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.     

Synthesis of two potential NK<Subscript>1</Subscript>-receptor ligands using [1-<Superscript>11</Superscript>C]ethyl iodide and [1-<Superscript>11</Superscript>C]propyl iodide and initial PET-imaging

Background

The previously validated NK₁-receptor ligand [O-methyl-¹¹C]GR205171 binds with a high affinity to the NK₁-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK₁-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK₁-receptor ligands with chemical structures based on [O-methyl-¹¹C]GR205171.

Methods

[1-¹¹C]Ethyl and [1-¹¹C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl-¹¹C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-¹¹C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-¹¹C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-¹¹C]GR205171.

Results

All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-¹¹C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-¹¹C]GR205171.

Conclusion

The propyl-analogue (II) cannot be used for detecting changes in NK₁-ligand levels, while further studies should be performed with the ethyl-analogue (I).

     

Characterization of vascular histamine H1-receptors: Multiple affinity states of aortic histamine H1-receptor

We have shown that [³H]mepyramine labels histamine H₁-receptor-binding sites in bovine aortic membranes. Further characterization of H₁-receptors in this tissue was done by the interaction of an unlabelled histamine receptor agonist or antagonist, with the radioantagonist [³H]mepyramine-binding sites. The competition-binding assays have uncovered differences in the characteristics of the agonist/receptor interaction not shared by antagonists. Agonists interact in the heterogeneous manner with the radioantagonist-labelled sites, showing shallow competition curves with then _H 0.50–0.72, whereas antagonists were devoid of this effect (steeper slopes of the inhibition curvesn _H1). The results suggest the presence in this tissue of multiple affinity states of histamine H₁-receptor, differentiated by high and low affinity for agonists and the same affinity for antagonists.     

Responses to histamine and selective H2-receptor agonists in lung parenchymal strips from normal and sensitized guinea-pigs

Histamine produces concentration-dependent contractions of lung parenchyma strips obtained from normal and sensitized guinea-pigs. The responsiveness of the sensitized lung strips to histamine was significantly increased compared to normal tissues. Clemizole (0.1 M) was equally effective as an H₁-antagonist in normal (dose-ratio 9.12) and sensitized (dose-ratio 9.77) tissues.The concentration-response curves to histamine were displaced to the left by cimetidine (0.1 M to 0.1 mM) with similar dose-ratios in normal and sensitized tissues. Cimetidine enhanced maximal responses to histamine only in normal lung strips. The effects of submaximal equieffective concentrations of histamine were augmented to the same extent by cimetidine (0.1 mM) in normal and sensitized tissues. The responses to histamine were not modified by indomethacin (5 M).The responsiveness and sensitivity of sensitized lung strips to isoprenaline, impromidine, 4-methylhistamine and dimaprit were not different from those of normal tissues. Cimetidine yielded, as antagonist of dimaprit, similar pA₂ values in normal and sensitized tissues.In conclusion, there is no experimental evidence in favour of the existence of an impairment of H₂-receptor activity in sensitized airways. Hyperreactivity to histamine is probably due to differences between normal and sensitized tissues with respect to Ca²⁺ entry and/or intracellular Ca²⁺ release in response to H₁-receptor activation.     

Influence of histamine release on postoperative vomiting (POV) following gynaecological laparoscopic surgery

Objective:The mechanisms leading to the high incidence of postoperative vomiting (POV) after gynaecological laparoscopic surgery are still unknown. The effectiveness of POV-prophylaxis using H₁ + H₂-receptor antagonists has been demonstrated, suggesting a role for histamine in the pathogenesis of POV. However, histamine levels were not measured in these studies. The aim of this study was to investigate the incidence of plasma histamine release and its association with POV after gynaecological laparoscopic surgery. Material or subjects:Twenty-two female patients, aged 20-56 y, classified ASA physical status I or II, undergoing elective gynaecological laparoscopic surgery were enrolled in the study. Blood samples for plasma histamine measurements were drawn at defined time points perioperatively. Emetic symptoms were recorded within the first 24 h after operation. A standardized balanced anaesthesia without any prophylactic antiemetic medication was applied. Formal causality analysis for histamine as a determinant for POV was performed. Results:The overall incidence of POV was 40.9% (9 out of 22 patients). Twelve out of 22 patients (54.5%) demonstrated a histamine release reaction during the whole observation period. Six out of 9 patients with POV (66.7%) had a histamine release. There was no difference in mean plasma histamine levels between POV-positive and POV-negative patients. The conditional probability for POV with histamine release was 6/12 = 0.5, in contrast to 3/10 = 0.3 for POV without histamine release. Conclusions:A high incidence of plasma histamine release was demonstrated in most but not all patients with POV. The probability of POV with histamine release (0.5) was higher than without histamine release (0.3), thus histamine release was shown to be one of the contributory determinants for POV in this clinical study. Thus, patients at risk for POV may benefit from a H₁ + H₂-receptor antagonists prophylaxis alone or in combination with other antiemetic strategies.     

