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3. Abstracts of papers and posters Pharmacological Meeting

Author

Adan, Roger A. H., Peter, J., Burbach, H., Gispen, Willem -Hendrik, Bax, Willem A., Saxena, Pramod R., Beenen, O. H. M., Pfaffendorf, M., van Zwieten, P. A., Biewenga, G. Ph., Nicastia, A. J., Haenen, G. R. M. M., Bast, A., Bouwknecht, J. A., Molewijk, H. E., van der Poel, A. M., Mos, J., Olivier, B., Broersen, L. M., Heinsbroek, R. P. W., de Bruin, J. P. C., Brouwers, D. L., Nelissen-Vrancken, H. J. M. G., Smits, J. F. M., Bruning, T. A., Kemme, M. J. B., Chang, P. C., Muizert, Y., Buckley, Theresa L., Nijkamp, Frans P., Cappendijk, S. L. T., Duval, S. Y., De Vries, R., Dzoljic, M. R., Compaan, J. C., Groenink, L., van der Gugten, J., Cox, E. H., van Hemert, A. G. N., de Jong, E., Danhof, M., Crijns, F. R. L., Wolffenbuttel, B. H. R., van Essen, H., Boudier, H. A. J. Struijker, Dam, J. P. M., Doornekamp, F. N. G., Velema, E., Post, M. J., Borst, C., de Boer, J., Meurs, H., Bottone, A. E., Koopal, M., Visser, J. C., Zaagsma, J., de Lannoy, L. M., Danser, A. H. J., Bouhuizen, A. M. B., Schoemaker, R. G., Saxena, P. R., Schalekamp, M. A. D. H., de Vlieger, J. F., van den Wijngaard, P., Koster, A. Sj., Buckley, T. L., Wilting, J., van Heuven-Nolsen, D., Nijkamp, F., Du, X. Y., Bos, E., Dubois, E. A., Vermeulen, R. J., Janssen, A. F. M., van Royen, E. A., Gaillard, P. J., de Boer, A. G., Breimer, D. D., Garrelds, I. M., de Graaf-in't Veld, C., van Wijk, R. Gerth, Zijlstra, F. J., Gerrits, Mirjam A. F. M., Patkina, Nadezda, Zvartau, Edwin E., van Ree, Jan M., Gho, B. C. G., Verdouw, P. D., Gingras, M. A., Cools, A. R., Gommans, J., Hijzen, T., Maes, R. A., Verdouw, P. M., Herremans, A. H. J., Hijzen, T. H., Slangen, J. L., Hoiting, B. H., Schuiling, M., Elzinga, C. R. S., Hoogstraate, A. J., Verhoef, J., Schrijvers, A. H. G. J., Pijpers, A., van Leengoed, L. A. M. G., Verheijden, J. H. M., Junginger, H. E., Boddé, H. E., Hüsken, B. C. P., Joordens, R. J. E., Kalkman, E. A. J., Bilgin, M. Y., Kam, K. L., Kraneveld, A. D., Muis, T., Nijkamp, F. P., Madretsma, G. S., van Dijk, A. P. M., Wilson, J. H. P., Mohede, C. M., Van Oosterhout, J. M., Niikamp, F. P., Nestby, P., Visser, D., Wardeh, G., Hogenboom, F., Mulder, A. H., Schoffelmeer, A. N. M., Oosting, J., Struijker Boudier, H. A. J., Janssen, B. J. A., Passier, P. C. J. J., Verluyten, M. J. A., Drexler, H., Daemen, M. J. A. P., Hashjin, Gudarz Sadeghi, Henricks, Paul A. J., Folkerts, Gert, Shirmohammadi, Mahnaz, Niikamp, Frans P., Santing, R. E., Olymulder, C. G., van der Molen, K., Scheerens, Heleen, Van Loveren, Henk, Sipma, H., den Hertog, A., Nelemans, A., Smit, J., Coppes, R. P., Tintelen, E. J. J. v., Roffel, A. F., Smit, M. J., Leurs, Rob, Timmerman, H., Stam, W. B., Avezaat, C. J. J., Stolte, J., Schiffers, P. M. H., Boudier, H. A. J. Struyker, ten Berge, R. E. J., Krikke, M., Teisman, B. C. H., Tjon, G. H. K., Michiels, N., Voorn, P., van Bergen, P., De Wildt, D. J., Versteeg, D. H. G., van den Tweel, M. C., Bloemen, P. G. M., Henricks, P. A. J., Engels, F., Blomjous, F. J., van der Geest, R., van Laar, T., Roos, R. A. C., van de Velde, M. J., van Kats, J. P., Sassen, L. M. A., Polak, M. P. J., Derkx, F. H. M., van Kesteren, C. A. M., Lamers, J. M. J., van Heugten, H. A. A., van Meeteren, N. L. U., Frankhuyzen-Sierevogel, A., Brakkee, J. H., Wiegant, V. M., Gispen, W. H., Vroom, M. B., van Wezel, H. B., Timmenga, E. J. F., van der Horst, C. M. A. M., Winkler Prins, E. A., Zwavelina, J., Maas, A., Zhang, J., Zwaveling, J., Jansen, F. P., Mochizuki, T., Yamatodani, A., Masereeuw, R., Moons, W. M., Russel, F. G. M., van de Meent, H., van den Berg, C., Wemer, J., Vleeming, W., Kasbergen, C. M., van der Aa, E. M., Wouterse, A. C., Peereboom-Stegeman, J. H. J. Copius, Hessel, E. M., Van Oosterhout, A. J. M., de Bie, J. J., Hofman, G., and Van Loveren, H.

Published
1994
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4. Abstracts of papers and posters

