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H Timmerman

Publications and source records attributed to H Timmerman.

At least 181 records · Page 10Linked to original sources
PubMed1991

Effects of histamine H1-, H2- and H3-receptor selective drugs on the mechanical activity of guinea-pig small and large intestine.

1. In this study we have evaluated the possible contribution of acetylcholine release in histamine-induced contractions of guinea-pig large and small intestinal smooth muscle. Moreover, the presence of the histamine receptor types involved in smooth muscle relaxations and inhibition of electrically-induced twitches was studied by use of several selective agents. 2. Histamine-induced contractions appeared to be a pure H1-receptor-mediated effect. Responses were not attenuated by the presence of 0.1 microM atropine and were competitively and stereoselectively inhibited by the two enantiomers of chlorpheniramine with pA2 values of 6.73 +/- 0.08, 7.30 +/- 0.06, 6.93 +/- 0.03 and 7.19 +/- 0.04 for the L-isomer and 8.63 +/- 0.09, 8.85 +/- 0.09, 9.01 +/- 0.16 and 0.11 for the D-isomer in the duodenum, jejunum, ileum and colon, respectively. 3. There appeared to be a marked regional difference in sensitivity to histamine. In ileal and jejunal preparations pD2 values of 6.24 +/- 0.06 (n = 22) and 6.37 +/- 0.07 (n = 22) were found, whereas the pD2 values in the duodenum and colon were 5.55 +/- 0.05 (n = 36) and 5.68 +/- 0.06 (n = 31) respectively. 4. This regional difference in sensitivity to histamine was not due to variations in receptor affinity since pA2 values for the two enantiomers of chlorpheniramine did not differ markedly among the four tested preparations. Since a similar variation in sensitivity was found for methacholine, it is likely that the signal transfer mechanism in guinea-pig ileum and jejunum is more efficient than in the duodenum and colon. 5. The H2-agonists dimaprit and impromidine relaxed methacholine-precontracted (+/- 70% of maximum contraction) intestine at high concentrations (pD2 values of 3.79 + 0.03 and 4.44 + 0.09 for the jejunum). These relaxations could not be antagonized by 0.1 microM tiotidine, famotidine or mifentidine and were observed in all parts of the intestine investigated. 6. The dimaprit analogues nordimaprit and homodimaprit (inactive at H2-receptors) were equipotent in relaxing the methacholine-precontracted smooth muscle. Since several H2-antagonists were also able to produce relaxations, we do not consider these relaxations to be mediated by a H2-receptor subtype, but to be due to some nonspecific effects at the high concentrations used. 7. The histamine receptor involved in the inhibition of electrically-induced contractions in the presence of atropine could be classified as an H3-receptor effect. In all parts of the intestine the H3-agonist R-alpha-amethylhistamine inhibited the twitches with pD2 values ranging from 8.10 + 0.06 (ileum) to 8.27 + 0.03(colon). This effect was competitively antagonized with the selective H3-antagonist thioperamine (pA2 values are 8.09 + 0.07, 8.13 + 0.05, 8.15 + 0.04 and 8.36 + 0.04 in duodenum, jejunum, ileum and colon, respectively. 8. The guinea-pig intestine is a suitable preparation for the evaluation of either H1- or H3-receptor effects. H2-receptors, causing smooth muscle relaxation appear not to be present in our preparations. At high concentrations of H2-receptor agents (agonists and antagonists) relaxations might be observed, due to unknown nonspecific effects.

Animals↗
PubMed1991

Histamine agonists and antagonists.

The role of histamine in brain function is discussed. A brief review is presented on the three types of histamine receptors with regard to their biochemistry and functions. The agonists and antagonists of these three classes of histamine receptors are discussed, together with the role such compounds play in clinical therapy and pharmacology.

Animals↗
PubMed1990

New selective histamine H1 agonists. Synthesis and pharmacology.

In this article the synthesis and histaminergic H1 activity of a series of substituted 2-phenylhistamines are described. It appeared that substitution of the phenyl ring of these compounds influences the H1 activity substantially. In general, substitution in para position causes a decrease in H1 activity. However, in the meta-substituted members both increases and decreases of H1 activity have been observed; thus the meta nitro and meta methoxy derivatives are four times as potent as the parent 2-phenylhistamine. As far as investigated, neither H1 nor H3 activity could be established.

Animals↗
PubMed1990

Inhibition of electrically evoked contractions of guinea-pig ileum preparations mediated by the histamine H3 receptor.