Antihistaminic drugs modify casein-induced inflammation in the rat

Introduction

All known antihistaminics may affect several inflammatory events, including chemotaxis, the survival of eosinophils, and the release of chemokines and cytokines from different sources, thus highlighting the potential for modulating chronic inflammation and immune responses. The aim of the study was to examine the effect of H₁–H₄ antihistaminic drugs in an acute model of casein-induced inflammation in rat.

Materials and methods

Inflammation was induced by injection of a 12% solution of casein into the peritoneal cavity of male Wistar rats. The rats were treated intraperitoneally with pyrilamine maleate (10 mg/kg), cimetidine (25 mg/kg), thioperamide maleate (2 mg/kg) or ciproxifan hydrogen maleate (0.14 mg/kg) twice: 2 hours prior and 4 hours after casein administration. The level of histamine in blood and chemiluminescence of stimulated and unstimulated PMNs was measured.

Results

The level of histamine in the casein-induced inflammation group was higher than in the control group. Treatment with pyrilamine and ciproxifan additionally increased the level of blood histamine during the inflammatory response. Peripheral blood neutrophils from rats with casein-induced inflammation tended to respond less to zymosan stimulation than the neutrophils in the controls. Selective H₁ and H₃ antagonists injected into the rats with casein-induced inflammation significantly increased the response of the neutrophils to zymosan (p < 0.01).

Conclusion

Histamine produced or released into the blood in the course of experimental inflammation exerts its effects on the PMN-s via stimulation of H₁ and H₃ receptors.

     

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.     

Overdose of the histamine H3 inverse agonist pitolisant increases thermal pain thresholds

Objective and design

Pitolisant (BF2.649) is a selective inverse agonist for the histamine H₃ receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H₃-ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models.

Materials and treatments

Behavioral effects of pitolisant and the structural different H₃ receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain.

Methods

Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions.

Results

Clinically relevant doses of pitolisant (10?mg/kg) had no relevant effect on mechanical or thermal pain thresholds in all animal models. Higher doses (50?mg/kg) dramatically increased thermal but not mechanical pain thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In peripheral sensory neurons high concentrations of pitolisant (30–500?μM), but not ciproxifan, partially inhibited calcium increases induced by capsaicin, a selective activator of transient receptor potential vanilloid receptor 1 (TRPV1). High doses of pitolisant induced a strong hypothermia.

Conclusion

The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H₃ receptor-independent.     

In vitro actions of ranitidine,a new histamine H2-receptor antagonist

Ranitidine has been tested on isolated guinea-pig right atrium and rat uterine horn, tissues known to possess histamine H₂-receptors; and on isolated guinea-pig ileum a tissue containing histamine H₁-receptors. These experiments have shown ranitidine to be a potent competitive antagonist of histamine at H₂-receptor sites in vitro. This action is selective since high concentrations of ranitidine do not affect -adrenoceptor, histamine H₁-receptor and muscarinic receptor mediated responses.     

Further characterization of the guinea pig left atrial tension response to histamine by use of selective agonists

1. The responses of guinea pig left atrial tension and right atrial rate to histamine receptor agonists and histamine were compared.
2. Single doses of histamine and another non-selective agonist,N,N-dimethylhistamine, produced biophasic inotropic responses, with an initial increase in tension and a secondary sustained tension increase separated by a negative inotropic component.
3. Selective H₁-receptor agonists — 2-methylhistamine, 3-methylhistamine and 2-pyridylethylamine (2-PEA) — also exhibited biphasic inotropic responses. 2-PEA did so only after blockade with propranolol or in atria from reserpine-pretreated animals, indicating an additional release of endogenous catecholamines which masked the biphasic response.
4. Selective H₂-receptor agonists — 4-methylhistamine and dimaprit — failed to produce biphasic responses except at high concentrations only in the case of 4-methylhistamine.
5. The biphasic responses were converted to monophasic responses by mepyramine. This was a result of antagonism of the initial positive component and the secondary negative component which were therefore mediated via H₁-receptors. The production of a biphasic inotropic response therefore depends upon these two components which were exhibited preferentially by the H₁-receptor-selective agonists.

     

The effects of histamine H2-receptor antagonists on PHA induced lymphocyte proliferation

Histamine H₂-receptor antagonists must be used with caution to define the pharmacology of histamine effects on lymphocyte mitogenesis induced by PHA

1. because they can enhance and/or suppress in their own right,
2. because these effects are similar to those of histamine itself
3. because mitogenic doses of PHA can release significant amounts of histamine from supposedly pure mononuclear cell preparations.