Author

Anthonio, R. L., Willemsen, A. T. M., Visser, T., van Waarde, A., Elzinga, P., Weemaes, A., Meeder, J. G., Pruim, J., Visser, G., Blanksma, P. K., Vaalburg, W., Bloemen, P. G. M., Henricks, P. A. J., van Bloois, L., van den Tweel, M. C., Nijkamp, F. P., Crommelin, D. J. A., Storm, G., de Boer, A. H., Winter, H. M. I., Lerk, C. F., de Boer, J., Meurs, H., Bottone, A. E., Koopal, M., Visser, J. C., Zaagsma, J., Borger P., Kauffman H. F., Vijgen J. L. J., Postma D. S., Vellenga E., Buckley, Theresa L., Buikema, H., van Gilst, W. H., van Veldhuisen, D. J., de Smet, B. J. G. L., Scholtens, E., Lie, K. I., Wesseling, H., Cheung, P. K., Dijkhuis, F. W. D., Bakker, W. W., Visser, J., Coopes, R. P., Benthem, L., van der Leest, J., Roffel, A. F., Coppes, R. P., Zeilstra, L. J. W., Vissink, A., Konings, A. W. T., Dijkstra, M., Veld, G. In't, Müller, M., van den Berg, G. J., Kuipers, F., Vonk, R. J., Elsinga, P. H., Franssen, E. J. F., van der Graaf, W. T. A., de Vries, E. G. E., Visser, G. M., Vos, M. G., Braker, A. H., Visser, T. J., Visser, G. M., Engels, F., van Houwelingen, A. H., van de Velde, M. J., Gansevoort, R. T., Sluiter, W. J., Hemmelder, M. H., de Zeeuw, D., de Jong, P. E., Gelissen, H. P. M. M., Henning, R. H., Epema, A. H., van Eekeren, J., Hennis, P. J., Den Hertog, A., de Graaf, S. S. N., Kellie, S. J., Bloemhof, H., Johnston, I., Besser, M., Chaseling, R. W., Ouvrier, R. A., Uqes, D. R. A., De Haan, A., Geerligs, H. J., Huchshorn, J. P., Van Scharenburg, G. J. M., Wilschut, J., Haas, M., Kluppel, C. A., Meijer, D. K. F., Moolenaar, F., Heerdink, Eibert R., Leufkens, Hubert G., Herings, Ron M. C., Stricker, Bruno H. Ch., Bakker, Albert, Heesen W. F., Beltman F. W., Smit A. J., May J. F., Meyboom-de Jong B., Duin, M., van den Akker, J., te Pas, M. F. W., van Popta, J. P., Nelemans, S. A., van der Linde, H. J., de Boer, A., Sturmans, F., Hessel, E. M., Van Oosterhout, A. J. M., Hofstra, C. L., Garssen, J., van Loveren, H., Savelkoul, H. F. J., Hoekstra, Y., Weersink, E. J. M., de Jong, J. W., van der Belt-Gritter, B., Jonkman, Lisa M., Kemner, Chantal, Koelega, Harry S., van Engeland, Herman, Verbaten, Marinus N., Kalivianakis, M., Zijlstra, I., Verkade, H. J., Elzinga, H., Stellaard, F., Kamps, J. A. A. M., Swart, P. J., Morselt, H., Scherphof, G. L., Kenemans, J. L., Lorist, M. M., Koopen, N. R., Kraneveld, A. D., Koster, A. Si., Kuipers, M. E., Groenink, M., Huisman, H., Schuitemaker, H., Lau, H. S., van den Broek, I. J. P. M., van Dijk, A., Oostinga, J., Porsius, A. J., Lin, Y., Havinga, R., Meijer, R. J., van der Mark, Th. W., Koëter, G. H., Michels, A. A., Nguyen, V. -T., Bensaude, O., Kampinga, H. H., Mohede, Inge C. M., Van Antoon J. M., Molema, Grietje, Edgington, Thomas S., Thorpe, Philip E., Olinga, P., Sandker, G. W., Slooff, M. J. H., Merema, M. T., Groothuis, G. M. M., Hofman, G., Van Ark, I., Paulussen, J. J. C., Fischer, M. J. E., de Mol, N. J., Janssen, L. H. M., Peters, E. Th. J., van der Werf, G. Th., Haaijer-Ruskamp, F. M., Pinto, Yigal M., Rooks, Gerrit, Grandjean, Jean G., Ebels, Tjark, Schunkert, H., Redegeld, Frank A., Garssen, Johan, van Loveren, Henk, Rigter, Irma M., van Groningen, Muck, Boks, Gertjan J., Tollenaere, Jan P., Trollope, Keith I., Vinter, Jeremy G., Hashjin, Gudarz Sadeghi, Folkerts, Gert, van de Loo, Peet G. F., Santing, R. E., Olymulder, C. G., van der Molen, K., Pasman, Y., Scheerens, Heleen, Van Loveren, Henk, Seppenwoolde-Waasdorp, T. J. A., de Boer, P., Van Engelen, H. M. J., Thijssen, J. H. H., Maes, R. A. A., Smit, J., Smit, J. W., Steen, H., Steurs, M. H., Kuks, P. F. M., Leusink, J. A., Szabó, Balázs M., Crijns, Harry J. G. M., Wiesfeld, Ans C. P., Talsma, H., Borchert, J. C. H., van Steenbergen, M. J., Hennink, W. E., Teeuw, K. B., Cromheecke, H., Schreudering, A., Teisman, B. C. H., Maselbas, W., Wolters-Keulemans, G. T. P., Tieleman, R. G., de Langen, C. D. J., Bel, K., Crijns, H. J. G. M., Grandjean, J., Wijffels, M., Klimp, A. H., van de Meer, P. F., Allessie, M. A., van Patot, H. A. Tissot, de Jongh, B. M., Tuininga, Y. S., Brouwer, J., Haaksma, J., Man in't Veld, A. J., Blomjous, F. J., Vingerhoeds, M. H., Belliot, S. O., Haisma, H. J., Visscher, C. A., Huisman, R. M., Navis, G. J., de Vlieger, J. F., van den Wijngaard, P., Wilting, J., van Heuven-Nolsen, D., Voors, A. A., van Brussel, B. L., Plokker, H. W. M., Van Waardenburg R. C. A. M., Meijer, Prins J., De Vries, C., Mulder N. H., Wierenga, P. K., Wilschut J., Schoen P., and Bron R.

Published
1994
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7. Virus- and Bradykinin-Induced Airway Hyperresponsiveness in Guinea Pigs

Author

Van Heuven-Nolsen D, Faas S, Janneke F. Westra-De Vlieger, Gert Folkerts, van Der Linde H, Frans P. Nijkamp, Verheyen Fa, de Jong Jc, Ferdi Engels, and de Vries A

Subjects
Male, Pulmonary and Respiratory Medicine, Contraction (grammar), Adrenergic beta-Antagonists, Guinea Pigs, Bradykinin, Blood Pressure, Cell Count, Stimulation, Pharmacology, Critical Care and Intensive Care Medicine, Respirovirus Infections, Virus, Guinea pig, chemistry.chemical_compound, In vivo, medicine, Animals, Lung, Respiratory Tract Infections, Bradykinin Receptor Antagonists, business.industry, Antagonist, respiratory system, Parainfluenza Virus 3, Human, respiratory tract diseases, medicine.anatomical_structure, chemistry, Immunology, Bronchial Hyperreactivity, business, Bronchoalveolar Lavage Fluid
Abstract

The involvement of bradykinin in virus-induced airway hyperresponsiveness (AHR) in guinea pig airways in vivo was determined with the B(2)-receptor antagonist Hoe 140. The efficacy of Hoe 140 treatment was assessed through its effect on the bradykinin-induced (up to 2.5 microgram/100 g B.W. administered intravenously) decrease in blood pressure (BP). Hoe 140 (0.1 micromol/kg), administered subcutaneously twice a day for 5 d almost completely blocked bradykinin-induced changes in BP. Four days after parainfluenza-3 (PI-3) virus infection, guinea pigs showed AHR; excessive airway contraction was found with histamine-receptor stimulation. This hyperresponsiveness was completely inhibited by pretreatment with Hoe 140 (0.1 micromol/kg) administered subcutaneously twice a day for five consecutive days, starting 1 d before virus inoculation. Interestingly, nebulized delivery of bradykinin itself to captopril-treated animals induced an AHR comparable to that observed in virus-treated guinea pigs. Viral infection also caused influx of bronchoalveolar cells into the lungs. Both histologic examinations and lung lavage experiments showed that this cell influx could not be inhibited by pretreatment with Hoe 140. In summary, the results of the study show that bradykinin is involved in a cascade of events leading to AHR after a viral infection in guinea pigs, without affecting bronchoalveolar cell influx.

