Effects of histamine on the circulatory system

Summary Experiments have been made in anaesthetised cats and dogs and in healthy, human volunteers to compare the changes in blood pressure and heart rate during systemic administration of histamine.Histamine, 1×10^–9 to 1×10^–7 mol/kg/min, lowered blood pressure in a similar dose-dependent fashion in all three species. In man and the cat this was accompanied by clear dose-dependent tachycardia whereas in the dog heart rate changes were minimal.Pharmacological analysis of the depressor responses to histamine in all three species and the reduction in total peripheral resistance in the cat and dog showed that the immediate responses to histamine in all three species involved H₁-receptors and that sustained responses involved H₂-receptors. Abolition of responses to histamine throughout infusions required H₁- and H₂-receptor blockade.Histamine antagonists, used in doses which cause abolition of cardiovascular responses to large doses of histamine, do not cause any significant change in the resting cardiovascular system.     

Activation of histamine H<Subscript>1</Subscript>-receptor enhances neurotrophic factor secretion from cultured astrocytes

Objective:Histamine stimulates nerve growth factor (NGF) secretion from cultured astrocytes. Histamine H₁-receptor antagonists completely block its effect. In the present study, we determined the involvement of histamine-receptor subtypes in this process.Materials and methods:Radioligand-binding assay was used to establish the presence of histamine H₁- and H₂-receptors on new-born rat cortical astrocytes in primary culture. Histamine H₁-, H₂- and H₃/H₄-receptor ligands, and highly selective protein kinase C (PKC) inhibitor were used to influence NGF secretion from cultured astrocytes. NGF, released into the culture medium, was measured by NGF-ELISA.Results:Histamine H₁-receptor agonists (histamine, selected histaprodifens) increased the secretion of NGF from cultured astrocytes in a concentration-dependent manner. H₁-receptor antagonists/inverse agonists (mepyramine, triprolidine) and PKC inhibitor completely blocked the effect of histamine. Histamine H₂- and H₃-receptor agonists did not enhance NGF secretion significantly. In addition, H₂- and H₃/H₄-receptor antagonists did not diminish histamine-stimulated NGF release.Conclusions:Our results indicate that histamine H₁-receptor and PKC are involved in the signal transduction pathway, responsible for histamine-stimulated NGF secretion from cultured astrocytes.Received 25 July 2003; returned for revision 4 November 2003; accepted by A. Falus 23 December 2003     

Dysrhythmias caused by histamine release in guinea pig and human hearts

Summary Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heartin vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heartin vitro.Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H₁ and H₂ antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine.We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.Post-Doctoral Research Fellow supported by 1F32 HL 05536     

Histamine-stimulated production of matrix metalloproteinase 1 by human rheumatoid synovial fibroblasts is mediated by histamine H1-receptors

The purpose of this study was to investigate the role of histamine in human rheumatoid synovial fibroblasts in the production of factors responsible for tissue remodelling and cartilage breakdown in rheumatoid arthritis. We examined the effects of histamine of tritiated thymidine incorporation, production of matrix metalloproteinase-1 (MMP-1), histamine H₁-receptor expression, phosphoinositide metabolism and intracellular calcium ion concentration ([Ca²⁺] _i ) in human rheumatoid synovial fibroblasts. Tritiated thymidine incorporation studies demonstrated that histamine markedly stimulated the proliferation of rheumatoid synovial fibroblasts. Immunofluorescence and Northern blot analyses revealed that proMMP-1 production was also stimulated by histamine. The levels of inositol phosphates and [Ca²⁺] _i in the cells were elevated in response to histamine, indicating that the cells expressed histamine H₁-receptors; and Northern blot analysis indicated that these H₁-receptors were up-regulated by histamine. In in situ hybridization, large amounts of histamine H₁-receptor mRNA were also detected in rheumatoid synovial tissue. These results suggest that the interaction between H₁-receptor expression in rheumatoid synovial fibroblasts and histamine secretion by mast cells and macrophages in the affected sites is an important event responsible for tissue remodelling and joint destruction in rheumatoid arthritis.     