We investigated the contraction responses of isolated guinea-pig ileum preparations under several conditions of electrical field stimulation. Histamine H3-agonists caused a dose-dependent inhibition of both cholinergic and nonadrenergic noncholinergic (NANC) responses (pD2 of histamine, 7.3; N alpha-methylhistamine, 8.4; (R)-alpha-methylhistamine, 8.3); H3-antagonists blocked this inhibition (pA2 of impromidine, 7.2; thioperamide, 8.5). Our results indicate that H3-receptors are present on both cholinergic and NANC nerves in the myenteric plexus and that the preparation can be used as a rapid and simple test system for histamine H3-receptors.

Animals↗
PubMed1990

Ebselen inhibits contractile responses of guinea-pig parenchymal lung strips.

Ebselen is a new anti-inflammatory drug with a wide spectrum of pharmacological activities. Since this compound might be useful in diseases related to airway inflammation we evaluated the effects of ebselen on the contractile responses of guinea-pig parenchymal lung strip. Ebselen and its sulfur analogue RP 62373 depressed both histamine H1-receptor-mediated and KCl-induced (50 mM) contractions of guinea-pig lung strips equipotently. The responses to histamine were only affected via depression of the maximal response; treatment with 3 microM ebselen for 30 min resulted in depression to 77 +/- 5% of the control value, whereas 10 and 30 microM inhibited the contractions to 53 +/- 4 and 52 +/- 4% of the control value respectively. The responses after membrane depolarisation (50 mM KCl) were less sensitive to ebselen pretreatment; 10 microM ebselen inhibited contractions by only 20%, whereas 30 and 100 microM depressed the response by approximately 50%. These observations were evaluated in the context of the activities of ebselen already described. The effects of lipoxygenase, cyclooxygenase, protein kinase C inhibition and thiol alkylation were studied, using established agents. However, although interaction with critical thiol groups might explain our data, the mode of action of ebselen is yet not fully elucidated.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity. I. Class I and class III compounds and lipid peroxidation.

The effect of nineteen antiarrhythmic agents on nonenzymatic lipid peroxidation, using rat hepatic microsomes, was studied. Lipid peroxidation was induced by Fe2(+)-ascorbic acid and assayed spectrophotometrically by measuring the 2-thiobarbituric acid reactive material. The compounds tested have various structural characteristics and represent class I and III of antiarrhythmics as classified by Vaughan Williams. The RM values, derived from reversed-phase thin-layer chromatography, were determined, and sigma f values calculated in order to correlate lipophilicity and antioxidant activity. The antiarrhythmics studied inhibited lipid peroxidation to various degrees. No apparent structural factor could definitely be attributed to this effect and antioxidants are found among both class I and class III compounds. There is a trend toward a parabolic relationship between antioxidant potency and lipophilicity. Three of the tested antiarrhythmics, namely the lipophilic amiodarone, aprindine and asocainol, were very potent antioxidants, and a further investigation of concentration and time dependency of lipid peroxidation was performed. It is suggested that, at least for some antiarrhythmic drugs, antioxidant activity may be part of their mode of action, and that it may form an additional beneficial feature for the treatment of cardiac failure.

Amiodarone↗
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity, II: Interaction of class I compounds with calmodulin.

We have tested the calmodulin (CaM) inhibitory potency of class I antiarrhythmics in the phosphodiesterase (PDE) assay. The lipophilicity of the test compounds has been quantified by two experimental (log P, RM) and two calculative (sigma f, C log P) procedures. Five antiarrhythmics (asocainol, aprindine, lorcainide, propafenone, and ethmozine) exhibit IC50 values less than 250 microM for the inhibition of the CaM-stimulated PDE activity. Lipophilicity seems to be a prime, but not the sole descriptor of CaM inhibitory potency. The functional means of CaM inhibition by the test compounds for their antiarrhythmic properties remains to be clarified in further investigations.

Anti-Arrhythmia Agents↗
PubMed1990

Identification of beta 2-adrenoceptors on guinea pig alveolar macrophages using (-)-3-[125I]iodocyanopindolol.

The beta-adrenoceptor antagonist (-)-3-[125I]iodocyanopindolol ([125I]ICYP) binds with high affinity and in saturable way to membranes of guinea pig alveolar macrophages. The equilibrium dissociation constant for [125I]ICYP is 24.3 +/- 1.2 pM, and the number of binding sites is 166.3 +/- 13.7 fmol/mg protein (N = 4, +/- SEM). Displacement studies with selective antagonists showed that [125I]ICYP labels beta 2-adrenoceptors on guinea pig alveolar macrophages.

