the guinea‐pig
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Pruneau, D., Luccarini, J.M., Defrêne, E., Paquet, J.L., and Bélichard, P.
- Abstract
1The present study addresses the possibility of the existence of different kinin B2receptor subtypes in the guinea‐pig by evaluating the affinity of peptide and nonpeptide receptor antagonists. For this purpose, jugular vein rings, ileum segments, lung parenchymal and trachea strips were set up in organ baths for isometric tension measurements. The experiments were conducted in the presence of indomethacin (3 μm), atropine (10 μm) and captopril (10 μm).2BK contracted jugular vein (JV), ileum (GPI), parenchyma (LP) and trachea (GPT) with an EC50of 13.2 ± 1.4 nM (n= 27), 11.2 + 2.1 (n= 26), 23.6 ± 6.3 nM (n= 26) and 33.0 ± 6.5 (n= 27), respectively. Thiorphan, a neutral endopeptidase (EC 3.4.24.11) inhibitor and MERGETPA (DL‐2‐mercaptomethyl‐3‐guanidinoethylthiopropanoic acid), a carboxypeptidase inhibitor, had no effect on the BK‐induced contractions of JV, GPI and LP. In the GPT, thiorpan potentiated the contractile response to BK and was thus added in the corresponding experiments.3The peptide B2receptor antagonist, Hoe 140 and the nonpeptide compound, WIN 64338, behaved as noncompetitive antagonists against contractile responses to cumulative BK in the four tissues although Hoe 140 appeared as a competitive inhibitor in the GPT only. In order to compare the inhibitory potency of these compounds between tissues, pKBvalues were determined. Mean values of pKBfor Hoe 140 were 8.05 ± 0.07, 8.43 ± 0.11, 8.13 ± 0.18 and 8.52 ± 0.25 in the JV, GPI, GPT and LP, respectively. WIN 64338 gave mean pKBvalues of 6.89 ± 0.10, 7.57 ± 0.12, 7.36±0.12 and 7.51 ± 0.28 in the JV, GPI, LP and GPT, respectively.4D‐Arg [Hyp3, D‐Phe7, Leu8]BK and D‐Arg [Hyp3, D‐Phe7]BK (NPC 567) inhibited in a competitive fashion the concentration‐response curves to BK. Values of pA2for each compound were not significantly different in the four tissues and were between 5.81 and 6.31 for D‐Arg [Hyp3, D‐Phe7, Leu8]BK and between 5.55 and 5.65 for NPC 567.5We conclude that the contractile response to BK in guinea‐pig vascular, intestine and lung tissue is mediated by a unique B2receptor. Thus, our results do not support the existence of a B3receptor in the trachea and we suggest that the previously reported B2Breceptor subtype simply represents the guinea‐pig isoform. The present study addresses the possibility of the existence of different kinin B2receptor subtypes in the guinea‐pig by evaluating the affinity of peptide and nonpeptide receptor antagonists. For this purpose, jugular vein rings, ileum segments, lung parenchymal and trachea strips were set up in organ baths for isometric tension measurements. The experiments were conducted in the presence of indomethacin (3 μm), atropine (10 μm) and captopril (10 μm). BK contracted jugular vein (JV), ileum (GPI), parenchyma (LP) and trachea (GPT) with an EC50of 13.2 ± 1.4 nM (n= 27), 11.2 + 2.1 (n= 26), 23.6 ± 6.3 nM (n= 26) and 33.0 ± 6.5 (n= 27), respectively. Thiorphan, a neutral endopeptidase (EC 3.4.24.11) inhibitor and MERGETPA (DL‐2‐mercaptomethyl‐3‐guanidinoethylthiopropanoic acid), a carboxypeptidase inhibitor, had no effect on the BK‐induced contractions of JV, GPI and LP. In the GPT, thiorpan potentiated the contractile response to BK and was thus added in the corresponding experiments. The peptide B2receptor antagonist, Hoe 140 and the nonpeptide compound, WIN 64338, behaved as noncompetitive antagonists against contractile responses to cumulative BK in the four tissues although Hoe 140 appeared as a competitive inhibitor in the GPT only. In order to compare the inhibitory potency of these compounds between tissues, pKBvalues were determined. Mean values of pKBfor Hoe 140 were 8.05 ± 0.07, 8.43 ± 0.11, 8.13 ± 0.18 and 8.52 ± 0.25 in the JV, GPI, GPT and LP, respectively. WIN 64338 gave mean pKBvalues of 6.89 ± 0.10, 7.57 ± 0.12, 7.36±0.12 and 7.51 ± 0.28 in the JV, GPI, LP and GPT, respectively. D‐Arg [Hyp3, D‐Phe7, Leu8]BK and D‐Arg [Hyp3, D‐Phe7]BK (NPC 567) inhibited in a competitive fashion the concentration‐response curves to BK. Values of pA2for each compound were not significantly different in the four tissues and were between 5.81 and 6.31 for D‐Arg [Hyp3, D‐Phe7, Leu8]BK and between 5.55 and 5.65 for NPC 567. We conclude that the contractile response to BK in guinea‐pig vascular, intestine and lung tissue is mediated by a unique B2receptor. Thus, our results do not support the existence of a B3receptor in the trachea and we suggest that the previously reported B2Breceptor subtype simply represents the guinea‐pig isoform.
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- 1995
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21. The Cap Pele model
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Pruneau, D., Arsenault, C., and Chouinard, O.