Published
2000
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9. Repeated challenge with dinitrobenzene sulphonic acid in dinitrofluorobenzene-sensitized mice results in vascular hyperpermeability in the trachea: a role for tachykinins

Author

van Houwelingen, A H, van der Avoort, L A, van Heuven-Nolsen, D, Kraneveld, A D, and Nijkamp, F P

Subjects
Male, Mice, Inbred BALB C, Indoles, Dose-Response Relationship, Drug, fungi, Benzenesulfonates, Isoindoles, Substance P, Capillary Permeability, Trachea, Mice, Neurokinin-1 Receptor Antagonists, Tachykinins, Papers, Animals, Dinitrofluorobenzene, Hypersensitivity, Delayed, Neurons, Afferent, Capsaicin
Abstract

1. This study investigates the role of tachykinins in a repeated challenge with dinitrobenzene sulphonic acid (DNS) on the tracheal vascular permeability in dinitrofluorobenzene (DNFB)-sensitized mice. 2. DNFB-contact sensitization was followed by an intranasal (i.n.) challenge with DNS. A second challenge with DNS was administered 24 h after the first challenge. To assess changes in tracheal vascular permeability, Evans blue dye accumulation in tracheal tissue was measured. 3. A repeated challenge with DNS in DNFB-sensitized mice led to a 2.8 fold increase in tracheal vascular permeability when compared to DNFB-sensitized and vehicle-challenged mice or a 2.5 fold increase when compared to DNFB-sensitized single DNS-challenged mice (P0.001, ANOVA). 4. RP67580 (10-9 mol mouse-1 i.v.) reduced the increased tracheal vascular permeability induced by a second exposure to DNS in DNFB-sensitized mice completely when injected 15 min before the second challenge (P0.001, ANOVA). 5. The increased tracheal vascular permeability response induced by the second exposure to DNS could be mimicked with i.n. application of capsaicin (10-10 mol mouse-1) or substance P (SP) (10-12 mol mouse-1) to DNFB-sensitized and single DNS-challenged mice. 6. These results suggest that both tachykinin NK1 receptors and sensory nerves are involved in the development of vascular hyperpermeability changes found in the trachea of DNFB-sensitized mice after a repeated DNS-challenge.

Published
1999

21. Induction of nitric oxide release by interferon-gamma inhibits vasodilation and cyclic GMP increase in bovine isolated mesenteric arteries.

Author

De Kimpe, S J, Van Heuven-Nolsen, D, van Amsterdam, J G, Radomski, M W, and Nijkamp, F P

Abstract

The influence of interferon (IFN)-gamma on vasodilation was examined in bovine isolated mesenteric arteries. Arterial rings were incubated with IFN-gamma (100 U ml-1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-gamma markedly inhibited endothelium-dependent relaxation to bradykinin and impaired vasodilation to nitroprusside, which was endothelium-independent. The decrease in relaxation was correlated with a decrease in bradykinin- and nitroprusside-induced cGMP production. Relaxation to the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine or zaprinast was not altered after IFN-gamma, which suggests that the IFN-gamma effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after IFN-gamma, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine during the 20-hr incubation with IFN-gamma completely prevented the decrease in relaxation and cGMP elevation to nitroprusside. We conclude that IFN-gamma induces a marked increase in release of arterial-derived nitric oxide resulting in a desensitization of guanylate cyclase, which contributes to a decrease in relaxation to bradykinin and nitroprusside. These results may implicate the existence of an important adaptive process in the regulation of vascular tone during pathological situations associated with the induction of nitric oxide synthesis.

Published
1994

22. Endotoxin-induced reduction of beta-adrenergic binding sites on splenic lymphocytes in vivo and in vitro: its modulation by anterior hypothalamic lesions

Author

Van Oosterhout, A J, Van Heuven-Nolsen, D, Thijssen, J H, Nijkamp, F P, and de Boer, S.F.

Subjects
Lipopolysaccharides, Male, Thyroid Hormones, Hypothalamic Hormones, Cell Membrane, Guinea Pigs, Lymphocyte Activation, Endotoxins, Catecholamines, Hypothalamus, Anterior, Pindolol, Receptors, Adrenergic, beta, Escherichia coli, Animals, Lymphocytes, Glucocorticoids, Spleen
Abstract

Bacterial endotoxin induced a 38% decrease in the number of beta-adrenergic binding sites (Bmax) on splenic lymphocytes, four days after intraperitoneal administration to guinea pigs. No change in the affinity (Kd) for [125-I]-cyanopindolol ([125-I]-CYP) binding was observed. Incubation of guinea pig splenocytes in vitro with different concentrations of bacterial endotoxin for 24 hours resulted in an increased incorporation of [3H]-thymidine, a parameter for lymphocyte activation. Activation of splenic lymphocytes with the optimal endotoxin concentration of 100 micrograms/ml for 24 hours induced a 27% decrease in the Bmax whereas the Kd for [125-I]-CYP binding was not changed. Based on these findings, we speculate that activation of lymphocytes with endotoxin in vitro and in vivo is associated with a reduction in the number of beta-adrenergic binding sites on these cells. Anterior hypothalamic (AHA) lesions protected against the endotoxin-induced reduction in the number of beta-adrenergic binding sites on lymphocytes. The protective effect of these lesions could not be related to alterations in the plasma levels of cortisol, triiodothyronine (T3), thyroxine (T4), adrenaline and noradrenaline or to splenic noradrenaline content. Since AHA lesions have been shown to inhibit several lymphocyte functions, it is suggested that these lesions prevent lymphocyte activation after in vivo endotoxin administration and through this abrogate the reduction of the beta-adrenergic binding sites.

Published
1989

23. Role of platelet activating factor in the endotoxin induced tracheal hyperreactivity to histamine in the guinea pig

Author

Braquet P, G C Kessels, Frans P. Nijkamp, and van Heuven-Nolsen D

Subjects
Pharmacology, Male, Allergy, Platelet-activating factor, Immunology, Pharmacology toxicology, Guinea Pigs, Toxicology, medicine.disease, Asthma, Guinea pig, Endotoxins, Trachea, chemistry.chemical_compound, chemistry, medicine, Animals, Pharmacology (medical), Platelet Activating Factor, Histamine
Published
1989

36. Mast cell-derived TNF-alpha primes sensory nerve endings in a pulmonary hypersensitivity reaction.

Author

van Houwelingen AH, Kool M, de Jager SC, Redegeld FA, van Heuven-Nolsen D, Kraneveld AD, and Nijkamp FP

