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

Inflammation Research -     

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).     

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.     

Prevention of anaphylactoid reactions after radiographic contrast media infusion by combined histamine H1- and H2-receptor antagonists: results of a prospective controlled trial

In a prospective randomized trial, 800 patients undergoing intravenous urography were pretreated with either intravenous prednisolone (group I), the H1-antagonist clemastine (group II), a combination of clemastine and the H2-antagonist cimetidine (group III) or 0.9% saline (group IV). There was an overall incidence of 18 - 19% side reactions, when subjective and objective symptoms were regarded together. There was no significant difference between the four groups in the total incidence. The same applies when considering subjective side effects including the symptom 'heat sensation' that occurred in 10 - 12% of all patients. However, when side effects excluding the symptom 'heat sensation' were regarded and the individual groups were compared, there was a significant difference in frequency between the control group (12%) and the combined H1/H2 group (6%). Prednisolone and clemastine did not produce a significant reduction of side effects. The combined application of histamine H1- and H2-antagonists might be useful in prophylaxis of radiographic contrast media-induced adverse reactions.     

Effects of histamine H1- and H2-receptor antagonists on cardiovascular function during systemic anaphylaxis in guinea pigs

The heart is a target organ of anaphylaxis. In isolated perfused hearts, an anaphylactic reaction is characterized by arrhythmias, coronary constriction, and severe impairment of ventricular contractile force. Various mediators such as PAF, thromboxane A₂ and leukotrienes, are responsible for anaphylactic coronary constriction and negative inotropic effects. The cardiac effects of anaphylactic histamine release are related to the stimulation of two antagonistic receptor types. Histamine induces atrioventricular conduction delay and constriction of the epicardial coronary vessels via H₁-receptor stimulation. H₂-receptors, however, mediatecoronary vasodilation and an increase in heart rate and myocardial contractility. It may therefore be concluded that administration of histamine H₂-receptor antagonists is disadvantageous. During anaphylactic states, the cardiodepressive effects of the other mediators of anaphylaxis are unmasked, resulting in a sustained coronary constriction and impairment of myocardial contractility. To verify this speculation, we investigated the effects of H₁- and H₂-receptor antagonists on cardiovascular function of guinea pigs during systemic anaphylaxis.In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed administration of the antigen induced severe cardiac dysfunction. Within a few minutes, cardiac output markedly decreased and left ventricular end-diastolic pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of an atrioventricular block. After 4 min, blood pressure rapidly declined. All animals died within 12 min. Pretreatment with the selective H₁-receptor antagonist astemizol (5 mg/kg i.v.) delayed the onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, left ventricular contractility and blood pressure steadily declined, leading to severe hypotension within 30 min. In the case of a pretreatment with astemizol (5 mg/kg i.v.) and the H₂-receptor antagonist famotidine (10 mg/kg i.v.), no relevant changes of cardiovascular function were seen compared to pretreatment with astemizol alone. It is therefore concluded that endogenous histamine, via H₁-receptor stimulation plays an important part during the early phase of systemic anaphylaxis, whereas mediators other than histamine are involved at a later stage of the process. Furthermore, H₂-receptor-mediated effects are of minor importance in cardiovascular manifestation of anaphylaxis. Pretreatment with H₂-receptor antagonists has no detrimental effects on cardiovascular function during anaphylactic reactions in guinea pigs underin vivo conditions.Supported by grant Fe250/1-1 from the Deutsche Forschungsgemeinschaft (DFG).     

Pharmacological characterization of histamine receptors in the mouse seminal vesicle: Sensitivity to H1- and H2-receptor agonists and antagonists

Neither histamine nor the more specific H₁- or H₂-receptor agonists (0.2–220 M) produced a contraction of the mouse seminal vesicle. However, all these agonists decreased resting tone and caused a dose-related inhibition of the electrically evoked twitch responses in these concentrations. The slopes of the percentage response versus log molar concentration curves for all agonists did not differ significantly from that of histamine. The rank order and relative potency of the compounds tested were: histamine (100%)>dimaprit (65%)4-methylhistamine (36%)>2-methylhistamine (4.5%)>2-(2-thiazolyl) ethylamine (1.7%). Inhibition of the twitch response by histamine was antagonized by cimetidine (3.5–140 M) but not by mepyramine (0.1–1.0 M). The slopes of Schild plots for cimetidine against histamine and dimaprit did not differ from unity, and the calculated pA₂ values of cimetidine were 5.70 and 5.55, respectively. Histamine (2.2 and 6.5 M) inhibited the contraction elicited by a submaximal concentration of exogenous noradrenaline (1 M); this inhibition could also be selectively antagonized by cimetidine. These results demonstrate that histamine and selective H₁- and H₂-receptor agonists have an inhibitory action on the mouse seminal vesicle, and that this action is mediated via a post-junctional H₂-receptor. The calculated pA₂ values of cimetidine against histamine and dimaprit also suggest that the receptor in the mouse seminal vesicle is of the conventional H₂-type. The results further indicate that an H₁-receptor is absent in the mouse seminal vesicle.     