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- 1998
22. Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates.
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Gauvain G, Akolkar H, Chaffiol A, Arcizet F, Khoei MA, Desrosiers M, Jaillard C, Caplette R, Marre O, Bertin S, Fovet CM, Demilly J, Forster V, Brazhnikova E, Hantraye P, Pouget P, Douar A, Pruneau D, Chavas J, Sahel JA, Dalkara D, Duebel J, Benosman R, and Picaud S
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- Animals, Equipment and Supplies, Female, Humans, Macaca fascicularis, Male, Pattern Recognition, Visual physiology, Primates, Retinal Degeneration physiopathology, Retinal Degeneration rehabilitation, Therapies, Investigational instrumentation, Therapies, Investigational methods, Optogenetics instrumentation, Optogenetics methods, Photic Stimulation instrumentation, Photic Stimulation methods, Retinal Degeneration therapy, Vision, Ocular physiology
- Abstract
Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 10
15 photons.cm-2 .s-1 . Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa.- Published
- 2021
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23. Pressure Infusion Cuff and Blood Warmer during Massive Transfusion: An Experimental Study About Hemolysis and Hypothermia.
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Poder TG, Pruneau D, Dorval J, Thibault L, Fisette JF, Bédard SK, Jacques A, and Beauregard P
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- Blood Transfusion instrumentation, Hemolysis, Hypothermia etiology, Pressure, Temperature, Transfusion Reaction
- Abstract
Background: Blood warmers were developed to reduce the risk of hypothermia associated with the infusion of cold blood products. During massive transfusion, these devices are used with compression sleeve, which induce a major stress to red blood cells. In this setting, the combination of blood warmer and compression sleeve could generate hemolysis and harm the patient. We conducted this study to compare the impact of different pressure rates on the hemolysis of packed red blood cells and on the outlet temperature when a blood warmer set at 41.5°C is used., Methods: Pressure rates tested were 150 and 300 mmHg. Ten packed red blood cells units were provided by Héma-Québec and each unit was sequentially tested., Results: We found no increase in hemolysis either at 150 or 300 mmHg. By cons, we found that the blood warmer was not effective at warming the red blood cells at the specified temperature. At 150 mmHg, the outlet temperature reached 37.1°C and at 300 mmHg, the temperature was 33.7°C., Conclusion: To use a blood warmer set at 41.5°C in conjunction with a compression sleeve at 150 or 300 mmHg does not generate hemolysis. At 300 mmHg a blood warmer set at 41.5°C does not totally avoid a risk of hypothermia., Competing Interests: The authors have declared that no competing interests exist.
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- 2016
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24. Autoradiographic analysis of mouse brain kinin B1 and B2 receptors after closed head trauma and ability of Anatibant mesylate to cross the blood-brain barrier.
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Ongali B, Hellal F, Rodi D, Plotkine M, Marchand-Verrecchia C, Pruneau D, and Couture R
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- Animals, Autoradiography, Binding, Competitive, Blood-Brain Barrier physiology, Brain drug effects, Male, Mice, Phenols pharmacokinetics, Propanols pharmacokinetics, Blood-Brain Barrier drug effects, Brain metabolism, Head Injuries, Closed physiopathology, Quinolines pharmacology, Receptor, Bradykinin B1 metabolism, Receptor, Bradykinin B2 metabolism
- Abstract
The potent non-peptide B2 receptor (R) antagonist, Anatibant mesylate (Ms) (LF 16-0687 Ms), reduces brain edema and improves neurological function recovery in various focal and diffuse models of traumatic brain injury in rodents. In the present study, alteration of kinin B1 and B2R after closed head trauma (CHT) and in vivo binding properties of Anatibant Ms (3 mg/kg, s.c.) injected 30 min after CHT were studied in mice by autoradiography using the radioligands [125I]HPP-Hoe 140 (B2R), and [125I]HPP-des-Arg10-Hoe 140 (B1R). Whereas B1R is barely detected in most brain regions, B2R is extensively distributed, displaying the highest densities in the hindbrain. CHT was associated with a slight increase of B1R and a decrease of B2R (10-50%) in several brain regions. Anatibant Ms (Ki = 22 pM) displaced the B2R radioligand from its binding sites in several areas of the forebrain, basal ganglia and hindbrain. Displacement was achieved in 1 h and persisted at 4 h post-injection. The inhibition did not exceed 50% of the total specific binding in non-injured mice. After CHT, the displacement by Anatibant Ms was higher and almost complete in the cortex, caudate putamen, thalamus, hippocampus, medial geniculate nucleus, ventral tegmental area, and raphe. Evans blue extravasation in brain tissue at 4 h after CHT was abolished by Anatibant Ms. It appeared that Anatibant Ms penetrated into the brain in sufficient amounts, particularly after disruption of the blood-brain barrier, to account for its B2R-mediated neuro- and vascular protective effects. The diminished binding of B2R after CHT may reflect the occupancy or internalization of B2R following the endogenous production of bradykinin (BK).
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- 2006
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25. LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces ischemic brain injury in a murine model of transient focal cerebral ischemia.