Reticuloendothelial system function and histamine release in shock and trauma: Relationship to microcirculation

Summary The material reviewed, and presented, here lends credence to the concept that the severity or course of the shock syndrome can be evaluated, quantitatively, at a tissue level by assessing RES phagocytic function. In general, the available data indicate that RE cell stimulants can adapt animals (and probably man) to the insults of circulatory shock and trauma; such substances could have important value in pretreating patients scheduled for massive surgery. The fact that a number of biologically active materials with vasotropic, and RE cell depressant, effects appear in the tissues and blood in shock, particularly when the organism becomes refractory to therapy, suggests that the final functional deterioration of the cardiovascular system may be due to the specific action of one or more of these biologically active materials; such a contender is, without doubt, histamine.Histamine has all the attributes of a typical shock-toxin. Evidence is presented that histamine can be a potent splanchnic (shock target-organ) arteriolar (microcirculatory) dilator even in physiologic (circulating) concentrations. Concentrations of histamine found in plasma of shocked animals and human subjects would produce extremely potent splanchnic vasodilator actions at the microcirculatory level. Evidence is also presented to indicate that microvessels can synthesize and release free, pharmacologically-active histamine.Endogenous release of histamine (e.g., with compound 48/80) produces dose-dependent and lethal shock-like anaphylactic actions; such release also produces, dose-dependently, RES phagocytic depression. Repeated administration of the histamine releaser, compound 48/80, results in almost a 400% enhancement of RES phagocytic function and cross-tolerance to lethal doses of whole-body trauma. Such results raise the possibility that the RES plays a pivotal role in the circulatory manifestations of compound 48/80 and anaphylactic-type (histamine release) shock syndromes.Evidence is presented to indicate that H₁-receptor antihistamines can ameliorate circulatory shock (and trauma) and prevent RES phagocytic depression, whereas H₂-receptor antihistamines do the reverse. Direct in situ microscopy revealed that the former types of histamine receptor blockers prevent tissue ischemia, whereas H₂-receptor blockers exacerbate tissue ischemia in circulatory shock. Histamineinduced vasodilatation via H₂-receptors may thus be a beneficial effect in circulatory shock and trauma; one must think seriously about the potential value of antihistamines as adjuvant drugs in the treatment of low-flow states and as preoperative medication.Collectively, the data reviewed herein could be taken as strong support for a pivotal role for the release (and possible synthesis) of free, pharmacologically-active histamine in shock.Supported by Research Grants H1 18002, HL 18015 and DA 02339 from the U.S.P.H.S.     

Presynaptic histamine H2 receptors modulate the sympathetic nerve transmission in the isolated rat vas deferens; no role for H3-receptors

The modulatory activity mediated by histamine receptors on the sympathetic nerve transmission was investigated in the rat vas deferens. Agonists and antagonists acting at the different histamine receptor subtypes (H₁, H₂ and H₃) were tested on electrically-driven preparationsin vitro. Low-frequency stimulation (0.1 Hz) evoked muscle contractions almost completelysustained by ATP release, while at high-frequency stimulation (5–10 Hz) norepinephrine was mainly involved. The H₁ receptor agonists, pyridilethylamine and 2-(2 aminoethyl)thiazole, enhanced the electrically evoked twitch responses, but not contractions induced by exogenously-applied norepinephrine and ATP. These effects were prevented by the H₁-blocking drugs, mepyramine and phenyramine, but only at high concentrations (10 mol/l). All these H₁-antagonists strongly enhanced muscle response to electrical stimulation. The H₂ receptor agonists, dimaprit, amthamine and impromidine, reduced the contractions evoked by field stimulation, but not by exogenously applied norepinephrine and ATP, the effect being antagonised by H₂-blocking drugs, ranitidine and famotidine. The H₃ receptor agonist,R()-methylhistamine, reduced the electrically evoked muscle contractions, the effect being not modified by the selective H₃-blocking drug, thioperamide, but prevented by famotidine. These data suggest that rat vas deferens contains presynaptic histamine H₂ receptors, able to mediate inhibitory effects on the sympathetic transmission, while histamine H₃ receptors are apparently not involved. On the contrary, the role of H₁ is still unclear, since both agonists and antagonists may have the same effects.     