Subjects
Administration, Topical, Animals, Antibodies, Monoclonal administration & dosage, Antigens, CD immunology, Benzenesulfonates administration & dosage, Benzenesulfonates immunology, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid immunology, Capillary Permeability drug effects, Capillary Permeability immunology, Capsaicin administration & dosage, Dinitrofluorobenzene administration & dosage, Dinitrofluorobenzene immunology, Haptens administration & dosage, Haptens immunology, Immunization, Secondary, Injections, Intravenous, Male, Mast Cells metabolism, Mast Cells pathology, Mice, Mice, Inbred BALB C, Mice, Mutant Strains, Nerve Endings drug effects, Neurons, Afferent drug effects, Receptors, Tumor Necrosis Factor immunology, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Respiratory Hypersensitivity chemically induced, Respiratory Hypersensitivity metabolism, Respiratory Hypersensitivity pathology, Trachea drug effects, Trachea immunology, Trachea innervation, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Mast Cells immunology, Nerve Endings immunology, Neurons, Afferent immunology, Respiratory Hypersensitivity immunology, Tumor Necrosis Factor-alpha physiology
Abstract

TNF-alpha is a cytokine associated with inflammatory diseases, including asthma. Increased levels of TNF-alpha were found in the bronchoalveolar lavage fluid of mice undergoing a dinitrofluorobenzene (DNFB)-induced non-IgE-mediated pulmonary hypersensitivity reaction. We report in this work that TNF-alpha increases the susceptibility of sensory neurons to dinitrobenzene sulfonic acid (DNS) and capsaicin, leading to a tracheal vascular hyperpermeability response in DNFB-sensitized and DNS-challenged mice. mAb against TNF-alpha or the TNFR1 inhibited this hyperpermeability response in DNFB-sensitized and DNS-challenged mice. Furthermore, the hyperpermeability response after DNS challenge was abolished in DNFB-sensitized mast cell-deficient WBB6F(1)-W/W(V) mice. These animals showed a remarked decrease of TNF-alpha bronchoalveolar lavage fluid levels after a single DNS challenge. The hyperpermeability response after DNS challenge was regained in mast cell-deficient mice after mast cell reconstitution. These findings indicate a prominent role for TNF-alpha and its TNFR1 in the DNFB-induced tracheal hyperpermeability response. We propose that a priming effect of mast cell-derived TNF-alpha on the sensory neurons could be the mechanism of action of TNF-alpha in the vascular hyperpermeability response in tracheas of mice undergoing a pulmonary hypersensitivity reaction.

Published
2002
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37. Bradykinin causes inhibition of methacholine-induced bronchoconstriction in vivo in mice.

Author

Folkerts G, van Heuven-Nolsen D, and Nijkamp FP

Subjects
Anesthesia, Animals, Bradykinin administration & dosage, Bradykinin analogs & derivatives, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred BALB C, Airway Resistance drug effects, Bradykinin pharmacology, Bronchoconstriction drug effects, Methacholine Chloride antagonists & inhibitors
Abstract

In this study the influence of bradykinin on airway responses was investigated in anaesthetised and ventilated mice. Airway resistance in mice was monitored using whole body plethysmography. Intravenous (i.v.) administration of bradykinin (4-40 microg/kg) did not cause a direct effect on airway resistance. Also pretreatment with propranolol (1 mg/kg, i.v.), atropine (1 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) did not result in any effect of intravenous bradykinin on baseline airway resistance. However, i.v. bradykinin (4-40 microg/kg) caused a dose-dependent inhibition of the (0.5 mg/kg, i.v.) methacholine-induced bronchoconstriction, with an ED50 value of 3.4 +/- 0.4 microg/kg. The maximal inhibition of the bronchoconstrictor response to methacholine was 65.5 +/- 2.0%. The inhibition of the methacholine-induced bronchoconstriction by bradykinin could be prevented by treatment with the B2 receptor antagonist icatibant (Hoe 140, 0.13 mg/kg, i.v.). Also pretreatment with either propranolol (1 mg/kg, i.v.), L-NAME (30 mg/kg, i.v.) or indomethacin (5 mg/kg, i.v.) completely blocked the inhibition of the methacholine-induced bronchoconstriction by bradykinin. The inhibition of the methacholine-induced bronchoconstriction after bradykinin was not affected by the NK1 receptor antagonist RP 67580 (17.5 microg/kg, i.v.). In conclusion, the results of this study demonstrate that bradykinin causes a dose-dependent inhibition of the methacholine-induced bronchoconstriction in vivo in mice. This response is B2 receptor-mediated and at least involves the activation of beta-adrenoceptors and the synthesis of nitric oxide and cyclo-oxygenase products.

Published
2001
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38. Virus- and bradykinin-induced airway hyperresponsiveness in guinea pigs.

Author

Folkerts G, Vlieger JW, de Vries A, Faas S, van Der Linde H, Engels F, de Jong JC, Verheyen FA, Van Heuven-Nolsen D, and Nijkamp FP

Subjects
Adrenergic beta-Antagonists pharmacology, Animals, Blood Pressure drug effects, Bradykinin analogs & derivatives, Bradykinin pharmacology, Bradykinin Receptor Antagonists, Bronchial Hyperreactivity chemically induced, Bronchial Hyperreactivity pathology, Bronchoalveolar Lavage Fluid cytology, Cell Count, Guinea Pigs, Lung pathology, Male, Respiratory Tract Infections pathology, Respirovirus Infections pathology, Bradykinin physiology, Bronchial Hyperreactivity physiopathology, Parainfluenza Virus 3, Human, Respiratory Tract Infections physiopathology, Respirovirus Infections physiopathology
Abstract

The involvement of bradykinin in virus-induced airway hyperresponsiveness (AHR) in guinea pig airways in vivo was determined with the B(2)-receptor antagonist Hoe 140. The efficacy of Hoe 140 treatment was assessed through its effect on the bradykinin-induced (up to 2.5 microgram/100 g B.W. administered intravenously) decrease in blood pressure (BP). Hoe 140 (0.1 micromol/kg), administered subcutaneously twice a day for 5 d almost completely blocked bradykinin-induced changes in BP. Four days after parainfluenza-3 (PI-3) virus infection, guinea pigs showed AHR; excessive airway contraction was found with histamine-receptor stimulation. This hyperresponsiveness was completely inhibited by pretreatment with Hoe 140 (0.1 micromol/kg) administered subcutaneously twice a day for five consecutive days, starting 1 d before virus inoculation. Interestingly, nebulized delivery of bradykinin itself to captopril-treated animals induced an AHR comparable to that observed in virus-treated guinea pigs. Viral infection also caused influx of bronchoalveolar cells into the lungs. Both histologic examinations and lung lavage experiments showed that this cell influx could not be inhibited by pretreatment with Hoe 140. In summary, the results of the study show that bradykinin is involved in a cascade of events leading to AHR after a viral infection in guinea pigs, without affecting bronchoalveolar cell influx.

Published
2000
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39. Opposite role of interferon-gamma and interleukin-4 on the regulation of blood pressure in mice.