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Ding-Zhou L, Margaill I, Palmier B, Pruneau D, Plotkine M, and Marchand-Verrecchia C
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- Animals, Blood Pressure drug effects, Blood-Brain Barrier drug effects, Brain metabolism, Brain Edema drug therapy, Brain Edema etiology, Brain Infarction drug therapy, Brain Infarction etiology, Brain Ischemia complications, Brain Ischemia metabolism, Disease Models, Animal, Male, Mice, Neutrophil Infiltration drug effects, Bradykinin B2 Receptor Antagonists, Brain drug effects, Brain Ischemia drug therapy, Quinolines therapeutic use
- Abstract
1. Bradykinin promotes neuronal damage and brain edema through the activation of the B(2) receptor. The neuroprotective effect of LF 16-0687 Ms, a B(2) receptor antagonist, has been described when given prior to induction of transient focal cerebral ischemia in rat, but there are no data regarding the consequence of a treatment when given after injury. Therefore, in a murine model of transient middle cerebral artery occlusion (MCAO), we evaluated the effect of LF 16-0687 Ms given prior to and/or after the onset of ischemia on neurological deficit, infarct volume and inflammatory responses including cerebral edema, blood-brain barrier (BBB) disruption and neutrophil accumulation. 2. LF 16-0687 Ms (1, 2 and 4 mg kg(-1)) administered 0.5 h before and, 1.25 and 6 h after MCAO, decreased the infarct volume by a maximum of 33% and significantly improved the neurological recovery. 3. When given at 0.25 and 6.25 h after MCAO, LF 16-0687 Ms (1.5, 3 and 6 mg kg(-1)) decreased the infarct volume by a maximum of 25% and improved the neurological score. 4. Post-treatment with LF 16-0687 Ms (1.5 mg kg(-1)) significantly decreased brain edema (-28%), BBB disruption (-60%) and neutrophil accumulation (-65%) induced by ischemia. Physiological parameters were not modified by LF 16-0687 Ms. 5. These data emphasize the role of bradykinin B(2) receptor in the development of infarct lesion, neurological deficit and inflammatory responses resulting from transient focal cerebral ischemia. Therefore, B(2) receptor antagonist might represent a new therapeutic approach in the pharmacological treatment of stroke.
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- 2003
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26. LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces brain edema and improves long-term neurological function recovery after closed head trauma in rats.
- Author
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Kaplanski J, Pruneau D, Asa I, Artru AA, Azez A, Ivashkova Y, Rudich Z, and Shapira Y
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- Animals, Brain Injuries physiopathology, Dose-Response Relationship, Drug, Head Injuries, Closed physiopathology, Neuroprotective Agents therapeutic use, Rats, Rats, Sprague-Dawley, Receptor, Bradykinin B2, Recovery of Function, Time Factors, Trauma Severity Indices, Bradykinin Receptor Antagonists, Brain Edema physiopathology, Brain Injuries drug therapy, Head Injuries, Closed drug therapy, Quinolines therapeutic use
- Abstract
Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. It had no effect on the brain water content of sham-operated rats. LF 16-0687 Ms also significantly improved neurological recovery evaluated by a Neurological Severity Score (NSS) based on motor, reflex, and behavioral tests. In time-window studies LF 16-0687 Ms (2.25 mg/kg) was given 1, 2, 4, and 10 h after CHT. The extent of edema was significantly reduced when LF 16-0687 Ms was given 1 h (-45%), 2 h (-52%), and 4 h (-63%) but not 10 h (-24%) after CHT. Given at any time-point, LF 16-0687 Ms significantly improved the recovery of the NSS at 24 h. In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.
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- 2002
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27. Control of conformational equilibria in the human B2 bradykinin receptor. Modeling of nonpeptidic ligand action and comparison to the rhodopsin structure.
- Author
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Marie J, Richard E, Pruneau D, Paquet JL, Siatka C, Larguier R, Poncé C, Vassault P, Groblewski T, Maigret B, and Bonnafous JC
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- Amino Acid Sequence, Asparagine chemistry, Asparagine metabolism, Humans, Ligands, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Conformation, Receptor, Bradykinin B2, Receptors, Bradykinin metabolism, Sequence Homology, Amino Acid, Tryptophan chemistry, Tryptophan metabolism, Receptors, Bradykinin chemistry, Rhodopsin chemistry
- Abstract
A prototypic study of the molecular mechanisms of activation or inactivation of peptide hormone G protein-coupled receptors was carried out on the human B2 bradykinin receptor. A detailed pharmacological analysis of receptor mutants possessing either increased constitutive activity or impaired activation or ligand recognition allowed us to propose key residues participating in intramolecular interaction networks stabilizing receptor inactive or active conformations: Asn(113) and Tyr(115) (TM III), Trp(256) and Phe(259) (TM VI), Tyr(295) (TM VII) which are homologous of the rhodopsin residues Gly(120), Glu(122), Trp(265), Tyr(268), and Lys(296), respectively. An essential experimental finding was the spatial proximity between Asn(113), which is the cornerstone of inactive conformations, and Trp(256) which plays a subtle role in controlling the balance between active and inactive conformations. Molecular modeling and mutagenesis data showed that Trp(256) and Tyr(295) constitute, together with Gln(288), receptor contact points with original nonpeptidic ligands. It provided an explanation for the ligand inverse agonist behavior on the WT receptor, with underlying restricted motions of TMs III, VI, and VII, and its agonist behavior on the Ala(113) and Phe(256) constitutively activated mutants. These data on the B2 receptor emphasize that conformational equilibria are controlled in a coordinated fashion by key residues which are located at strategic positions for several G protein-coupled receptors. They are discussed in comparison with the recently determined rhodopsin crystallographic structure.