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     

Polyclonal anti-histamine H<Subscript>2</Subscript> receptor antibodies detect differential expression of H<Subscript>2</Subscript> receptor protein in primary vascular cell types

Objective and Design:One of the factors defining cellular response might be the distribution and density of receptor subtypes on cell membranes. It was our aim to quantify and compare histamine H₂ receptor expression in primary vascular cell types. We have therefore generated antibodies directed against the second extra-cellular loop of the H₂ receptor.Methods:The specificity of polyclonal anti-H₂ receptor antibodies designed for this purpose was examined by Western blot analysis and immunohistochemistry. H₂ receptor expression was quantified by ELISA. Regulation of H₂ receptor gene expression was analyzed by competitive RT-PCR.Results:Our results indicate that the polyclonal antibodies specifically interact with the histamine H₂ receptor. Furthermore, utilizing these antibodies we were able to show significant differences in H₂ receptor levels in human umbilical arterial and vein endothelial cells as well as smooth muscle cells.Conclusions:We conclude that the antibodies generated against the extra-cellular domain of the H₂ receptor are specific and can be utilized to detect and quantify H₂ receptor expression. Furthermore, the significant differences in H₂ receptor expression in different vascular cell types might play a critical role in defining histamine induced cellular responses during physiological or pathophysiological processes.Received 25 August 2003; returned for revision 10 October 2003; accepted by A. Falus 22 December 2003     

Effects of histamine on hippocampal pyramidal cells of the rat in vitro

Summary The actions of bath applied histamine on CA1 pyramidal cells were investigated in hippocampal slices of the rat. Histamine caused a) a slight depolarization but no significant change in resting membrane conductance; b) an abbreviation of long afterhyperpolarizations after single action potentials, bursts of action potentials or TTX resistant spikes; c) a loss of accommodation of firing. In the presence of TEA or barium, histamine prolonged and increased the size and number of the slow TTX resistant spikes. A depolarizing plateau which follows such spikes was also increased by histamine. Evoked synaptic potentials were unaffected by histamine, but the population spike was increased. The frequency of spontaneous chloride dependent potentials, which reflect interneurone firing, was also increased. These effects considerably outlasted histamine application and were mimicked by the H₂-agonist impromidine but not the H₁-agonist thiazolethylamine, and blocked by the H₂-antagonists cimetidine and metiamide but not the H₁-antagonists mepyramine or the beta-antagonist propranolol. It is concluded that histamine, by activating H₂-receptors, antagonizes a calcium mediated potassium conductance in hippocampal pyramidal cells without affecting calcium current. By this mechanism histaminergic afferent fibres could effectively regulate cortical responsiveness by selectively potentiating large excitatory inputs of target neurones.     

Histamine H2-receptor antagonists and gastric acid secretion — A progress report

Summary Histamine H₂-receptor antagonists, including burimamide, metiamide and cimetidine, are effective antagonists of histamine-stimulated acid secretion from mammalian, avian or reptilian gastric mucosa. Acid secretion stimulated by gastrin or pentagastrin is also inhibited by these drugs, but there is disagreement about the effects of these drugs on acid secretion resulting from activation of acetylcholine receptors. Based on the pharmacological evidence possibilities of treatment by these drugs were discussed in cases with excessive stimulation of acid secretion due to high blood levels of histamine or gastrin. The positive results in several trials on Zollinger-Ellison syndrome and peptic ulcer were very impressive. Some practical problems have still to be solved, for example the appropriate phase for applying the drugs. The demonstrated clinical effectiveness, however, against peptic ulceration offers a clear alternative to surgery for many patients.Presented at the meeting on Gastric and duodenal ulcer disease: Basic principles and clinics of treatment by drugs and operations, Marburg, November 22, 1975     