Adrenergic beta-Antagonists↗
PubMed1990

Labelling of non-H1-receptor binding sites by [3H]-mepyramine on the rat liver plasma membrane.

In the present study we characterized [3H]-mepyramine binding to rat liver plasma membranes. Binding of [3H]-mepyramine proved to be of high affinity (Kd = 7.7 +/- 0.4 nM) and saturable, resulting in a Bmax-value of 70.4 +/- 9.5 pmol/mg protein. However, displacement studies revealed that this binding site was different from other H1-receptor systems. The two stereoisomers of chlorpheniramine were rather ineffective in displacing [3H]-mepyramine and showed a stereospecificity in favour of the L-isomer. Also several H1-receptor agonists were not potent in displacing [3H]-mepyramine from rat liver plasma membranes. Moreover, the histamine metabolite imidazole-4-acetic acid was about as potent as the H1-agonists, whereas imidazole was even more potent. These data strongly suggest that [3H]-mepyramine labels a non-H1-receptor binding site on the rat liver plasma membrane.

Aminopyridines↗
PubMed1990

Cytochrome P-450 metabolic-intermediate complex formation with a series of diphenhydramine analogues.

A series of diphenhydramine analogues have been studied with regard to their formation of a metabolic intermediate (MI) during their biotransformation in phenobarbital induced rat hepatic microsomes. The MI forms a complex with reduced cytochrome P-450. MI complexation of cytochrome P-450 may result in drug-drug interactions and/or in cumulation of the parent compound. The extent of MI complex formation could be correlated with the lipophilicity of the substrates in a parabolic manner. A hydrophobic pocket of limited dimensions in cytochrome P-450 for the N-alkyl substituent of the substrates can be assumed. Moreover our data indicate a role for the O-atom in the diphenhydramine analogues for the interaction with cytochrome P-450.

Animals↗
PubMed1990

Irreversible H2-antagonism of the four isomeric butyl analogues of mifentidine.

It has been hypothesized that bidentate hydrogen bonding plays an important role in the interaction of imidazolylphenylformamidines with the H2-receptor. The present study, in which the degree of pseudo-irreversible H2-antagonism of the four isomeric butyl substituted mifentidine analogues was determined on the spontaneously beating right atrium of the male guinea-pig, lends further support to this hypothesis. In solution the EE/EZ ratio is different for the four isomeric butylated mifentidine analogues. The rank order of the percentage of E,E conformation, which favors a bidentate interaction, of the formamidine moiety parallels the rank order of pseudo-irreversible H2-antagonism.

Animals↗
PubMed1990

Essential thiol and disulphide groups in the histamine H1-receptor signal transfer of guinea-pig parenchymal lung strips.

Guinea-pig parenchymal lung strips contract after H1-receptor stimulation and membrane depolarisation with KCl. Contractions after 50 mM KCl were similar to the maximal histamine response. Treatment of lung strips with micromolar concentrations of the thiol-alkylator N-ethylmaleimide markedly affects both histamine H1-receptor mediated and 50 mM KCl-induced contractions. The H1-receptor response was only affected via a decrease in the maximal response. The response to 50 mM KCl was also inhibited after thiol-alkylation. However, H1-receptor responses appeared to be slightly more sensitive towards thiol-alkylation compared to KCl-responses. Reduction of disulphide groups with 1,4-dithiothreitol also modified the contractile responses to both stimuli. It is concluded that both thiol- and disulphide moieties play important roles in the regulation of histamine H1-receptor activity.

Animals↗
PubMed1990

Autoinhibition of histamine release by H3 receptors in rat brain cortex depends on stimulation frequency.

Rat cortical slices preloaded with [3H]histidine released [3H]histamine upon electrical stimulation or after depolarization with elevated K+ levels. The release was dependent on the presence of Ca2+, suggesting a neurosecretory process. Histamine has been shown to inhibit its own release mediated by an autoreceptor belonging to the H3-receptor subclass. In this study we have investigated the autoinhibition using different electrical field stimulation conditions (1, 10, 20 and 33.3 Hz). Applying electrical stimulation, the inhibition of [3H]histamine release by histamine is decreased when the stimulation frequency is elevated. When stimulated with 1 Hz histamine is able to block [3H]histamine release completely, with a p(EC50) of 8.1 +/- 0.1. At higher frequencies histamine still blocks [3H]histamine release completely, but with a lower p(EC50).