- Published
- 2001
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28. Role of bradykinin B2 receptors in the formation of vasogenic brain edema in rats.
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Plesnila N, Schulz J, Stoffel M, Eriskat J, Pruneau D, and Baethmann A
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- Algorithms, Animals, Blood Pressure drug effects, Blood Pressure physiology, Body Water physiology, Bradykinin Receptor Antagonists, Brain Edema drug therapy, Functional Laterality physiology, Male, Organ Size physiology, Quinolines therapeutic use, Rats, Rats, Sprague-Dawley, Receptor, Bradykinin B2, Brain Edema pathology, Cerebrovascular Circulation physiology, Quinolines pharmacology, Receptors, Bradykinin physiology
- Abstract
Bradykinin is a mediator of brain edema acting through B2 receptors. However, it is not known if bradykinin mediates the formation of cytotoxic or vasogenic brain swelling. To investigate this question we subjected rats to a cryogenic brain lesion over the left parietal cortex, a model well known to produce predominantly vasogenic brain edema. We inhibited bradykinin B2 receptors with the recently characterized nonpeptide B2 receptor antagonist, LF 16-0687. The animals were assigned to three groups (n = 10, each) receiving 10, or 100 microg/kg/min LF 16-0687 or vehicle (0.9% NaCl). Treatment started 15 min before trauma and was continued for 24 h. Another three groups of animals (n = 10, each) received 10 microg/kg/min LF 16-0687 starting 30 or 60 min after trauma or vehicle (0.9% NaCl) for 24 h. Animals were then sacrificed and swelling and water content of the brain were determined. In the vehicle treated group the traumatized hemisphere swelled by 9.3 +/- 1.1% as compared to the untraumatized contralateral side. Pretreatment with 10 microg/kg/min LF 16-0687 decreased brain swelling significantly to 6.4 +/- 1.3% (p < 0.05). Pre-treatment with 100 microg/kg/min was found to be less effective and did not result in a significant reduction of brain swelling (7.4 + 1.3%). Treatment with LF 16-0687 for 24 h (10 microg/kg/min) started 30 or 60 min after trauma did not reduce brain water content or hemispheric swelling. These results demonstrate that brain injury-mediated bradykinin production induces vasogenic brain edema by B2 receptor stimulation. Our findings further clarify the role of bradykinin in the pathophysiology of brain edema formation and confirm the therapeutic potency of bradykinin B2 receptor inhibition.
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- 2001
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29. Effect of LF 16-0687MS, a new nonpeptide bradykinin B2 receptor antagonist, in a rat model of closed head trauma.
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Pruneau D, Chorny I, Benkovitz V, Artru A, Roitblat L, and Shapira Y
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- Animals, Brain Edema physiopathology, Head Injuries, Closed physiopathology, Rats, Rats, Sprague-Dawley, Receptor, Bradykinin B2, Blood Pressure drug effects, Bradykinin Receptor Antagonists, Brain Edema drug therapy, Head Injuries, Closed drug therapy, Quinolines therapeutic use
- Abstract
Bradykinin is an endogenous nonapeptide which potently dilates the cerebral vasculature and markedly increases vascular permeability. These effects are mediated by B2 receptors located on the vascular endothelium. Previous experimental studies have shown that blockade of the kallikreinkinin system, which mediates the formation of bradykinin, afforded a reduction of the brain edema that developed following a cryogenic cortical lesion. In the present study, we investigated the effect of LF 16-0687MS, a novel nonpeptide B2 receptor antagonist, on cerebral edema and neurological severity score (NSS) after closed head injury to rats. LF 16-0687MS or its vehicle (NaCl 0.9%) was continuously infused at 10, 30, and 100 microg/kg/min over 23 h starting 1 h after a focal trauma to the left hemisphere was induced using a weight-drop device. The extent of edema formation was evaluated 24 h after trauma from left and right hemispheres samples by measurement of specific gravity and water content. In a separate study, a neurological severity score based on scoring of behavioural and motor functions was evaluated 1 h and over 1 week after trauma. LF 16-0687MS at 100 microg/kg/min markedly reduced the development of brain edema as indicated by a 68% increase in specific gravity (p<0.05) and a 64% decrease of water content (p<0.05) in the left hemisphere. In addition the recovery of neurological function was significantly improved by 100 microg/kg/min LF 16-0687MS from day 3 to day 7 after CHT. In a separate experiment, we also showed that LF 16-0687MS at 100 microg/kg/min given either 1 h before or 30 min after CHT did not affect mean arterial blood pressure. These results show that blockade of bradykinin B2 receptors is an effective approach to reduce cerebral edema and to improve neurological outcome after a focal contusion to the cranium.
- Published
- 1999
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30. Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses.