Chemotactic activity of guinea pig eosinophils for the ECF-A acidic tetrapeptides, histamine, histamine metabolites, and the effect of H1- and H2-receptor antagonists.

Histamine and one of its major metabolites, imidazoleacetic acid, were selectively chemotactic for guinea pig eosinophils, whereas L-histidine, 1,4-methylimidazoleacetic acid, 1,4-methylhistamine and N-acetylhistamine were inactive. The response to histamine was unaffected by concentrations of eosinophils of between 30 and greater than 90% but it was abrogated by preincubation of the cells with histamine prior to assay (self-deactivation). Eosinophilotaxis was also inhibited by H1-(mepyramine-) and H2-)burimamide)-receptor antagonists at high doses (10(-3)m), although at lower concentrations (10(-5) M) inhibition was principally associated with burimamide. The human tetrapeptide, alanine-glycine-serine-glutamic acid, and the analogue, valine-glycine-aspartic acid-glutamic acid, were inactive whereas alanine-glycine-serine-glutamic acid was chemotactic for the guinea pig eosinophil. These results support the concept that the tissue accumulation of eosinophils following anaphylaxis depends on a complex interaction of factors, which in part may be mediated by H2 receptors on the target cells. There may be species differences in the composition of ECF-A.     

Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H1- plus H2-receptor antagonists: Synopsis of three randomized controlled trials

Summary To demonstrate the efficacy of a premedication with H₁- +H₂-receptor antagonists against histamine-release responses in anaesthesia and surgery 3 randomized controlled trials were conducted in patients, volunteers and experimental animals (dogs). Cutaneous anaphylactoid reactions following infusion of polygeline (Haemaccel^®) in orthopedic patients were successfully abolished by premedication with 0.1 mg/kg dimethpyrindene (Fenistil) and 5 mg/kg cimetidine (Tagamet). Chlorpheniramine (Piriton) was also useful, but dimethpyrindene was more effective in the doses recommended and used. Side-effects of the premedication were not observed when the 2 drugs were slowly administered (2 min each).Systemic anaphylactoid reactions following infusion of polygeline were completely prevented in volunteers by the same premedication (0.1 mg/kg dimethpyrindene and 10 mg/kg cimetidine). Life-threatening reactions could not be tested in human subjects, but were elicited in experimental animals (dogs). In this species which resembles man in its sensitivity against histamine, in plasma histamine levels and in response to polygeline life-threatening reactions were prevented or in especially severe cases diminished to such an extent by the premedication with H₁- +H₂-blockers that this premedication was finally judged to be very effective against histamine-release responses of any grade of severity.To confirm this clinically very important hypothesis more clinical trials in patients at risk for anaphylactoid reactions to drugs are urgently needed.Supported by Grant of Deutsche Forschungsgemeinschaft (Lo 199/10 and Lo 199/13-6)     

Histamine release with intravenous narcotics: Protective effects of H1 and H2-receptor antagonists

Summary High dose narcotic anesthesia with fentanyl or morphine is not associated with significant direct myocardial depression. Morphine is reported to produce arteriolar dilatation and a decrease in SVR (probably due to histamine release) while fentanyl is not. Studies were undertaken to determine if morphine or fentanyl caused histamine release; if such a release correlated with hemodynamic changes, and if H₁ and H₂ antagonists could provide protection. In a randomized double blind study of 40 patients in 4 groups, patients who received morphine (1 mg/kg) demonstrated significant increases in plasma histamine (880±163 to 7,437±2,684 pg/ml–p<0.01) accompanied by an increase in CI (2.4±0.2 to 3.0±0.2 l/min/m²–p<0.01) and decreases in (88±4 to 61±4 torr–p<0.01) and SVR (15.5±1 to 9.0±1 torr-l-min^–1 p<0.01). The prior administration of H₁ (dyphenhydramine 1 mg/kg) and H₂ (cimetidine 4 mg/kg) antagonists provided significant protection (SVR 17.4±1 to 14.6±1 torr-l-min^–1–p<0.05) although histamine increased comparably (1,059±22 to 7,653±4,242 pg/ml–p<0.05). In a separate study, seven patients receiving fentanyl 50 µg/kg showed no histamine changes (935±51 to 685±51 pg/ml) and no significant hemodynamic response. Eight patients receiving morphine 1 mg/kg again showed significant increases in plasma histamine (880±163 to 7,480±2,230 pg/ml–p<0.05) which collelated with the decrease in SVR (r=0.81). These data demonstrate that morphine releases histamine in amounts which correlate with the hemodynamic changes seen. Prior administration of H₁ and H₂ histamine antagonists provide significant protection — more so than either alone. Fentanyl produced no histamine release which may account for much of the cardiovascular stability reported with this drug.     

