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Biomedical subjects

O H Wilhelms

Publications and source records attributed to O H Wilhelms.

At least 19 recordsLinked to original sources
PubMed1998

Comparison of the effects of ularitide acetate and other bronchorelaxing substances on the thrombin-induced permeability raise of human endothelial cell monolayers.

Endothelial cell contraction plays a pivotal role in vascular leakage. It increases the extravasation of fluid and macromolecules from the lumen into the interstitium. This is also true for bronchial edema. Previous studies have indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxation of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), aminophylline (CAS 317-34-0), and combinations of these compounds, their effects on thrombin-induced macromolecular permeability raise in relation to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all increased the amount of cyclic nucleotides and decreased the raise in permeability in the following order of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a weaker amount and was not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline resulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-data indicate that ularitide-acetate, especially in combination with phosphodiesterase (PDE) inhibitors, could probably have beneficial effects in bronchial permeability edema.

Albumins↗
PubMed1998

Synergistic effects of ularitide acetate with classical bronchorelaxants on guinea-pig tracheal smooth muscle.

Ularitide (CAS 118812-69-4, urodilatin) is a member of the family of the atrial natriuretic peptides. In the present study, the relaxant effects of ularitide acetate, isoproterenol (isoprenaline) hemisulfate, aminophylline, zaprinast, and different combinations between these drugs were investigated on methacholine chloride-precontracted guinea-pig tracheal smooth muscle. Ularitide acetate was a weaker bronchorelaxant than isoproterenol hemisulfate and aminophylline. Moreover the relaxation induced by ularitide acetate was reversible, while the relaxation induced by isoproterenol hemisulfate, aminophylline, and zaprinast was irreversible. Combinations between in each case two of these substances were overadditive, if the phosphodiesterase-inhibiting component was applicated before the combination partner. Their effects were only additive, if the combination partners were applicated simultaneously. All combinations between ularitide acetate and isoproterenol hemisulfate, aminophylline, or zaprinast respectively relaxed the tracheas irreversibly. These results suggest that ularitide acetate might be a novel partner for classical bronchorelaxants in potent bronchorelaxing combinations in the therapy of asthma bronchiale.

Aminophylline↗
PubMed1996

Effect of urodilatin on platelet-activating factor-induced bronchoconstriction, vasoconstriction and edema formation in isolated rat lung.

In the isolated perfused rat lung, perfusion with platelet-activating factor causes bronchoconstriction, vasoconstriction and edema formation. The bronchoconstriction and vasoconstriction are largely mediated by thromboxane, whereas the edema formation is due to enhanced vascular permeability unrelated to eicosanoids. Since natriuretic peptides are known to relax smooth muscle and were suggested to attenuate enhanced vascular permeability, we investigated the effect of urodilatin on the PAF-induced alterations in lung function. Pretreatment with urodilatin (0.25 microM or 0.75 microM) reduced the PAF-induced increase in airway and vascular resistance by approximately 50%. Urodilatin pretreatment, however, was completely ineffective against the PAF-induced increase in weight gain and in vascular permeability, as assessed by the vascular filtration coefficient. Furthermore, urodilatin failed to affect the release of thromboxane into the perfusate in PAF-exposed lungs. Thus, urodilatin relaxes airway and vascular smooth muscle, but fails to reduce edema formation in PAF-perfused rat lungs.

Analysis of Variance↗
PubMed1996

Sephadex induced bronchial hyperreactivity in the rat: hematology, histology, histochemistry and immunohistology of the lung.