- Author
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Paquet JL, Luccarini JM, Fouchet C, Defrêne E, Loillier B, Robert C, Bélichard P, Cremers B, and Pruneau D
- Subjects
- Animals, Binding, Competitive, Bradykinin metabolism, Bradykinin pharmacology, Bradykinin Receptor Antagonists, CHO Cells, Cricetinae, Humans, Inositol Phosphates, Peptides metabolism, Rats, Receptor, Bradykinin B2, Species Specificity, Tromethamine analogs & derivatives, Umbilical Veins drug effects, Umbilical Veins physiology, Vasoconstriction drug effects, Adrenergic beta-Antagonists pharmacology, Bradykinin analogs & derivatives, Receptors, Bradykinin metabolism
- Abstract
1. The present study addresses the differences in binding profiles and functional properties of the human and rat bradykinin (BK) B2 receptor using various kinin receptor peptide derivatives as well as the non-peptide receptor antagonists WIN 64338 (phosphonium, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2-naphtalenyl)1- oxopropyl]amino]-phenyl]-methyl]tributyl, chloride, monohydro-chloride), and FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[-N-[2,4-dichloro-3-[(2-methyl-8-quinoli nyl)oxymethyl]-phenyl]N-methylamino carbonyl methyl] acrylamide. 2. [3H]-BK bound with a similar affinity to membranes of Chinese hamster ovary cells (CHO-K1) expressing the cloned human (hB2-CHO) or rat (rB2-CHO) B2 receptor, human embryonic intestine cells (INT407) expressing the native B2 receptor, human umbilical vein (HUV) and rat uterus (RU). WIN 64338 and FR173657 bound with a 3.8-6.6 fold and 7.0-16.3 fold higher affinity the rat than the human B2 receptor, respectively. The affinity values of BK derivatives as well as non-peptide antagonists were reduced by 6-23 fold in physiological HBSS compared to low ionic strength TES binding buffer. 3. BK (0.01-3000 nM) increased inositol triphosphates (IP3) levels in hB2-CHO, rB2-CHO and INT407 cells. The B2 receptor antagonist, Hoe 140 (D-Arg0-[ Hyp3, Thi5, D-Tic7, Oic8]-BK) at 10(-7) M, significantly shifted to the right the IP3 response curves to BK giving apparent pKB values of 8.56, 9.79 and 8.84 for hB2-CHO, rB2-CHO and INT407 cells, respectively. 4. In human isolated umbilical vein, Hoe 140, D-Arg0-[Hyp3, D-Phe7, Leu8]-BK and NPC 567 had a lower potency in functional assays (pKB 8.18, 5.77 and 5.60, respectively) than expected from their affinity in binding studies (pKi 10.52, 8.64 and 8.27, respectively). 5. FR173657 behaved as a high affinity ligand with pKi values of 8.59 and 9.81 and potent competitive antagonist with pKB values of 7.80 and 8.17 in HUV and RU, respectively. FR173657 bound with a similar affinity the cloned and native bradykinin B2 receptor in human (pKi of 8.66 and 8.59, respectively) and in rat (pKi 9.67 and 9.81, respectively). 6. In conclusion, we suggest that the binding buffer composition has to be taken into account when screening new compounds and that inter-species differences should be considered when setting up animal models with the aim of developing bradykinin B2 receptor antagonists as therapeutic agents.
- Published
- 1999
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31. LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor.
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Pruneau D, Luccarini JM, Fouchet C, Defrêne E, Franck RM, Loillier B, Duclos H, Robert C, Cremers B, Bélichard P, and Paquet JL
- Subjects
- Amidines chemistry, Binding, Competitive, Cells, Cultured, Dose-Response Relationship, Drug, Humans, In Vitro Techniques, Phosphatidylinositols biosynthesis, Piperazines chemistry, Receptor, Bradykinin B2, Umbilical Veins drug effects, Umbilical Veins metabolism, Vasoconstriction drug effects, Amidines pharmacology, Bradykinin pharmacology, Bradykinin Receptor Antagonists, Piperazines pharmacology
- Abstract
1. In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-p henyl]sulphonyl] -2(S) - [[4 -[4-(aminoiminomethyl)phenylcarbonyl]piperazin-1-yl]ca rbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B2 receptor. 2. LF 16.0335 displaced [3H]-BK binding to membrane preparations from CHO cells expressing the cloned human B2 receptor, INT 407 cells and human umbilical vein with Ki values of 0.84+/-0.39 nM, 1.26+/-0.68 nM and 2.34+/-0.36 nM, respectively. 3. In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, max values of [3H]-BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist. 4. LF 16.0335 had no affinity for the cloned human kinin B1 receptor stably expressed in 293 cells. In addition, this compound at 1 microM did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M2 and M1 receptors for which an IC50 value of 0.9 and 1 microM was obtained. 5. BK stimulates in a concentration-dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration-response-curves to BK were shifted to the right in the presence of LF 16.0335 (0.1 microM) without reduction of the maximum. LF 16.0335 inhibited the concentration-contraction curve to BK in the human umbilical vein giving a pA2 value of 8.30+/-0.30 with a Schild plot slope that was not different from unity. 6. These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B2 receptor.
- Published
- 1998
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32. Stable expression of human kinin B1 receptor in 293 cells: pharmacological and functional characterization.
- Author
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Bastian S, Loillier B, Paquet JL, and Pruneau D
- Subjects
- Calcium metabolism, Cell Line, Enzyme Activation, Humans, Kallidin metabolism, Kallidin pharmacology, Receptor, Bradykinin B1, Receptors, Bradykinin metabolism, Transfection, Type C Phospholipases metabolism, Kallidin analogs & derivatives, Receptors, Bradykinin drug effects
- Abstract
1. We compared the binding properties of [3H]-desArg10-[Leu9]-kallidin, a radiolabelled kinin B1 receptor antagonist, to membranes from IMR-90 human embryonic fibroblasts and from 293 cells transiently or stably transfected with the human B1 receptor. 2. The dissociation constant (KD) of [3H]-desArg10-[Leu9]-kallidin and the affinity of several kinin receptor agonists and antagonists were similar between the native and cloned receptor, either transiently or stably expressed in 293 cells. In IMR-90 cells, the rank order of potency was that expected for a kinin B1 receptor. 3. The receptors transiently or stably expressed in 293 cells were fully functional with respect to their signalling properties. Phosphoinositide hydrolysis was increased in a concentration-dependent manner by the B1 receptor agonist, desArg10-kallidin. Functional coupling to the calcium pathway was also demonstrated for the native and stably expressed human B1 receptor. 4. In conclusion, the established stable and functional 293 cell clone may provide an important tool for further analysis of the molecular mechanisms involved in binding, activation, and coupling of the kinin B1 receptor.