Author

van Heuven-Nolsen D, De Kimpe SJ, Muis T, van Ark I, Savelkoul H, Beems RB, van Oosterhout AJ, and Nijkamp FP

Subjects
Animals, Hypertension physiopathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Species Specificity, Blood Pressure physiology, Interferon-gamma physiology, Interleukin-4 physiology
Abstract

There is growing evidence that T-lymphocyte dysfunction contributes to the development of hypertension. IL-4 and IFN-gamma are important regulators of T-lymphocyte function. Therefore, we investigated the effect of neutralizing antibodies against IL-4 (alpha-IL-4) and IFN-gamma (alpha-IFN-gamma) on the development of hypertension in NZBNZWF1 hybrid compared to normotensive NZW control mice. Antibody-producing cells were encapsulated and injected intraperitoneally in mice at 6,8 and 10 weeks of age. This treatment resulted in significant levels of antibody in the serum. At 12 weeks of age blood pressure was recorded under anesthesia. Mean arterial blood pressure (MAP) increased in NZBNZWF1 hybrids between the age of 6 and 12 weeks. This increase was inhibited by treatment with alpha-IL-4, but was not affected by alpha-IFN-gamma. Treatment with alpha-IL-4 did not influence MAP in normotensive NZW or C57B1/6J mice. However, in these mice, treatment with alpha-IFN-gamma increases MAP. This increase in MAP by alpha-IFN-gamma was prevented by simultaneous treatment with alpha-IL-4. The present study demonstrates the influence of endogenous IL-4 and IFN-gamma on blood pressure., (Copyright 1999 Academic Press.)

Published
1999
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40. The tachykinin NK1 receptor antagonist, RP67580, inhibits the bradykinin-induced rise in intracellular Ca2+ concentration in bovine pulmonary artery endothelial cells.

Author

Westra-De Vlieger JF, Van Den Wijngaard PW, Koster AS, Wilting J, Leysen J, Van Heuven-Nolsen D, and Nijkamp FP

Subjects
Animals, Bradykinin pharmacology, Cattle, Cells, Cultured, Endothelium, Vascular drug effects, Fluorescent Dyes, Fura-2, Isoindoles, Muscle, Smooth, Vascular drug effects, Pulmonary Artery drug effects, Bradykinin antagonists & inhibitors, Calcium metabolism, Endothelium, Vascular metabolism, Indoles pharmacology, Muscle, Smooth, Vascular metabolism, Neurokinin-1 Receptor Antagonists, Pulmonary Artery metabolism
Abstract

The bradykinin-induced rise in intracellular Ca2+ concentration ([Ca2+]i) and the bradykinin receptor involved in this response were characterized in bovine pulmonary artery endothelial cells. It was found that bradykinin induces an intracellular biphasic Ca2+ response, consisting of a transient peak followed by an elevated plateau phase. Both bradykinin and the bradykinin B1 receptor agonist, des-Arg9-bradykinin, induced a concentration-dependent increase in [Ca2+]i, but the bradykinin-induced rise was much greater. Moreover, the bradykinin-induced [Ca2+]i rise could be inhibited by the bradykinin B2 receptor antagonists, D-Arg0[Hyp3, Thi(5,8), D-Phe7]bradykinin and Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]bradykinin), but not by the bradykinin B1 receptor antagonist, des-Arg9-[Leu8]bradykinin. From these results it can be concluded that a bradykinin B2 receptor is involved in this response. Furthermore, we found that the tachykinin NK1 receptor antagonist, RP67580 ([imino 1 (methoxy-2-phenyl)-2 ethyl]-2 diphenyl 7,7 perhydroisoindolone-4 (3aR, 7aR)), and its negative enantiomer, RP68651 (2-[1-imino 2-(2 methoxy phenyl) ethyl] 7,7 diphenyl 4-perhydroisoindolone (3aS-7aS)), could inhibit the bradykinin-induced [Ca2+]i response, although no functional tachykinin NK1 receptors were found. Binding studies evidenced no binding of RP67580 or RP68651 to the bradykinin receptor. We conclude that RP67580 inhibits the bradykinin-induced rise in [Ca2+]i via a bradykinin B2 receptor-independent mechanism.

Published
1998
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41. Pharmacology and mode of action of bradykinin on mouse-isolated trachea.

Author

van Heuven-Nolsen D, Westra-De Vlieger JF, Muis T, Denee JH, Rivas TO, and Nijkamp FP

Subjects
Animals, Bradykinin antagonists & inhibitors, Bradykinin Receptor Antagonists, Capsaicin pharmacology, In Vitro Techniques, Indoles pharmacology, Indomethacin pharmacology, Isoindoles, Male, Mice, Mice, Inbred BALB C, Muscle, Smooth drug effects, NG-Nitroarginine Methyl Ester pharmacology, Receptors, Bradykinin agonists, Receptors, Bradykinin drug effects, Bradykinin pharmacology, Muscle Contraction drug effects, Trachea drug effects
Abstract

In the present study, the effect of bradykinin on basal and precontracted mouse-isolated trachea was investigated. In basal conditions mouse-isolated tracheal rings do not respond to bradykinin. However, when the tracheal rings were precontracted with carbachol (10(-7) M) a relaxation with bradykinin (3 x 10(-9)-3 x 10(-7)) was found. The maximal response amounted 69.7+/-4.1% (n=15) with a pD2 value of 7.2+/-0.21. The selective bradykinin B2 receptor antagonist HOE 140 (10(-10)-10(-8) M) antagonized the bradykinin-induced relaxation, while the bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin (10(-6) M) had no influence. The selective bradykinin B1 receptor agonist des-Arg9-bradykinin (10(-6) M) caused a small relaxation (8.4+/-2.5%, n=6), which could be antagonized completely by the selective bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin (10(-6) M) while addition of the selective bradykinin B2 receptor antagonist HOE 140 (10(-8) M) was without effect. In the presence of indomethacin (10(-6) M) the relaxation of bradykinin was completely abolished. Pretreatment of the tracheal rings with capsaicin, or the presence of the selective NK1 receptor antagonist RP 67851 (10(-6) M) or the presence of the nitric oxide synthase inhibitor L-NAME (3 x 10(-4) M) had no effect on the bradykinin-induced relaxation. In conclusion, these results demonstrate that the mouse-isolated tracheal is a preparation in which bradykinin exerts a relaxant response via stimulation of bradykinin B2 receptors. This response is probably mediated by prostaglandins.

Published
1997
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42. Hypotensive effect of 13-hydroxylinoleic acid in the rat: mediation via the release of a CGRP-like mediator from capsaicin-sensitive nerves.