Animals↗
PubMed1990

Copper complexes of 1,10-phenanthroline and related compounds as superoxide dismutase mimetics.

In a preliminary study we tested CuSO4.5H2O, (Cu(II]2[3,5-diisopropylsalicylate]4.2H2O and a number of copper complexes of substituted 1,10-phenanthrolines for superoxide anion dismutase activity. It appeared that this activity depends on the ligands involved and might be governed by the redox potential of the Cu(I) complex/Cu(II) complex couple. The strong superoxide anion dismutase activity of Cu(II)[DMP]2 complex can be expected considering its high redox potential. Rather surprisingly is the superoxide anion dismutase activity of the Cu(I)[DMP]2 complex since it involves oxidation to Cu(II)[DMP]2 complex. From regression analysis it was established that steric and field effects of the substituents of the investigated phenanthrolines play an important role in SOD activity and therefore it is concluded that complex formation is important for the superoxide dismutase-like activity.

Copper↗
PubMed1990

Histamine receptors: subclasses and specific ligands.

In this review the three main types of histamine receptors are discussed together with their specific ligands. For the classical H1-receptors much emphasis is put on the mechanism by which the receptor is stimulated. For the H1- and H2-receptor the review includes information on the several models available for establishing agonistic or antagonistic activity. In the section on the H3-receptor the ligands are discussed as well as the possible physiological role of this receptor. In the final paragraphs some less well defined activities are presented.

Animals↗
PubMed1990

The value of the macerated skull as a model used in orthopaedic research.

In this study a method was developed to enable the measurement of initial bone displacement in vivo, post-mortem, and in vitro. Speckle interferometry was used as measuring technique. Through the construction of the centres of rotation, the different orthopaedic effects could easily be compared. Also the magnitude of the bone displacement could be calculated. The initial post-mortem displacement of the maxilla corresponds very well with the initial in vivo displacement. After maceration and drying of the skull, however, clear differences from the in vivo displacement were found. The orthopaedic effects on a macerated skull can be manipulated considerably by changing, for instance, the degree of humidity. Only a limited number of skulls was examined in these experiments and probably still other variables exert an influence on the bone displacement in the macerated skull. Nevertheless, it is certain now that the dry skull cannot reliably be used as a model to simulate the initial bone displacement in vivo. The experimental set-up of this study will be used in the future to evaluate the effect of environmental factors (humidity, temperature, etc.) in an attempt to improve the value of the skull as a model for orthopaedic research. Moreover, this technique permits investigation of the link between initial displacements in vivo and longitudinal changes.

Aging↗
PubMed1990

Different profiles of desensitization dynamics in guinea-pig jejunal longitudinal smooth muscle after stimulation with histamine and methacholine.

1. In the present study we investigated desensitization phenomena of guinea-pig jejunal longitudinal smooth muscle responses after stimulation with 100 microM histamine or methacholine, using a superfusion method. 2. Histamine H1-receptor-mediated contractions appear to be rapidly reduced after application of 100 microM histamine. Muscarinic responses were not affected following desensitization with 100 microM histamine, indicating a homologous desensitization. 3. Initial contractions to 0.3 microM histamine were reduced by 90%, recovered quickly, but did not reach control levels within 1 h. Desensitization of histamine responses could be separated into two phases; a rapid, but transient, desensitization and a more sustained desensitization. As a consequence of this sustained effect the pD2 for histamine shifted from 6.7 +/- 0.1 (control) to 6.1 +/- 0.1 (desensitized). 4. Desensitization with 100 microM methacholine caused a heterologous desensitization, reflected by the development of a refractory period, in which neither histamine nor methacholine was able to elicit a contraction. After a few minutes responses to both agents recovered to control levels. 5. During the refractory period after methacholine desensitization, muscle strips were still responsive to 40 mM KCl but did not contract in response to 10 mM caffeine, suggesting that the heterologous desensitization is caused by a modification of an intracellular Ca2(+)-store, which is used by both histamine and methacholine. 6. The recovery of the responses after methacholine desensitization was not dependent on extracellular Ca2+, suggesting that the recovery is not dependent on refilling of the intracellular Ca2+ store with extracellular Ca2+. 7. The protein kinase C activator, phorbol-12,13-dibutyrate, concentration-dependently inhibited histamine- and methacholine-induced contractions. Protein kinase C seems therefore not to be implicated in the observed homologous H,-receptor desensitization. 8. These data suggest that different forms of desensitization can be distinguished in this model, each with a different time course and dependent on the applied stimulus.

Animals↗