Insulin-induced up-regulation of histamine H1-receptors

Inflammation Research -     

Structure elements of histamine H1- and H2-receptors

Conclusion Naturally, the suggested structure schemes of the histamine receptors do not exhaust all possible complexities of their structure; however, they may be a basis when predicting activity of many newly synthesized compounds.     

The histamine H1-receptor antagonist cetirizine does not interact with bradykinin B1 or B2-receptors in vitro

Inflammation Research -     

Specific binding of [3H]mepyramine to histamine H1-receptors in vascular smooth muscle membranes

The antagonist-sensitive binding of [³H]mepyramine to beef aortic membranes was as expected for binding to histamine H₁-receptors. [³H]mepyramine binds rapidly and in saturable fashion to the specific receptor sites, specific binding reaching equilibrium in 3 min at 37°CScatchard's analysis of the binding data gave a dissociation constant of 3.0 nM for the radioligand-receptor complex and maximal number of binding sites: 31 fmol/mg protein. In the competition studies histamine H₁-antagonists are more potent inhibitors of radioligand binding than H₂-antagonist. They inhibit [³H]mepyramine binding in the following order: mepyramine >triprolidine     

Does the gastric mucosa contain inhibitory histamine H1-receptors?

Conclusion From the results it is concluded that in contrast to data reported in the literature, in cats histamine, dimaprit and tolazoline produce an identical acid response and differ only in their affinity to the histamine H₂-receptor. The effects of mepyramine and phenoxybenzamine do not indicate the presence of H₁-receptors, which is confirmed by missing inhibitory effects of PEA. The effects of the former two, however, suggest that reversal of the histamine dose-response curve is caused by histamine-released catecholamines which are prevented from being released by mepyramine and blocked in their peripheral action by phenoxybenzamine.     

Unexpected partial H1-receptor agonism of imidazole-type histamine H3-receptor antagonists lacking a basic side chain

Objective and design:The putative partial H₁-receptor agonism of some H₃-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. Methods:Whole segments of guinea-pig ileum were mounted in Tyrode’s solution under isotonic conditions in the presence of atropine (10^-7 M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H₁-receptor agonists were added cumulatively to determine agonist potency (pEC₅₀) and intrinsic activity (E_max) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H₁-receptor antagonists were incubated for 3–15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H₁ receptor (pK_P or pA₂ value, respectively). Results:Several analogues of FUB 372 displayed low H₁-receptor affinities (pA₂ or pKP 4.2–5.5) except for a methyl benzoate derivative (pA₂ = 6.81, Schild plot slope unity). FUB 372, four ortho-substituted derivatives (R = F, CH₃, OCH₃, CF₃), and ciproxifan were weak contractile agents (E _max 9–38%, pEC₅₀ 4.73–5.68, histamine: 6.70) susceptible to antagonism by the H₁-antihistaminergic drug mepyramine (2·10^-9–10^-7 M). Agonist potency and H₁-receptor affinity of these compounds did not correlate with the data of a set of H₁-histaminergic 2-phenylhistamines bearing the same substituents. Conclusions:A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H₁-receptor agonists lacking a basic side chain.     

Labeling of histamine H1-receptors in the brain of the living mouse

Labeling of cerebral H1-receptors is obtained following i.v. administration of [3H]mepyramine in tracer dose as shown by saturability, stereospecificity, regional distribution and pharmacological specificity. Cerebral H1-receptors are occupied following administration of most H1-antihistamines at low therapeutic dosage, which probably accounts for the sedative side-effects of these agents.     

The role of central histamine H1- and H2-receptors in hypothermia induced by histamine in the rat

Histamine administered intraventricularly or into the anterior hypothalamic preoptic region induced dosedependent hypothermia in rats with chronic i.c.v. cannula. This hypothermia was almost totally abolished by both the histamine H₁-and H₂-receptor antagonists, mepyramine or chloropyramine and metiamide or cimetidine, respectively, given i.c.v. prior to histamine. In behavioural thermoregulation studies histamine considerably diminished the mean duration of dwelling of the rat under the heat lamp. This effect was abolished by histamine H₁- but not by H₂-receptor antagonists. It is concluded that histamine induces hypothermia by lowering the set point of the hypothalamic thermostat by means of H₁-receptors. Histamine H₂-receptor blockers antagonized the increase in tail skin temperature after histamine administration, suggesting that H₂-receptors are involved in a heat loss mechanism.     