     

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.

     

Histamine modification of spontaneous rate and rhythm in infarcted canine ventricle

1. Histamine (10^?3 M) increased the spontaneous rate similarly in isolated preparations of normal left ventricular tissue from control, i.e. normal and sham-operated, dogs (control preparations) and in preparations consisting of normaland contiguous infarcted left ventricular tissue from dogs with subacute, i.e. 24 hours after left coronary artery ligation, myocardial infarction (infarcted preparations).
2. Histamine (10^?3 M) markedly enhanced the irregular rhythm of infarcted preparations.
3. The H₁-receptor antagonist, chlorpheniramine (10^?4 M), and the H₂-receptor antagonist, cimetidine (10^?3 M), antagonized the effects of histamine (10^?3 M) on the spontaneous rate of both control and infarcted preparations.
4. The H₁-receptor agonist, 2-pyridyl ethylamine (PEA, 10^?4 M), increased the spontaneous rate of control and infarcted preparations; these effects were antagonized by chlorpheniramine (10^?4 M). The H₂-receptor agonist, dimaprit, had no effect.
5. Similar to histamine (10^?3 M), PEA (10^?4 M) enhanced the irregular rhythm of infarcted preparations; dimaprit had no effect.
6. High local concentrations of histamine may occur in poorly perfused ischemic tissue. The enhancement of irregular rhythm produced by histamine, and the specific H₁-receptor agonist, PEA, leads us to suggest its involvement in arrhythmias associated with subacute myocardial infarction.

     

H1+H2-receptor antagonists for premedication in anaesthesia and surgery: A critical view based on randomized clinical trials with haemaccel and various antiallergic drugs

Histamine release by drugs used in anaesthesia and surgery has been often demonstrated in human volunteers, but only occasionally in patients. Three questions arose from these studies. (1) Is the incidence of histamine release high in patients during routine anaesthesia and surgery? (2) Can the clinical effects of histamine release in man be prevented by H₁+H₂-receptor antagonists? (3) Are there any side-effects of such a premedication? These problems were investigated in patients and volunteers by randomized controlled clinical trials using only one of the histamine-liberating drugs in man, the plasma substitute Haemaccel. This drug was chosen because it causes a reproducible histamine release in man and because its mechanism of action in man is largely known.

1. Out of 600 orthopaedic patients 30 (5%) showed anaphylactoid reactions following Haemaccel infusion. 26 of these had a histamine release of more than 1 ng histamine/ml plasma. Using predictive values this gives an efficiency of the test by nearly 98%.
2. In volunteers the combination of an H₁-plus H₂-receptor antagonist (dimethpyrindene and cimetidine) completely prevented the clinical effects of histamine release by Haemaccel (9 allergoid and anaphylactoid reactions in the control group, none in the H₁+H₂-group). The incidence of histamine release, however, remained unchanged.
3. The premedication was found to release histamine itself. Cimetidine was effective when given alone but especially in combination with chlorpheniramine (4 events out of 7 applications). The clinical side-effects of these premedication were mild since apparently the free histamine was largely blocked at the receptor sites.

It is concluded that premedication with a combination of H₁- and H₂-receptor antagonists is indicated due to the high incidence of histamine release during anaesthesia and surgery induced by various drugs and treatments. Such premedication is effective but associated with mild side-effects. For this reason more extended clinical trials with dimethypyrindene plus cimetidine in patients are necessary before this premedication can be generally recommended.     

Effect of a histamine H2-receptor antagonist on immunologically induced mediator release in vitro

The histamine H₂-receptor has been implicated in the autoregulation of endogenous histamine release from actively sensitized human basophils. Consequently, the activity of metiamide (SK & F 92058), a specific histamine H₂-receptor antagonist, was investigated for its effect on immunologically-induced histamine release in several in vitro models of immediate hypersensitivity. Metiamide enhanced the release of histamine from passively sensitized fragmented Rhesus monkey lung and skin when these tissues were challenged in a reversed type anaphylactic reaction with antihuman IgE. The enhancing effect of metiamide on the release of ‘slow reacting substance of anaphylaxis, from monkey lung was considerably less pronounced. In contrast, metiamide failed to significantly enhance the antigen-induced release of histamine from fragmented rat lung which had been passively sensitized with rat anti-ovalbumin serum. The data supports a species-specific enhancement of immunologic histamine release in vitro, perhaps by H₂-receptor blockade on cells responsible for such release.     