24 hours after an i.v. injection of 2 mg Sephadex G 200 particles ovalbumin sensitized Sprague Dawley rats show an antigen specific bronchial hyperreactivity and an unspecific hyperreactivity against serotonin. The aim of this study was to investigate the effects of Sephadex on blood parameters and lung pathology to find the morphological substrate of bronchial hyperreactivity in this animal model. In the blood neutrophilia (p < 0.01) but no eosinophilia was present. We conclude that a blood eosinophilia needs not to be necessarily correlated with hyperreactivity of the airways like claimed by other investigators for this animal model. Histologically we found that Sephadex particles are trapped in smaller-diameter arteries of the lung and lead to a granulomatous arteritis consisting mainly of ED1 positive and widely ED2 negative macrophages interspersed with eosinophils and neutrophils. Larger vessels not occluded by particles showed perivascular oedema with infiltration of eosinophils. We report here for the first time a significant hypertrophy of PAS positive goblet cells (p < 0.01) accompanied by a peribronchial infiltration with eosinophils (p < 0.01) and macrophages positive for ED1, ED2 and Ox-6 (p < 0.01) but not Ox-19 positive T-lymphocytes. The authors suggest that the peribronchial inflammation contributes importantly to the onset of bronchial hyperreactivity in this animal model and that the hypertrophy of goblet cells indicates the pathophysiological importance of peribronchial leukocytes.

Animals↗
PubMed1992

Intratracheal application of Sephadex in rats leads to massive pulmonary eosinophilia without bronchial hyperreactivity to acetylcholine.

Fourteen Brown-Norway rats were pretreated with physiological saline (n = 7) or 500 micrograms Sephadex (n = 7) intratracheally. 24 h later, a bronchial provocation test was performed under pentobarbital anaesthesia using increasing doses of acetylcholine aerosol and the degree of bronchospasm was measured using a modified Konzett-Rössler method. Subsequently, leucocyte counts were determined in the bronchoalveolar lavage fluid (BALF), BALF cells were differentiated, and the chemiluminescence of the BALF leucocytes were measured. Finally, the lungs were removed and histologically examined. The cell count in the BALF was significantly (p less than 0.05) increased in the animals pretreated with Sephadex compared to those in the saline group (mean value +/- SEM: 0.38 +/- 0.07 vs. 0.15 +/- 0.02 x 10(6)/ml). This difference was also reflected in the chemiluminescence measurements (2.51 +/- 0.53 vs. 0.20 +/- 0.03 x 10(6) counts/0.5 ml). In the Sephadex-treated animals there was also a significant increase in the absolute number of neutrophil (0.040 +/- 0.010 vs. 0.011 +/- 0.002 x 10(6)/ml) and, in particular, eosinophil granulocytes (0.188 +/- 0.055 vs. 0.003 +/- 0.001 x 10(6)/ml) in the total leucocytes of the BALF. Lung histology showed massive perialveolar and peribronchial oedema and granulomatous infiltrates, primarily with eosinophils, after intratracheal application of Sephadex; these findings were not observed in the saline group. None of these changes in the rats pretreated with Sephadex manifested themselves in increased bronchial reactivity to acetylcholine aerosol. It is uncertain if the Sephadex-induced increase in the eosinophil count is accompanied by an activation of this cell population, which appears to be of importance for the occurrence of bronchial hyperreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Animal models for testing anti-inflammatory drugs for treatment of bronchial hyperreactivity in asthma.

In the first part of this review the important role played by the bronchial hyperreactivity caused by chronic bronchopulmonary inflammation in asthma is described. Deliberately, more emphasis is placed on the role of pro-inflammatory eosinophils, alveolar macrophages, lymphocytes and platelets rather than on mast cells and neutrophils or the numerous mediators. The reason for this is that, on account of the large number of mediators and their multitude of functions and interactions in asthma, antagonism of a specific mediator will probably not be clinically relevant for optimally effective curative treatment of asthma. Inhibition of the infiltration and activation of pro-inflammatory cells is likely to be a more successful approach. In the second part, various animal models of bronchial hyperreactivity, which could be suitable for testing anti-asthmatic drugs, are discussed. Most animal models pay too little attention to chronic bronchopulmonary inflammation as the cause of bronchial hyperreactivity in asthma. In various models the bronchial hyperreactivity is provoked by a single mediator and this leads to selection of specific antagonists which are unlikely to be of clinical benefit. Rats appear to have certain advantages over guinea-pigs as experimental animals for bronchial hyperreactivity.

Animals↗
PubMed1991

In vitro generation of smooth muscle-contracting leukotrienes from isolated epidermal cells.