Effects of histamine H1-receptor stimulation on coronary hemodynamics in man

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H₁ and H₂-receptors present on human heart and on coronary arteries. We studied the effects of selective H₁-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 g/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO₂) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103±5 to 85±6 mmHg (p<0.02) and CVR from 1.00±0.16 to 0.81±0.14 mmHg/ml/min (p<0.05); CSBF and MVO₂ did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D₃, reduction in CSBF and an increase in CVR. These results indicate that H₁-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.     

Structure-activity relationship of histamine H2-receptor agonists

Conclusions As demonstrated by the results the active C-5(4) substituted histamines and N-methyl-histamines are to various extents selective H₂-receptor agonists.In contrast to the ileal H₁-receptors the atrial H₂-receptors appear to be noticeably stereoselective.     

Characterization of coexistent histamine H1- and H2-receptor binding sites in the purified guinea pig myocardial membranes from ventricles

In the present work, we identified and characterised histamine H1-and H2-receptors in highly purified myocardial membranes isolated from female guinea pig ventricles. We determined the binding parameters for the interactions of³H-mepyramine with the histamine H1-receptor binding site and³H-tiotidine with the histamine H2-receptor binding site. Binding of both ligands in our study was saturable, reversible and of high affinity. Scatchard's analysis of the specific³H-mepyramine binding revealed the existence of high and low affinity binding sites with apparent K_D values of 0.4 nM and 4.5 nM, respectively. The density of binding sites (B_max) was 100 fmol/mg protein for the high and 466 fmol/mg protein for the low affinity binding site.³H-tiotidine binds to a single population of binding sites with a K_D of 1.0 nM and a B_max of 27 fmol/mg protein. These data suggest that both histamine H1-and H2-receptors coexist in the guinea pig myocardium with a significantly higher prevalence of the histamine H1-receptor population.     

Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors

The regulation of histamine synthesis was studied on rat brain slices or synaptosomes labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration enhanced by about twofold the [3H]histamine formation in slices of cerebral cortex. This stimulation was also observed, although to a lesser extent, in synaptosomes from cerebral cortex and slices from the posterior hypothalamus where most histaminergic cell-bodies are located, suggesting that it may occur in nerve endings as well as in perikarya. In the presence of exogenous histamine in increasing concentrations the K+-induced stimulation was progressively reduced by up to 60-70%. The effect of exogenous histamine appears to be receptor-mediated as shown by its saturable character, high pharmacological specificity and competitive reversal by histamine antagonists. The EC50 value of histamine for synthesis reduction (0.34 +/- 0.03 microM) was similar to its EC50 value for release inhibition known to be mediated by H3-receptors. In addition, whereas mepyramine and tiotidine, two potent antagonists at H1- and H2-receptors, respectively, were poorly effective, the H3-receptor antagonists burimamide and impromidine reversed the histamine effect in an apparently competitive manner. These effects were observed in slices of cerebral cortex or posterior hypothalamus as well as in cortical synaptosomes. Furthermore, even in the absence of added histamine, H3-receptor antagonists enhanced the depolarization-induced stimulation of [3H]histamine synthesis, indicating a participation of released endogenous histamine in the synthesis control process. The potencies of H3-receptor antagonists were similar to those of these agents at presynaptic autoreceptors controlling [3H]histamine release. It is concluded that H3-receptors control not only release but also synthesis of histamine at the level of nerve endings and also, presumably, of perikarya. A relationship between the two regulatory processes, possibly via intracellular calcium, seems likely but remains to be investigated at the molecular level.     

Lack of influence of histamine H1-, and H2-receptor antagonists on histamine level in rat brain

The intraperitoneal administration of three antihistaminic drugs of H1 type: mepyramine, diphenyhydramine (each 5 and 30 mg/kg) and danitracen (2 and 10 mg/kg) did not modify histamine level in the rat brain after 2 h. Histamine H2-receptor antagonists: cimetidine (25-250 microgram) and metiamide (100 microgram) given directly into the brain had no significant effect on histamine content after 1.5 h. L-histidine (0.5 g/kg i.p.) increased after 1.5 h histamine level in various experiments by 50-75% above control. All antihistaminic drugs did not change significantly histamine level in the brains of L-histidine-treated rats though a slight but consistent tendency to decrease the L-histidine effect in the group of H2-receptor blocking drugs was observed.     