A postsynaptic inhibitory histamine H2-receptor in the mouse isolated vas deferens

The effect of histamine on adrenergic neurotransmission in the mouse isolated vas deferens preparation was investigated. Concentrations of histamine ranging from 0.2 to 650 M depressed, in a dose-related manner, not only the contractile response elicited by field stimulation but also the response caused by the addition of exogenous noradrenaline and acetylcholine. However, the release of [³H]-NA evoked by field stimulation or by high K⁺ remained unchanged in the presence of these concentrations of histamine. The inhibitory effect of histamine on the contractile responses caused by various stimuli was reduced or completely antagonized by cimetidine, a histamine H₂-receptor antagonist but not by mepyramine, a conventional antihistamine. The inhibitory effect of histamine was found to be inversely proportional to both the Ca²⁺ concentration in the bathing medium and to the frequency of field stimulation. Further, the inhibitory effect of histamine was markedly reduced when Mg²⁺ was omitted from the bathing medium. It is concluded that the mouse vas deferens preparation contains a post-junctional inhibitory H₂-receptor. The stimulation of H₂-receptors by histamine inhibits the contractile response of the vas deferens, possibly by decreasing the availability of Ca²⁺ required for contraction by depressing the influx of Ca²⁺.     

Effects of the H2-receptor agonist dimaprit on lymphocyte responsivenessin vitro

The histamine H₂-agonist dimaprit was found to increase the response of rat spleen cells to the T-cell mitogen Concanavalin A, when present at concentrations of 10^–5 and 10^–4 M. Higher concentrations of dimaprit were cytotoxic. The enhanced response seemed to be associated with an inhibitory effect of dimaprit on T-suppressor cell activity rather than with a direct mitogen-like stimulation of lymphocyte proliferation or with an interference with monocyte/macrophage functions. The stimulatory effects of dimaprit were not reversed by the H₂-receptor antagonist, cimetidine, nor by the -receptor antagonists metoprolol and H 35/25. Addition of the H₁-receptor antagonist, mepyramine, further increased the stimulatory effect of dimaprit on lymphocyte responsiveness.     

H1- and H2-receptor mediated responses to histamine on contractility and cyclic AMP of atrial and papillary muscles from guinea-pig hearts

On guinea-pig heart we investigated whether cyclic AMP serves as a messenger for H₁- and/or H₂-mediated responses to histamine.

1. On papillary muscle histamine elicited positive inotropic responses which were antagonized by burimamide but not by promethazine. The stimulation of H₂-receptors was not only associated with an increase in contractility but also with an increase in cAMP. As shown by the time course of effects for 10^?5 M histamine, the maximal increase in cAMP preceded the maximum in contractility. The mechanical and biochemical responses to histamine were potentiated by the phosphodiesterase inhibitor papaverine, but antagonized by burimamide.
2. On the left guinea-pig atrium containing H₁-receptors the inotropic response to histamine (10^?5 M) was not accompanied by increases in cAMP at stimulation frequencies of 0.5 and 2 Hz, respectively. In addition, in the presence of papaverine (3×10^?5 M) no change in the cyclic AMP level occurred after application of histamine. Papaverine by itself, however, concomitantly increased contractility and cyclic AMP at a stimulation frequency of 0.5 Hz. In contrast, at 2 Hz papaverine increased only cAMP leaving the contractility unchanged. At this frequency the well-known Ca²⁺-antagonistic effect comes into prominence, thus masking the positive inotropic effect atributable to the inhibition of the phosphodiesterase.
3. On the right guinea-pig atrium the mediation of the positive charonotropic response to histamine by H₂-receptors which is partly involved in the inotropic effect via the frequency-force relationship does not lead to a concomitant increase in cAMP. Also, in the presence of papaverine, histamine had no influence on the cAMP. However, papaverine potentiated the cardioacceleration produced by histamine. Although it is very likely that the cAMP in the sinus node rises, we were not able to detect an increase in cAMP in the whole atrial tissue.

From the present results the conclusion can be drawn that the mediation of the inotropic effect due to stimulation of H₂-receptors by histamine is associated with an increase of cyclic AMP, whereas that of H₁-receptors is not. The view that cAMP may be the second messenger in the chronotropic action of histamine needs further elucidation by experiments on sino-atrial cells.     

Histamine H3-receptor activation inhibits acetylcholine release from the guinea pig myenteric plexus

The role of histamine H₃-receptors in the control of acetylcholine release from peripheral cholinergic neurons was evaluated in the isolated guinea pig ileum, previously loaded with³H-choline. When tested in the presence of H₁- and H₂-blockade, histamine (0.1–100 mol/l) and (R)-methylhistamine (0.01–1 mol/l) dose-dependently reduced the electrically-evoked choline outflow, with (R)-methylhistamine being a partial agonist. Selective H₃-receptor blocking drugs, thioperamide (0.1 mol/l) and impromidine (0.1 mol/l) reversed the histamine-induced inhibitory, effect. These data suggest that intestinal cholinergic nerves are endowed with histamine H₃-receptors whose activation produces an inhibitory effect upon acetylcholine release. The practical implications of these findings are obvious.