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.     

Histamine release in anaesthesia and surgery. Premedication with H1- and H2-receptor antagonists: Indications,benefits and possible problems

Summary Our clinical and experimental studies have so far demonstrated, that the drugs used in anaesthesia; such as hypnotics, sedatives, narcotics or muscle relaxants, release histamine.The intravenous short acting anaesthetic etomidat has not shown either in experimental studies or in clinical use for 10 years any anaphylactoid reaction. The benzodiazepines are another group of drugs which appear not to release high amounts of histamine.Accurate studies on volunteers as well as on patients on the application of H₁- and H₂-receptor antagonists have demonstrated an effective inhibition of the anaphylactoid reaction. We suggest that in case of a history of allergy H₁- and H₂-receptor antagonists should be administered as a prophylactic premedication.Supported by Grant of Deutsche Forschungsgemeinschaft (Lo 199) 13-6     

Histamine response to various stimuli during CABG-surgery: A study in patients with and without prophylactically administered H1- and H2-receptor antagonists

Inflammation Research -     

Central effects of histamine H2-receptor agonists and antagonists on nociception in the rat

The effects of intracerebroventricular injection of histamine H₂-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H₂-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SK&F 91487 on hot-plate latency in rats were examined. Both DIM (0.4–0.8 mol/rat) and 4-MeH (0.4–0.8 mol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H₂-antagonists CIM (0.8 mol/rat) and RAN (0.6 mol/rat) also enhanced the pain threshold, while FAM (0.03 mol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H₂-receptors and that the activation of HA-H₂-receptors is inhibitory to nociception.     

Electrophysiological actions of histamien and H1-,H 2-receptor antagonists in cardiac tissue

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results:

1. Histamine and the H₂-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments.
2. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD₉₀) in atria. Histamine effects in atrial myocardium are completely reversed by the H₁-antagonist dimetindene. Stimulation of atrial H₁-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content.
3. Histamine reduces AH-interval, increases \(\dot V_{max} \) of NH — cells and may induce AV — node arrhythmias (at concentrations ≥ 3 μmol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV — nodal conduction via H₂-receptors.
4. Unspecific membrane actions of cimetidine are not observed up to 100 μmol/l. Dimetindene increases action potential duration (APD) in left atria and decreases \(\dot V_{max} \) at concentrations ≥ 10 μmol/l. However, H₁-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA₂—values 8.39–9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.

     

Effect of H1- and H2-receptor antagonists on the hemodynamic changes induced by the intravenous administration of ketamine in sevoflurane-anesthetized cats

Objective: The anesthetic ketamine has been reported to cause both an increase of the plasma histamine concentration, notably in cats, and a cardiovascular depression. The latter has been described in humans and in other species. However the relevance of the histamine fluctuation for the ketamine-induced hemodynamic changes has not been determined.Subjects and treatment: We studied the contribution of histamine to the hemodynamic effects induced by IV ketamine (7 mg/kg) in 12 sevoflurane anesthetized cats, of which half had been pre-treated with combined H₁- and H₂ -receptor antagonists.Methods: The mean arterial pressure (MAP) and the heart rate (HR) from both untreated (group C) and pre-treated (group AH) cats were recorded before and after the ketamine administration. The plasma histamine concentration was also measured.Results: Plasma histamine fluctuations in the control and the antihistamine-treated group followed a similar pattern (no statistical differences); an initial rise that peaked 2 min after ketamine injection (from 0.63 ± 0.11 ng/ml to 2.22 ± 0.69 ng/ml in the C group, and from 0.71 ± 0.10 ng/ml to 1.09 ± 0.28 ng/ml in the AH group) followed by an immediate decrease in plasma concentrations. As for the hemodynamic variables under analysis, in the control group ketamine administration was followed by an early 30.3 ± 8.1% reduction (p < 0.005) in the MAP with no associated changes in the HR. In the antihistamine pre-treated group, ketamine caused a further decrease of the MAP (41.7 ± 2.3%), and a significant (p < 0.01) 11.6 ± 2.9% reduction of the HR.Conclusion: Ketamine in anesthetized cats triggers histamine release and induces cardiovascular depression. The depression is more pronounced under the blockade of histamine activity through histamine receptor antagonists.Received 22 October 2004; returned for revision 5 January 2005; accepted by A. Falus 14 February 2005