Studies on the mode of action of histamine H1- and H2-receptor antagonists on gastric histamine methyltransferase

Histamine methyltransferase from pig antrum mucosa was inhibited by 33 H₁-receptor antagonists, by the H₂-receptor antagonists burimamide and metiamide and by the burimamide analogue 5-methylburimamide, which did neither act on H₁-nor on H₂-receptors. Whereas all H₁-receptor blocking agents as well as metiamide and 5-methylburimamide inhibited the enzyme in a competitive manner, the type of inhibition found for burimamide was a mixture of non-competitive and uncompetitive with respect to histamine, which is similar to that one observed with 1-methylhistamine, the product of the histamine methylation reaction. Furthermore, all compounds tested — with the only exception of burimamide — activated the gastric histamine methyltransferase in lower concentrations, the most potent activator being piprinhydrinate (180% increase of the enzyme activity). This enhancement of 1-methylhistamine formation by antihistaminic drugs was not due to a true activation of the enzyme by increasingV _max, but was caused by partially abolishing the inhibition of histamine methyltransferase by so-called optimum concentrations of histamine. Two explanations were given for the different mode of action of burimamide compared with that of metiamide and the other antihistaminic drugs: (1) The change in the type of inhibition from burimamide to metiamide seemed to be due to the introduction of a methylgroup into position 5 of the imidazole ring. (2) Burimamide and 1-, 2- and 3-methylhistamine were the only compounds tested in which the imidazole nucleus was substituted at position 4, but not at position 5, and which thus probably produced substrate or product inhibition.supported by a grant of the Deutsche Forschungsgemeinschaft (Lo 199/3).     

Autoregulation of histamine release in brain by presynaptic H3-receptors

Regulation of histamine release was studied mainly on brain slices prelabeled with L-[3H]-histidine and depolarized by increased extracellular K+ concentration or veratridine in a non-superfused system. The released 3H-labeled amines, isolated by ion-exchange chromatography from a large excess of 3H-labeled precursor consisted by more than 95% of unchanged [3H]histamine. Exogenous histamine reduced the release of neosynthesized [3H]histamine via stimulation of previously characterized H3-receptors whereas it did not modify the 3H-labeled amine release from slices prelabeled with preformed [3H]histamine. The maximal inhibitory effect of exogenous histamine progressively diminished as the strength of the depolarizing stimulus or the external Ca2+ concentration were elevated. On the contrary H3-receptor antagonists like impromidine or burimamide enhanced the depolarization-induced release of [3H]histamine, an effect which was particularly marked when slices were loaded with histamine by preincubation with [3H]histidine in high concentration. These results suggest that the inhibition of [3H]histamine release by exogenous histamine acting via H3-receptor stimulation is mediated by a restricted access of Ca2+ and that its extent is influenced by the degree of autostimulation by endogenous histamine as well as, possibly, by actual internal Ca2+ concentration. In addition the decrease in external Ca2+ concentration shifted rightwards the concentration-response curve to histamine. The autoinhibitory effect of exogenous histamine was found on slices from various regions, known from lesion studies to contain terminals of extrinsic histaminergic neurons. It did not apparently involve interneurones, not being prevented in slices in which the traffic of action potentials was blocked by tetrodotoxin. It also remained unaffected in striatal slices in which the neuronal cell-bodies were selectively destroyed by prior local infusion of kainic acid. Finally exogenous histamine inhibited [3H]histamine release from depolarized synaptosomes of rat cerebral cortex, with an EC50 value similar to that found with slices and was antagonised by impromidine with an apparent Ki value similar to that displayed at H3-receptors. It is concluded that histamine modulates its own release from cerebral neurones by interacting with H3-presynaptic autoreceptors and via mechanisms similar to those previously evidenced on other aminergic systems.     

The effect of group selective reagentsN-ethylmaleimide and dithiothreitol on histamine H1-receptor binding sites in the vascular smooth muscle membranes

The chemical nature of the histamine H₁-receptors of beef aortic membranes has been elucidated by introducing two group selective reagents in the [³H]-mepyramine binding studies: dithiothreitol (DTT), a protein-disulphide group reducing reagent, andN-ethylmaleimide (NEM), a proteinthiol group alkylating agent.In the binding experiments, NEM independently inhibits [³H]-mepyramine binding. The inhibition is time and concentration dependent. DTT on the other hand potentiates the binding of the radioligand to its receptor and changes the affinity of histamine in competing for [³H]-mepyramine binding site. In the DTT-pretreated membranes (100 M), histamine shows a higher affinity for [³H]-mepyramine binding (K _i 0.35 M) than in the untreated membranes (K _i 3.7 M). Comparison of the pharmacological studies on the DTT-treated rabbit aortic strips and above binding studies, revealed a good correlation between the changes in the affinity of histamine for its receptor, when DTT was present. The results suggest an important role of the S-S and SH groups in the function of aortic histamine H₁-receptor.     

The influence of histamine H1-, H2- and H3-receptor antagonists on histamine stimulated NGF release from cultured astrocytes

Inflammation Research -