- Published
- 1997
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33. Haemodynamic and cardiac effects of kinin B1 and B2 receptor stimulation in conscious instrumented dogs.
- Author
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Bélichard P, Loillier B, Paquet JL, Luccarini JM, and Pruneau D
- Subjects
- Animals, Arginine analogs & derivatives, Arginine pharmacology, Blood Pressure drug effects, Bradykinin analogs & derivatives, Bradykinin analysis, Bradykinin pharmacology, Bradykinin Receptor Antagonists, Coronary Vessels metabolism, Dogs, Enzyme Inhibitors pharmacology, Ganglionic Blockers pharmacology, Hexamethonium pharmacology, Indomethacin pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitroarginine, Receptor, Bradykinin B1, Receptor, Bradykinin B2, Vascular Resistance drug effects, Coronary Circulation drug effects, Hemodynamics drug effects, Receptors, Bradykinin agonists
- Abstract
1. Mongrel dogs were chronically instrumented with an intra-aortic catheter, a Königsberg intraventricular pressure transducer and a Döppler flow probe around the left coronary artery. After ganglionic blockade with hexamethonium, the cardiovascular effects of bradykinin B1 and B2 receptor agonists, des-Arg9-bradykinin and bradykinin (BK), were investigated in the presence and absence of specific antagonists. The contribution of nitric oxide (NO) and prostanoids to the cardiovascular effects of kinins was also examined. 2. BK (1 microgram kg-1 min-1) and des-Arg9-BK (1 microgram kg-1 min-1) both given as a 2 min i.v. infusion, produced a significant decrease in mean arterial pressure (MAP, -34 +/- 4% for BK and -45 +/- 2% for des-Arg9-BK) and coronary vascular resistance (CVR, -37 +/- 5% for BK and -50 +/- 2% for des-Arg9-BK), without affecting cardiac contractility, left ventricular end diastolic pressure, and coronary velocity. BK caused a significantly greater decrease in MAP and CVR than des-Arg9-BK (P < 0.05). 3. Pretreatment with the B1 receptor antagonist, des-Arg9-[Leu8]-BK (25 micrograms kg-1) significantly inhibited the decrease in MAP and CVR produced by des-Arg9-BK but not by BK. Infusion of des-Arg9-[Leu8]-BK alone also induced a significant decrease in MAP and CVR (P < 0.05). In the presence of the B2 receptor antagonist, Hoe 140 (25 micrograms kg-1), only the decreases in MAP and CVR caused by BK were significantly reduced (P < 0.05). 4. Inhibition of NO synthase with N omega-nitro-L-arginine (L-NOARG, 45 mg kg-1) significantly (P < 0.05) prevented the decrease in CVR but not MAP induced by des-Arg9-BK, whilst responses to BK were not affected by L-NOARG pretreatment. Inhibition of prostanoid synthesis with indomethacin (25 mg kg-1) did not affect the reductions in MAP and CVR induced by des-Arg9-BK or BK. 5. In conclusion, i.v. des-Arg9-BK and BK administration induced reductions in MAP and CVR suggesting that in conscious instrumented dogs both B1 and B2 receptors are present and can affect systemic blood pressure and coronary resistance regulation. Our results also suggest that prostanoids are not involved in the vascular response to kinins and that coronary vascular B1 receptors are at least in part coupled to the release of NO.
- Published
- 1996
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34. Reduction of intimal hyperplasia by naroparcil, a 4-methylumbelliferyl beta-D-xyloside analogue, after arterial injury in the hypercholesterolemic rabbit.