Author

van Heuven-Nolsen D, Muis T, Engels F, Henricks PA, Buckley TL, and Nijkamp FP

Subjects
Acetylcholine pharmacology, Animals, Animals, Newborn, Bradykinin pharmacology, Calcitonin Gene-Related Peptide antagonists & inhibitors, Dose-Response Relationship, Drug, Histamine pharmacology, Leukotriene B4 pharmacology, Linoleic Acids pharmacology, Male, Neurons drug effects, Neurons, Afferent drug effects, Neurons, Afferent metabolism, Nitroprusside pharmacology, Rats, Rats, Wistar, Ruthenium Red pharmacology, Blood Pressure drug effects, Calcitonin Gene-Related Peptide metabolism, Capsaicin pharmacology, Neurons, Afferent physiology
Abstract

1. The effect of 13-hydroxylinoleic acid (13-HODE) on changes in blood pressure in the rat was measured. 2. 13-HODE (0.1 - 100 micrograms kg-1) had no direct effect on blood pressure in the rat and had no effect on histamine (0.1 - 1000 micrograms kg-1)-induced changes in blood pressure. In contrast, it was found that 13-HODE itself induced a decrease in diastolic arterial blood pressure when it was injected intravenously after either a single dose of histamine (10, 100 or 1000 micrograms kg-1) or after a dose-response curve of histamine (0.1 - 1000 micrograms kg-1). 3. This hypotensive effect of 13-HODE was not observed after administration of the endothelium-dependent vasodilator, acetylcholine (0.1 - 10 micrograms kg-1), the endothelium-independent vasodilator, sodium nitroprusside (0.1 - 100 micrograms kg-1) or the inflammatory mediator, leukotriene B4 (0.1 - 300 micrograms kg-1). However, prior injection of bradykinin (0.1 - 100 micrograms kg-1) allowed a dose-dependent hypotensive effect of 13-HODE to be revealed. 4. The hypotensive effect of 13-HODE after histamine and bradykinin could be inhibited by neonatal capsaicin treatment of the rats (50 mg kg-1, s.c. on day 1 and 2 after birth). 5. Ruthenium red (120 micrograms kg-1 min-1), an inhibitor of excitatory effects on sensory nerves, and the CGRP antagonist, CGRP8-37 (1-3 micrograms kg-1 min-1) also inhibited the hypotensive effect of 13-HODE. 6. It is concluded that the hypotensive effect of 13-HODE in the rat after histamine and bradykinin is due to the release of a CGRP-like substance from sensory nerves. These results highlight the possibility that endogenous 13-HODE could be involved in the neurogenic regulation of blood pressure.

Published
1995
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43. Delayed-type hypersensitivity-induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade.

Author

Kraneveld AD, Buckley TL, van Heuven-Nolsen D, van Schaik Y, Koster AS, and Nijkamp FP

Subjects
Animals, Capsaicin pharmacology, Dipeptides pharmacology, Indoles pharmacology, Isoindoles, Male, Mice, Mice, Inbred BALB C, Peptides, Cyclic pharmacology, Capillary Permeability drug effects, Hypersensitivity, Delayed immunology, Intestine, Small drug effects, Neurokinin-1 Receptor Antagonists, Neuropeptides pharmacology
Abstract

1. This study investigates the effects of capsaicin-induced depletion of sensory neuropeptides and of neurokinin1 (NK1) receptor blockade on delayed-type hypersensitivity (DTH)-induced changes of vascular permeability in the small intestine of the mouse. 2. The DTH reaction in the small intestine was elicited by dinitrofluorobenzene (DNFB)-contact sensitization followed by oral dinitrobenzene sulphonic acid (DNBS) challenge. To assess vascular leakage the accumulation of the plasma marker, Evans blue (EB), was measured 2, 24 and 48 h after the challenge. 3. The small intestinal DTH reaction was characterized by a significant increase in vascular permeability 24 h after the challenge of previously sensitized mice when compared to vehicle-sensitized mice (P < 0.05, ANOVA). Capsaicin-induced depletion of sensory neuropeptides, two weeks before the sensitization, completely inhibited the DTH-induced increase in small intestinal vascular permeability at 24 h (P < 0.05, ANOVA). Vehicle/control: 108.2 +/- 8.6 ng EB mg-1 dry weight; vehicle/DTH 207.8 +/- 25.1 ng EB mg-1 dry weight; capsaicin/control: 65.8 +/- 11.9 ng EB mg-1 dry weight; capsaicin/DTH: 84.3 +/- 7.6 ng EB mg-1 dry weight. 4. The tachykinins, substance P and neurokinin A (1.5 to 50 x 10(-11) mol per mouse, i.v.), induced an increase in vascular leakage in the small intestine of naive mice. The specific NK1 receptor antagonist, RP67580 (10(-9) mol per mouse, i.v.) was the most effective in reducing the substance P-induced plasma extravasation when compared with other NK receptor antagonists, FK224 and FK888. 5. Treatment of DNFB-sensitized mice with RP67580 (10-9 mol per mouse, i.v.) immediately before and 1 h after the DNBS challenge resulted in a significant reduction of the DTH-induced increase in vascular permeability at 24 h (vehicle/control: 107.5 +/- 8.8 ng EB mg-1 dry weight; RP67580/control:95.4 +/- 5.4 ng EB mg-1 dry weight; vehicle/DTH: 206.6 +/- 22.6 ng EB mg-1 dry weight; RP67580/DTH:132.6 +/- 13.6 ng EB mg-1 dry weight, P<0.05, ANOVA).6. These results suggest that sensory nerves are involved in the development of small intestinal DTH reactions in the mouse. NK1 receptors could play an important role in the initiation of the DTH-induced changes in vascular leakage.

Published
1995
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44. Reversal of bradykinin-induced relaxation to contraction after interferon-gamma in bovine isolated mesenteric arteries.

Author

De Kimpe SJ, Tielemans W, Van Heuven-Nolsen D, and Nijkamp FP

Subjects
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Amino Acid Sequence, Animals, Bradykinin pharmacology, Cattle, Cycloheximide pharmacology, In Vitro Techniques, Mesenteric Arteries drug effects, Mesenteric Arteries metabolism, Methylene Blue pharmacology, Molecular Sequence Data, Muscle, Smooth, Vascular metabolism, Nitric Oxide metabolism, Prostaglandin Endoperoxides, Synthetic pharmacology, Receptors, Bradykinin drug effects, Thromboxane A2 analogs & derivatives, Thromboxane A2 pharmacology, Up-Regulation drug effects, Vasoconstrictor Agents pharmacology, Bradykinin antagonists & inhibitors, Interferon-gamma pharmacology, Muscle Contraction drug effects, Muscle Relaxation drug effects, Muscle, Smooth, Vascular drug effects
Abstract

Bovine isolated mesenteric arterial rings were preincubated for 20 h with interferon-gamma (100 U ml-1) and relaxation in response to bradykinin (10(-12) to 3 x 10(-8) M) was then measured isometrically in an organ bath. Interferon-gamma pretreatment for 20 h markedly attenuated the endothelium-dependent bradykinin relaxation in arteries precontracted with 9,11-dideoxy-11 alpha,9 alpha-epoxymethano prostaglandin F2 alpha (U46619), and the relaxation was reversed to contraction at the highest bradykinin concentrations (-72 +/- 5% for control vs. + 6 +/- 10% for interferon-gamma). Cycloheximide (20 micrograms ml-1) present during the 20-h preincubation completely prevented the interferon-gamma effect. Methyl-L-arginine (1 mM) treatment during the 20-h preincubation also inhibited the interferon-gamma effect on bradykinin relaxation (-47 +/- 18% for interferon-gamma and methyl-L-arginine), which suggests involvement of nitric oxide during the 20-h preincubation with interferon-gamma. In control arteries, des-Arg9-bradykinin, a bradykinin B1 receptor agonist, evoked contractions, which were augmented in rings preincubated for 20 h with interferon-gamma. The bradykinin B1 receptor antagonist, des-Arg9-Leu8-bradykinin (2 microM), present in the organ bath in combination with methyl-L-arginine (1 mM) only present during the 20-h preincubation with interferon-gamma completely restored the bradykinin relaxation (-79 +/- 12%). We suggest two mechanisms. Firstly, prolonged nitric oxide release induced by interferon-gamma during the 20-h preincubation may inhibit bradykinin stimulated endothelium-derived nitric oxide release and action. Secondly, interferon-gamma caused upregulation of the bradykinin B1 receptor-mediated contraction, which may contribute to the decrease in bradykinin-induced vasodilation and cause a reversal to contraction.