Single-cell suspensions of murine and human epidermal cells were studied for the presence of peptidoleukotrienes (LTs), using in vitro guinea pig ileum contraction as bioassay and a commercial radioimmunoassay. The calcium ionophore A23187 at 5 x 10(-6) M alone or in combination with arachidonic acid at 10(-4) M caused release of LTC4/D4 within 10-30 min and for up to 18 h. LTB4, as was measured in the chemotaxis assay, was released at different levels and with different kinetics from the same cells. Epidermal cells may thus regulate cutaneous inflammation by secreting potent vasoactive and muscle-contracting in addition to chemotactic lipid mediators.

Animals↗
PubMed1991

Time course of immediate release and relationships between thrombin-like proteinase, other proteinases, histamine, protein and dye extravasation in rat passive peritoneal anaphylaxis.

A thrombin-like proteinase (THROLP) was detected colorimetrically as the main proteolytic activity (PROA) in the lavage fluid some minutes after antigen challenge of rats for passive peritoneal anaphylaxis (PPA) reaction. THROLP is equivalent to histamine (H) as parameter for the early phase of PPA: both increased significantly after 6 min, but decreased to prechallenge levels 20 min after challenge. H was released from serosal mast cells, in contrast THROLP originates predominantly from plasma leakage and activation of the clotting reaction in PPA. These findings underline the importance of PROA in the sequence of allergic reactions.

Anaphylaxis↗
PubMed1991

Late phase increase of thrombin-like proteinase, protein, leukocytes in bronchoalveolar lavage (BAL) fluid and chemiluminescence of BAL after ovalbumin aerosol inhalation by actively immunized rats.

A thrombin-like proteinase (THROLP) was detected colorimetrically as the main proteolytic activity (PROA) in bronchoalveolar lavage fluid (BALF) 4 and 24 h after ovalbumin aerosol (OVA) challenge of actively immunized rats. Other proinflammatory parameters increased also significantly in BALF, like chemiluminescence of leukocytes (1 h), protein and cell number (24 h after challenge). In parallel, increased bronchoconstrictions against 5-HT aerosols are detected 24 h post OVA challenge. THROLP is an indicator for plasma leakage, activation of the clotting reaction and the protracted inflammation in the airways, which induced bronchial hyperreactivity.

Administration, Inhalation↗
PubMed1991

Picumast dihydrochloride (Auteral), a new anti-allergic inhibitor of mediator release and action.

Picumast dihydrochloride (PDH), (3,4-dimethyl-7-[4-chlorobenzyl) piperazine-1-yl]propoxycoumarin dihydrochloride) is a prophylactically active anti-allergic compound which combines inhibition of mediator release and action. The activity profile of PDH differs clearly from that of known prophylactic anti-allergic drugs such as DSCG and ketotifen. Other inhibitory actions of PDH in addition to its H1-antagonism (and that of its metabolites M2 and M1) may be the cause of the suppression of immediate and late phase allergic reactions in animals as well as allergic rhinitis and bronchial responsiveness and symptom scores in asthmatic patients.

Anaphylaxis↗
PubMed1990

Nimesulide, indomethacin, BW 755 C, phenidon, mepacrin and nedocromil inhibit the activation of human and rat leucocytes.

This study confirms the strong inhibition of therapeutic concentrations of the antiinflammatory agent nimesulide (NI) on the chemiluminescence (CL) of human leucocytes (HL) after stimulation with opsonized zymosan (C3Z), and extends the findings to peritoneal (RPL) and bronchoalveolar leucocytes (RBAL) collected from actively immunized rats 24 h after i.v. injection of Sephadex. Additionally we demonstrate that NI is a strong inhibitor of proteinase release (PR) from HL. The reference drugs tested for comparison were indomethacin (I), BW 755 C (BW), phenidon (PH), mepacrin (M) and nedrocromil (NE). The rank order of potency for suppression of PR and CL was nearly independent of the cell type and stimulus: PH greater than or equal to BW greater than M greater than NI = 4-OH-NI much greater than I greater than NE. NI was the superior inhibitor of HL activation compared with I as measured either by PR or CL (factor 7), and also of CL of RPL and RBAL (factor 2-3). NI inhibited the PR from HL and CL of RPL or RBAL almost equipotently (IC30: 10-20 micrograms/ml), whereas PH, BW, M and I were 6-10 times more effective as CL inhibitors compared with their PR inhibition. In contrast NE showed a preferential inhibition of PR. This unique inhibition profile on leucocyte activation in vitro may be related to the differences of NI and I which are also existing in their antiinflammatory activities in vivo.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Antiallergic activity of picumast dihydrochloride in several animal species.

Picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) was compared with cromoglycate, ketotifen and mepyramine as an inhibitor of allergic and anaphylactoid reactions. 1. In guinea-pigs, pretreatment with picumast dihydrochloride given intravenously, orally or by inhalation prevented bronchospasm induced by antigen or histamine. The fraction of the bronchospasm remaining after mepyramine pretreatment was further reduced by picumast dihydrochloride. 2. Systemic administration of picumast dihydrochloride inhibited antigen-induced conjunctivitis, whereas mepyramine and ketotifen were inactive. 3. Intravenous and oral pretreatment with picumast dihydrochloride inhibited the antigen-induced mast cell degranulation in rat mesentery. The effective doses of cromoglycate given intravenously were twice as high as those of picumast dihydrochloride. Picumast dihydrochloride did not inhibit antigen-induced bronchoconstriction in rats. 4. The cutaneous reaction induced with Ascaris antigen in atopic monkeys was insensitive to the antihistaminic action of ketotifen, whereas it was inhibited by low doses of picumast dihydrochloride. Both compounds suppressed skin reactions induced by histamine. 5. Picumast dihydrochloride decreased IgE production in atopic high responder mice. It did not prevent autoimmune nephritis in NZB/W mice. 6. In rats, picumast dihydrochloride did not reduce cotton pellet granuloma, nor adjuvant arthritis. The inhibition of carrageenin oedema is presumably due to its anti-oedematous properties rather than to an antiproliferative activity. In conclusion, the inhibition of allergic and anaphylactoid reactions by picumast dihydrochloride can be attributed to a combined inhibition of liberation and action of histamine and other mediators.

Airway Resistance↗
PubMed1989

Metabolism of picumast after administration of picumast dihydrochloride and antiallergic activity of the main metabolites.

The present experiments were carried out to elucidate the chemical structure and the pharmacological activity of the main metabolites of picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ). The metabolic pathways were identical in animals and man, but there were major quantitative differences. The fraction of the radioactivity in the plasma attributable to the parent compound 0.5 to 3 h after oral administration of picumast dihydrochloride was less than 15% in animals but 95% to 57% in man. Inhibition of the C3-zymosan-induced chemilumiescence of human leucocytes was taken as an indicator of the diminished liberation of mediators and inhibition of the histamine-induced contraction of isolated guinea-pig lung strips as an example for the antagonism of picumast dihydrochloride to mediators of allergic reactions. Stepwise oxidation of the 3-methyl substituent of the coumarin ring to the alcohol and the carbonic acid increased the histaminolytic potency, but decreased the inhibition of chemiluminescence. Another metabolite formed by cleavage of the piperazine-containing side chain was inactive in both tests.

Animals↗
PubMed1987

Antagonism of picumast and ketotifen against histamine, acetylcholine, LTC4, slow-reacting substance of anaphylaxis and barium chloride in the guinea pig ileum bioassay.

The antagonism of the antiallergic compounds picumast (PIC; Boehringer Mannheim) and ketotifen (K; Sandoz) against pro-allergic mediators like histamine (H), acetylcholine (ACh), SRS-A and LTC4 as well as against the unspecific spasmogen BaCl2 was compared in the bioassay of superfused guinea pig ileum. For the evaluation of an SRS-A antagonism crude SRS-A from antigen-stimulated guinea pig lung fragments in Krebs buffer was used with the addition of atropine and mepyramine. PIC (approximately 10(-6)-10(-5) mol/l) antagonized clearly all tested spasmogens in a concentration-dependent manner. Its predominant antagonism (IC30: 2-3 X 10(-6) mol/l) was against H, LTC4 and SRS-A, which are presumably important mediators of allergic reactions. ACh- or BaCl2-induced spasms were inhibited to the same extent with a 4 or 6 times higher concentration of PIC. K was approximately 20 times more potent as antagonist against H and approximately 8 times more potent against ACh, whereas the antagonism against LTC4- or BaCl2-induced spasms reached only 1/3 of that of PIC. An antagonism of PIC against SRS-A, LTC4 and H may contribute to its antiallergic activity in vivo. K showed little activity against LTC4 but could antagonize more selectively H- and ACh-mediated effects.