- Author
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Steg PG, Ziol M, Tahlil O, Robert C, Masson P, Pruneau D, Bruneval P, and Bélichard P
- Subjects
- Administration, Oral, Angioplasty, Balloon, Animals, Antithrombins administration & dosage, Biochemical Phenomena, Biochemistry, Cholesterol blood, Diet, Atherogenic, Glycosaminoglycans blood, Glycosaminoglycans metabolism, Hypercholesterolemia blood, Hyperplasia, Immunohistochemistry, Proteoglycans blood, Proteoglycans metabolism, Rabbits, Random Allocation, Thioglycosides administration & dosage, Time Factors, Antithrombins pharmacology, Arteries injuries, Hypercholesterolemia metabolism, Thioglycosides pharmacology, Tunica Intima drug effects, Tunica Intima pathology
- Abstract
4-Methylumbelliferyl beta-D-xylosides (beta-D-xylosides) inhibit proteoglycan synthesis, and this is associated with reduced proliferation and extracellular matrix production by vascular smooth muscle cells. This study evaluated whether treatment with naroparcil, a beta-D-xyloside analogue, reduced intimal hyperplasia after arterial injury in the hypercholesterolemic rabbit. Forty-two rabbits were assigned to three groups that received either a 1% cholesterol-enriched diet (group 1, n = 15) or the same diet with added 100 mg.kg-1 naroparcil (group 2, n = 15) or 300 mg.kg-1 naroparcil (group 3, n = 12). All animals underwent iliac artery endothelial abrasion at day 14 and were killed at day 56. At the time of death, the angiographic minimal luminal diameter was significantly larger in both treated groups. Morphometric analysis showed a larger luminal area in treated rabbits (groups 2 and 3) compared with control rabbits (group 1) (0.75 +/- 0.54 and 0.85 +/- 0.61 mm2 versus 0.32 +/- 0.25 mm2, respectively; P < .05), with a decreased intimal thickness in groups 2 and 3 (average reduction of 37% and 39%, respectively, compared with group 1; P < .05) but without changes in medial area. Total vessel area was comparable among all groups. In the media, immunohistochemistry suggested reduced infiltration by macrophages and a larger fractional area of smooth muscle cells. There were no differences in plasma or arterial wall cholesterol content between groups. Plasma levels of glycosaminoglycans and dermatan sulfate content were increased only in group 3. In this model, oral treatment with naroparcil appears to preserve the arterial lumen and reduce intimal thickness after arterial injury.
- Published
- 1995
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35. Mediation by 5-HT1D receptors of 5-hydroxytryptamine-induced contractions of rabbit middle and posterior cerebral arteries.
- Author
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Deckert V, Pruneau D, and Elghozi JL
- Subjects
- Animals, Cerebral Arteries cytology, Endothelium, Vascular physiology, In Vitro Techniques, Muscle Contraction drug effects, Muscle, Smooth, Vascular cytology, Rabbits, Receptors, Serotonin drug effects, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology, Cerebral Arteries drug effects, Muscle, Smooth, Vascular drug effects, Receptors, Serotonin physiology, Serotonin pharmacology
- Abstract
1. 5-Hydroxytryptamine (5-HT) receptor-mediated contraction of endothelium denuded rabbit middle (MCA) and posterior (PCA) cerebral arteries was characterized by use of selective agonists and antagonists for different 5-HT receptor subtypes. 2. 5-HT and various 5-HT receptor agonists contracted the arteries with the following rank order of potency in MCA: 5-carboxamidotryptamine (5-CT) > 5-HT > 5-methoxytryptamine (5-MeOT) > sumatriptan > alpha-methyl-5-HT (alpha-Me-5-HT) >> 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and in PCA: 5-CT > 5-HT > sumatriptan > 5-MeOT > alpha-Me-5-HT >> 8-OH-DPAT. With few exceptions, the maximal contractile responses of these agonists were similar to that induced by 5-HT. 3. The selective antagonists of 5-HT2A/2C (ketanserin), 5-HT4 (SDZ 205-557) and 5-HT1A/1B (S-(-)-propranolol) sites were devoid of inhibitory effect on 5-HT-mediated contraction in both MCA and PCA, thus excluding activation of the corresponding receptors. 4. In both arteries, the contraction-response curve to 5-HT was unaffected by the 5-HT3 receptor antagonist, ICS 205-930 (0.01 and 0.1 microM) whilst a small (3 and 6 fold displacement) was seen with MDL 72222 (0.1 and 1 microM). 5. The mixed 5-HT1-like/5-HT2A receptor antagonist, methiothepin (0.001-0.1 microM), was a potent antagonist of 5-HT-induced contractions in both arteries, giving pA2 values of 9.4 +/- 0.7 and 9.6 +/- 0.8 in MCA and PCA, respectively. 6. Rauwolscine (O.1-10 MicroM) and yohimbine (0.3, 3 MicroM) inhibited contractions to 5-HT in a competitive manner, pA2 values of 7.1 +/- 0.6 and 6.7 +/-0.6 were determined for rauwolscine in MCA and PCA,respectively. An apparent pA2 value of 6.9 +/-0.2 was calculated for yohimbine (3 MicroM) in both MCA and PCA.7. In conclusion, these results suggest that the contractile response to 5-HT in rabbit isolated MCA and PCA is predominantly mediated by the 5-HTID receptor subtype, although a small contribution by 5-HT3 receptors cannot be excluded.
- Published
- 1994
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36. Electrophysiological responses of hypertrophied rat myocardium to combined hypoxia, hyperkalemia, and acidosis.