Published
1994
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45. 5-HT receptors mediating contractions of the isolated human coronary artery.

Author

Bax WA, Renzenbrink GJ, Van Heuven-Nolsen D, Thijssen EJ, Bos E, and Saxena PR

Subjects
Adolescent, Adult, Arteries drug effects, Arteries physiology, Blood Platelets physiology, Child, Child, Preschool, Coronary Vessels drug effects, Dose-Response Relationship, Drug, Female, Humans, In Vitro Techniques, Infant, Ketanserin pharmacology, Male, Metergoline pharmacology, Middle Aged, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Pindolol analogs & derivatives, Pindolol pharmacology, Potassium pharmacology, Serotonin pharmacology, Serotonin Antagonists, Substance P pharmacology, Yohimbine pharmacology, Coronary Vessels physiology, Ergotamine pharmacology, Muscle, Smooth, Vascular physiology, Receptors, Serotonin physiology, Sumatriptan pharmacology
Abstract

We investigated contractile responses of the isolated human coronary artery to 5-hydroxytryptamine (5-HT), washed human platelets, sumatriptan and ergotamine. 5-HT (pD2: 6.8 +/- 0.1, Emax: 47.7 +/- 6.8 mN) and platelets (effect 14.4 +/- 2.8 mN with 3.10(10) platelets/l) caused contractile responses which were attenuated by ketanserin (1 microM). In the presence of ketanserin (1 microM), both rauwolscine (1 and 10 microM) and cyanopindolol (1 and 10 microM) caused concentration-dependent additional antagonism against contractions induced by low (< or = 1 microM) concentrations of 5-HT. Sumatriptan-induced contractions (pD2: 6.2 +/- 0.1; Emax: 10.7 +/- 2.4 mN) were antagonized to a similar extent by both rauwolscine (1 microM) and cyanopindolol (1 microM) (pKB: 6.5 +/- 0.1 and 6.4 +/- 0.1, respectively) and also by metergoline (0.1 microM; pKB: 7.2 +/- 0.1). The order of potency of antagonists against sumatriptan resembles the order reported for the human saphenous vein 5-HT1D-like receptor. No significant additional antagonism by cyanopindolol (1 microM) or rauwolscine (1 microM) against platelet-induced contractile responses was observed. Ergotamine caused potent contractile responses (pD2: 8.4 +/- 0.3, Emax: 19.4 +/- 2.4 mN). It is concluded that although 5-HT2 receptors predominantly mediate 5-HT-induced contractions, the 5-HT1-like receptor seems to play a role in coronary vasospasm caused by low concentrations of 5-HT.

Published
1993
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46. Acetylcholine-induced relaxation in bovine isolated mesenteric arteries is suppressed by polymorphonuclear leukocytes.

Author

De Kimpe SJ, Van Heuven-Nolsen D, and Nijkamp FP

Subjects
Animals, Arginine analogs & derivatives, Arginine pharmacology, Catalase pharmacology, Cattle, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Free Radical Scavengers, In Vitro Techniques, Indomethacin pharmacology, Mesenteric Arteries drug effects, Muscle Relaxation drug effects, Neutrophils drug effects, Nitroprusside pharmacology, Superoxide Dismutase pharmacology, Superoxides metabolism, omega-N-Methylarginine, Acetylcholine pharmacology, Muscle, Smooth, Vascular drug effects, Neutrophils physiology
Abstract

1. The endothelium plays a critical role in maintaining vascular tone via generation of potent vasoconstrictor and dilator substances. We examined the effect of bovine purified polymorphonuclear leukocytes (PMN) on the endothelium-dependent relaxation to acetylcholine in isolated mesenteric arteries. 2. In the presence of PMN (2.5 x 10(6) cells ml-1) the maximal relaxation to acetylcholine was decreased from 76.1 +/- 2.4% to 44.9 +/- 7.4% of the precontraction (P < 0.001). This effect was inhibited by superoxide dismutase and NG-mono-methyl-L-arginine, but not by catalase or indomethacin. 3. PMN were not able to influence significantly the endothelium-independent relaxation to nitroprusside. 4. Removal of PMN after preincubation and prior to precontraction and relaxation did not influence the acetylcholine-induced relaxation, indicating that no irreversible vascular damage had occurred. 5. Superoxide anion production by unstimulated PMN was less than 10% compared to phorbol myristate acetate-activated PMN, measured by chemiluminescence and reduction of ferricytochrome c. 6. We conclude that small amounts of superoxide anions produced by unstimulated PMN contribute to a decrease in relaxation to acetylcholine by interfering with endothelium-derived nitric oxide.

Published
1993
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47. 5-Hydroxytryptamine-induced contractions of the human isolated saphenous vein: involvement of 5-HT2 and 5-HT1D-like receptors, and a comparison with grafted veins.

Author

Bax WA, Van Heuven-Nolsen D, Bos E, Simoons ML, and Saxena PR

Subjects
Coronary Artery Bypass, Histamine Antagonists pharmacology, Humans, In Vitro Techniques, Receptors, Serotonin drug effects, Receptors, Serotonin physiology, Saphenous Vein transplantation, Saphenous Vein drug effects, Serotonin pharmacology, Vasoconstriction drug effects
Abstract

The receptors mediating the contractile effect of 5-hydroxytryptamine (5-HT) on the human isolated saphenous vein, obtained from 42 patients undergoing coronary bypass surgery, have been further characterized using a number of 5-HT-related drugs. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT) approximately 5-HT greater than methysergide approximately sumatriptan approximately alpha-methyl-5-HT approximately 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesuccinate (RU 24969) approximately 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) greater than 2-methyl-5-HT greater than 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT). Flesinoxan was inactive as an agonist. Ketanserin (1 mumol/l) hardly affected sumatriptan-induced contractions but it caused a rightward shift of the upper part of the concentration-response curve of 5-HT and 5-CT. The same concentration of ketanserin caused a parallel rightward shift of the concentration-response curves of alpha-methyl-5-HT and DOI with pKB values of 7.1 and 7.1, respectively. The responses to sumatriptan were antagonized by methiothepin (0.1 mumol/l), metergoline (0.1 and 1 mumol/l), rauwolscine (1 mumol/l) and cyanopindolol (1 mumol/l); the calculated pKB values were 7.3, 6.9, 7.3, 6.7 and 6.5, respectively. Contractions to 5-HT were antagonized by methysergide (1 mumol/l), methiothepin (0.1 mumol/l; pKB = 7.1), ICS 205-930 (1 mumol/l; pKB = 5.9) and flesinoxan (30 mumol/l; pKB = 5.3). Remarkably, the contractions elicited by 2-methyl-5-HT were not attenuated by ICS 205-930, but were antagonized by methiothepin (0.1 mumol/l) and, more markedly, by ketanserin (1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1992
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48. Bovine polymorphonuclear leukocytes increase sensitivity to noradrenaline in isolated mesenteric arteries.