Acetylcholine↗
PubMed1987

Inhibition profiles of picumast and ketotifen on the in vitro release of prostanoids, slow-reacting substance of anaphylaxis, histamine and enzyme from human leukocytes and rat alveolar macrophages.

The inhibitory potency of the antiallergic compounds picumast (PIC; Boehringer Mannheim) and ketotifen (K; Sandoz) on the release of 3 preformed and 3 newly generated inflammatory mediators was estimated as an indicator for their antiallergic activity. Peripheral human leukocytes (HL) or rat alveolar macrophages (RAM) were stimulated by opsonized zymosan (C3-Z) and/or anti-IgE antibody, following preincubation times with PIC and K. SRS-A was measured with the help of a guinea pig ileum bioassay, PGE2 and TxB2 by RIA (NEN), histamine (H) by an automated fluorimetric procedure, tryptic proteinase (P) by a colorimetric test employing Tos-Gly-Pro-Arg-pNA (Chromozym TH; Boehringer Mannheim) as chromogenic substrate and beta-glucuronidase (beta-G) by a colorimetric test (Sigma). PIC (IC30: 2 X 10(-5) mol/l) was 100 times more potent than K as inhibitor of the anti-IgE-induced release of H and P and also 5 times more potent as inhibitor of SRS-A-formation/release in/from HL. In contrast, on RAM, K (IC30: 7 X 10(-6) mol/l) had a 3 times greater potency as inhibitor of the C3-Z-induced SRS-A formation and suppressed PGE2 release (4 X 10(-5)-2 X 10(-4) mol/l), whereas PIC (2 X 10(-5) mol/l) potentiated PGE2 release remarkably. TxB2 release from RAM was inhibited nearly equipotently by PIC and K. beta-G release was strongly potentiated by K (greater than or equal to 8 X 10(-6) mol/l), but weakly inhibited by PIC (2 X 10(-5) mol/l). PIC (greater than or equal to 4 X 10(-5) mol/l) also increased the beta-G release and in the same manner the anti-IgE- or C3-Z-induced release of other 'preformed' mediators like H and P from HL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Selective antigen-stimulated release of proteolytic activity from rat mast cells.

Stimulation of rat mast cell suspension from actively sensitized rats with antigen in vitro produced a parallel release of histamine and enzyme, probably proteolytic activity, which releases p-nitrophenol from an L-tyrosine-p-nitrophenyl ester derivative (TPNE). The histamine and enzyme release correlated with respect to their dependence on antigen concentration, reaction time and inhibition by 2,4-DNP and papaverine. In contrast, more than 50% of total histamine but nearly no enzyme was released by the ionophore A 23.187 and C 48/80 (each less than or equal to 1 microgram/ml). The enzyme was apparently secreted predominantly in a particular form. It was approximately 50% inactivated by heating for 1 h at 56 degree C or by incubation for 3 h at 37 degrees C with the chymotrypsin inactivator tosyl-phenylalanine chloromethylketone (TPCK; 2.5 X 10-4 M) or for 5 min at 37 degrees C with benzyl sulphonyl fluoride (2.5 X10-4 M), which reacts with SH groups. Heating for 3 min at 100 degrees C destroyed it completely. On the basis of these properties we suggest that the antigen released enzyme is the known granulabound chymase from rat mast cells. TPNE was not only a cleavable substrate for the enzymatic activity in the 800 g cell supernatant following antigen stimulation, but also a strong inhibitor of the histamine release on administration before antigen (IC50 approximately 10-6 M). It appears that the same enzyme activity acts initially intracellularly as activator of the histamine secretion and then is subsequently released along with histamine as a further mediator. Extracellularly this enzyme may act as a modulator of inflammatory reactions in type I allergy both locally and systemically.

Animals↗