- Author
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Bélichard P, Pruneau D, Rouet R, and Salzmann JL
- Subjects
- Action Potentials, Animals, Organ Size, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Species Specificity, Acidosis physiopathology, Cardiomegaly physiopathology, Heart physiology, Hyperkalemia physiopathology, Hypoxia physiopathology
- Abstract
We studied whether electrophysiological response to ischemia could be different in hypertrophied left ventricle of spontaneously hypertensive rats (SHRs) and in normal left ventricle of normotensive Wistar-Kyoto (WKY) rats. For that purpose, we used a two-compartment tissue bath in which one-half of a left ventricular strip was exposed to normal conditions and the other part to ischemic conditions (low pH, hypoxia, and hyperkalemia). Electrical activity was recorded using standard microelectrodes in normal and hypertrophied preparations. Under basal conditions, the action potential duration (APD) and effective refractory period (ERP) were longer in SHRs than in WKY rats (118 +/- 9 ms vs 81 +/- 3 ms, p less than 0.05 and 90 +/- 9 ms vs. 74 +/- 4 ms, p less than 0.05, respectively). During ischemia, the APD and ERP changed in opposite ways in both groups and we observed the development of postrepolarization refractoriness that was greater in hypertrophied than in normal hearts. Maximum upstroke velocity (Vmax) values were 229 +/- 12 and 227 +/- 10 V/s in the SHR and the WKY preparations, respectively. Three minutes after the induction of ischemia, Vmax values decreased to 46 +/- 7 V/s in SHRs and to 106 +/- 12 V/s in WKY rats. A significant increase in subendocardial collagen density was measured in SHR left ventricle compared to WKY rats (4.39 +/- 0.34% vs. 1.66 +/- 0.15%, p less than 0.05), which might partly explain the impaired conduction observed in hypertrophied preparations during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1991
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37. Omega-conotoxin GVIA, the N-type calcium channel inhibitor, is sympatholytic but not vagolytic: consequences for hemodynamics and autonomic reflexes in conscious rabbits.
- Author
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Pruneau D and Angus JA
- Subjects
- Analysis of Variance, Animals, Drug Evaluation, Preclinical, Heart Rate drug effects, Male, Nasal Cavity innervation, Neurons, Efferent drug effects, Pressoreceptors drug effects, Rabbits, Reflex drug effects, Splanchnic Circulation drug effects, omega-Conotoxin GVIA, Calcium Channel Blockers pharmacology, Hemodynamics drug effects, Peptides, Cyclic pharmacology, Sympatholytics pharmacology, Vagus Nerve drug effects
- Abstract
We investigated the effects of the N-type calcium channel blocking agent, omega-conotoxin GVIA, on the resting hemodynamics and on some autonomic reflexes in the conscious rabbit. omega-Conotoxin 3 and 10 micrograms/kg i.v. reduced mean arterial blood pressure by 16 +/- 2 and 25 +/- 3 mm Hg, respectively, over 30 min accompanied by a tachycardia. Renal vascular conductance (Doppler flowmeter) increased by 27.6 +/- 3.7 and 38.6 +/- 10.3% at 30 min after omega-conotoxin 3 and 10 micrograms/kg, respectively. Vasodilatation was also observed but to a lesser extent in the hindquarter and mesenteric vascular beds. The baroreceptor-heart rate reflex was evoked by a drug method (bolus injection of sodium nitroprusside and phenylephrine) and by inflation of perivascular balloons implanted on the thoracic vena cava and aorta. omega-Conotoxin (3 micrograms/kg) abolished the sympathetic component of the cardiac baroreceptor reflex without affecting vagal efferent activity. In addition, marked vagal-mediated bradycardia from (a) the "Bezold-Jarisch-like" reflex evoked by serotonin (1-10 micrograms/kg i.v.) and (b) the nasopharyngeal reflex evoked by cigarette smoke were unaffected by omega-conotoxin (3-10 micrograms/kg). We conclude that omega-conotoxin-induced N-type calcium channel blockade abolishes sympathetic but not vagal cardiac efferent activity. The hypotension and peripheral vasodilatation are probably due to the prejunctional sympatholytic action of the peptide. These N-type calcium channels are thus limited to the sympathetic varicosities in the rabbit.
- Published
- 1990
- Full Text
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38. Omega-conotoxin GVIA is a potent inhibitor of sympathetic neurogenic responses in rat small mesenteric arteries.
- Author
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Pruneau D and Angus JA
- Subjects
- Animals, Electric Stimulation, Evoked Potentials drug effects, In Vitro Techniques, Membrane Potentials drug effects, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Norepinephrine pharmacology, Potassium Chloride pharmacology, Rats, Rats, Inbred WKY, Sympathetic Nervous System physiology, omega-Conotoxin GVIA, Mesenteric Arteries innervation, Mollusk Venoms pharmacology, Sympathetic Nervous System drug effects
- Abstract
1. We have investigated the effects of the N-type calcium channel blocker, omega-conotoxin GVIA, on contractile responses to nerve stimulation, noradrenaline and KCl in rat small mesenteric arteries. In separate experiments, single and summated excitatory junctional potentials (e.j.ps) evoked by nerve stimulation were recorded with an intracellular electrode in the absence and presence of omega-conotoxin. 2. Electrical field stimulation of intramural sympathetic nerves (30 V; 0.25 ms pulse width; 3 s train length; 4-24 Hz) caused frequency-dependent contractions. Cumulative concentration-response curves for the contractions induced by noradrenaline and KCl were constructed in the same preparations. Stimulation at 0.2 Hz and 10 Hz induced respectively single e.j.ps without contractions and summated e.j.ps associated with a contractile response. 3. omega-Conotoxin (0.1 to 3 nM) inhibited markedly and in a concentration-dependent manner both the contractions and e.j.ps to electrical field stimulation. The concentration-response curves to exogenous noradrenaline and KCl remained unaffected. 4. The time-course for the effects of omega-conotoxin (0.3 to 3 nM) indicated a slow onset of action with at least one hour to achieve an equilibrium. 5. The experiments indicate that omega-conotoxin acts prejunctionally to inhibit sympathetic neurotransmission in rat small arteries presumably by inhibition of noradrenaline release. We suggest that omega-conotoxin could be a useful tool to study the control of vascular tone through the autonomic nervous system.
- Published
- 1990
- Full Text
- View/download PDF
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