Author

De Kimpe SJ, Van Heuven-Nolsen D, and Nijkamp FP

Subjects
6-Ketoprostaglandin F1 alpha biosynthesis, Animals, Arachidonic Acid metabolism, Arginine analogs & derivatives, Arginine pharmacology, Cattle, Free Radical Scavengers, In Vitro Techniques, Luminescent Measurements, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Muscle Contraction drug effects, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular physiology, Radioimmunoassay, Thromboxane B2 biosynthesis, omega-N-Methylarginine, Muscle, Smooth, Vascular drug effects, Neutrophils physiology, Norepinephrine pharmacology
Abstract

1. The effects of polymorphonuclear leukocytes (PMN) on vascular function to (-)-noradrenaline were examined in vitro. Purified bovine PMN were incubated in siliconized organ baths containing rings of bovine mesenteric arteries, after which a concentration-effect curve in response to (-)-noradrenaline was obtained. 2. PMN-derived products induced a long lasting concentration-dependent contraction of the blood vessels generating 24.4 +/- 6.8% of the maximal tension to (-)-noradrenaline at a cell concentration of 2.5 x 10(6) ml-1. The contractile response was also found in endothelium-denuded vascular rings. 3. PMN present in the organ bath caused an increase in the sensitivity of vascular rings to (-)-noradrenaline. At a cell number of 2.5 x 10(6) PMN ml-1 the pD2-value for (-)-noradrenaline was augmented 0.40 +/- 0.05 (P less than 0.001), while total contraction at the highest concentration (-)-noradrenaline was not affected. This increase in sensitivity was dependent on an intact endothelium. 4. The increase in sensitivity to (-)-noradrenaline by PMN was inhibited by superoxide dismutase, but not by catalase, dimethylthiourea, indomethacin or nordihydroguaiaretic acid. The non-stimulated bovine PMN produced oxygen radicals as measured by chemiluminescence. 5. Simultaneous incubation of PMN and (-)-noradrenaline with arterial rings induced an increase in the release of prostacyclin, measured by an elevated concentration of 6-keto-prostaglandin F1 alpha in the supernatant. 6. It is concluded that PMN can increase vascular tone directly or indirectly probably via the interaction of PMN-derived superoxide anions with endothelium-derived relaxing factor.

Published
1992
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49. Reversal of the endotoxin-induced bronchial hyperreactivity to histamine by the platelet activating factor antagonist BN 52021.

Author

Nijkamp FP, Kessels GC, van Heuven-Nolsen D, and Braquet P

Subjects
Airway Resistance drug effects, Animals, Bronchial Hyperreactivity chemically induced, Bronchial Provocation Tests, Endotoxins, Ginkgolides, Guinea Pigs, Histamine, Male, Premedication, Bronchial Hyperreactivity prevention & control, Diterpenes, Lactones pharmacology, Platelet Activating Factor antagonists & inhibitors
Published
1992

50. Analysis of the 5-HT receptors mediating contractions in the rabbit isolated renal artery.

Author

Tadipatri S, van Heuven-Nolsen D, Feniuk W, and Saxena PR

Subjects
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, 8-Hydroxy-2-(di-n-propylamino)tetralin, Animals, Cocaine pharmacology, In Vitro Techniques, Indoles pharmacology, Ketanserin pharmacology, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Norepinephrine pharmacology, Oxidopamine pharmacology, Phentolamine pharmacology, Prostaglandin Endoperoxides, Synthetic pharmacology, Rabbits, Receptors, Serotonin drug effects, Renal Artery drug effects, Renal Artery physiology, Serotonin analogs & derivatives, Serotonin pharmacology, Serotonin Antagonists pharmacology, Sulfonamides pharmacology, Sumatriptan, Sympathectomy, Tetrahydronaphthalenes pharmacology, Tyramine pharmacology, Vasoconstrictor Agents pharmacology, Vasodilation drug effects, Muscle, Smooth, Vascular physiology, Receptors, Serotonin physiology
Abstract

1. Using a number of agonist and antagonist compounds, we have attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the rabbit isolated renal artery. 2. In vessel segments precontracted with the thromboxane-mimetic agent, U46619 (100 nM), neither 5-HT (10(-8) to 10(-4) M) nor 5-carboxamidotryptamine (5-CT; 10(-8) to 3 x 10(-4) M) caused relaxations like those observed with methacholine. Both 5-HT and 5-CT further increased the tone of the vessels, with pD2 values of 7.1 and 7.9, respectively. 3. In the absence of U46619, both 5-HT (10(-7) to 3 x 10(-3) M) and 5-CT (10(-7) to 10(-3) M) contracted the rabbit renal artery, but with reduced potencies. The contractions to 5-HT were reproducible and the rank order of potency (pD2) of the agonists was: alpha-methyl-5-HT (5.7), sumatriptan (5.3), 5-HT (5.1), 8-hydroxy-2(di-n-propylamino)tetralin (5.0), 5-CT (4.7) and 5-methoxytryptamine (4.3). 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, flesinoxan and RU 24969 elicited either only small contractions or none at all. 4. The contractile effect of 5-HT was unaffected by MDL 72222 (10(-6) M) and metergoline (10(-8) and 10(-7) M), was weakly antagonized by ketanserin and phentolamine (pKB: 6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pKB: 8.6). Responses to 5-CT and sumatriptan were affected by ketanserin, phentolamine and methiothepin similarly to 5-HT-induced responses. 5. Ketanserin was ineffective against noradrenaline-induced contractions, which were antagonized by phentolamine with a pKB of 7.3. The pKB values of phentolamine against 5-HT, 5-CT or sumatriptan were about half a log unit lower than against noradrenaline.6. In vascular preparations treated with cocaine (3 x 10- I M), the potency (pKB) of phentolamine as an antagonist of the responses to noradrenaline (7.6) and 5-HT (6.7) did not differ significantly from the values in untreated preparations. However, the difference between the pKB values of phentolamine against the two agonists was now about one log unit.7. Pretreatment of the vascular strips with 6-hydroxydopamine (1.5 x 10- 3M) did not significantly affect responses to 5-HT or 5-CT, but almost eliminated those to tyramine. Cocaine (3 x 10- 5M) slightly potentiated noradrenaline-induced contractions, but did not significantly affect those induced by 5-HT.8. These data suggest that: (i) 5-HT receptors mediating vasodilatation are not present in the rabbit renal artery smooth muscle or endothelium; (ii) the contractile effect of 5-HT does not involve the release of noradrenaline from sympathetic nerve stores; (iii) the 5-HT receptor in the rabbit renal artery is not of the 5-HT2, 5-HT3 or 5-HT4 type. The pharmacological properties of this receptor most closely resemble those described for the heterogeneous 5-HT1-like category.

Published
1991
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