The source and action of histamine in the isolated guinea-pig gallbladder

We have investigated the effects of histamine on motility of the gallbladder and characterized the receptor types involved. Histamine and the histamine H₁-receptor agonist, 2-thiazolylethylamine (2-TEA) contracted the isolated guinea-pig gallbladder strip in a dose dependent manner. The contractile response to histamine was shifted to the right by the H₁-receptor antagonist, mepyramine. In pre-contracted gallbladder strips, the H₂-receptor agonist dimaprit reduced the tension generated in a dose dependent fashion. The histamine H₂-receptor antagonist, ranitidine shifted the histamine concentration effect curve to the left and attenuated the dose dependent relaxations elicited at high concentrations. The histamine H₃-receptor agonist, (R)--methylhistamine (RMHA) elicited dose dependent contraction of the tissue which was significantly inhibited in the presence of mepyramine. The effects of electrical field stimulation (EFS) on the strips were not significantly altered by the presence of RMHA (10^–10–10^–7 M) indicating little pre-synaptic H₃ activity in this tissue. Histamine immunoreactivity (IR) was detected in gallbladder whole mount preparations of the mucosa and the muscularis/serosa. The histamine IR appeared cell bound in cells of varying morphological characteristics but no IR was detected in nerve fibres or cell bodies (ganglia). Alcian blue staining was consistent with the distribution of histamine IR cells as mast cells. The results indicate that histamine is distributed in the guinea-pig gallbladder and it can regulate contractile activity via activation of H₁ and H₂ but not H₃ receptors.     

Histaminwirkungen am Herzen unter besonderer Berücksichtigung kardialer Nebenwirkungen von H2-Rezeptor-Antagonisten

Summary The existence of cardiac h₁- and h₂-receptors is evidenced by pharmacologic studies. Despite of the relatively high content of cardiac histamine it is not clarified whether histamine actually plays a physiologic role — apart from pharmacologic effects — in the regulation of myocardial function and coronary blood flow. Under pathophysiologic conditions (during anaphylaxis, surgical procedures, accidents, stress etc.), however, when a local or systemic histamine release occurs both hemodynamic and arrhythmogenic effects are evident. Numerous studies in animal models conclusively demonstrated a role of cardiac histamine as a major mediator of serious arrhythmias. Consequently, a combination of h₁- and h₂-receptor antagonists (f.e. Dimetinden/Cimetidin) was recommended as a prophylactic treatment against severe anaphylaxis including life-threatening arrhythmias for cardiac patients at risk.There is pharmacologic evidence of both a positive inotropic and chronotropic effect in the human heart via h₂-receptor and stimulation of adenylate cyclase. Histamine-induced coronary effects such as vasoconstriction via h₁-receptor and coronary dilatation via h₂-receptor are not yet sufficiently validated. Studies on the human heart in vitro using coronary strips from explanted hearts and in vivo investigations on the intact coronary system yielded conflicting results.H₂-receptor blocking agents cimetidine, ranitidine and famotidine have qualitatively a different pharmocodynamic spectrum of side effects due to differences in chemical structure. Data on cardiac arrhythmias are mostly associated to cimetidine. Symptomatic bradycardia were reported for both ranitidine and cimetidine. A possible negative inotropic effect of famotidine, although presently not validated, requires further studies.— Causative and adverse side effects of cimetidine on the cardiovascular system, however, are to be expected extremely seldom due to easily reversible competetive h₂-receptor binding. For prophylaxis rapid intravenous injections of h₂-blockers, particularly in elder patients with cardiac diseases, should be avoided. Compared to cimetidine, a tendency of explainable difference seems to become apparent for ranitidine and famotidine due to higher receptor affinity.

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Abkürzungsverzeichnis A Atrium - AVN AV-Knoten - HF Herzfrequenz - V Ventrikel     

Analysis of histamine and modeling of ligand-receptor interactions in the histamine H<Subscript>1</Subscript> receptor for Magic Angle Spinning NMR studies

Objective and Design: Investigation of the principles of ligand-receptor interaction in histamine receptors can help to provide a solid foundation for structure-based drug design. Stable isotope labelling of the ligand 'Histamine' has been performed and 1D ¹³C CP MAS and 2D Radio Frequency Dipolar Recoupling (RFDR) spectra for the ligand are presented. Hyperfine signals were well spread and did not suffer from any sizable line broadening. The production of H₁ receptor for Magic Angle Spinning NMR studies is currently in progress. Treatment: An agonist binding domain is proposed using homology modeling, database searches and mutagenesis data for the H₁ receptor. Methods: Homology modeling, Database searches for Expressed sequence Tag (ESTs), Magic Angle Spinning Nuclear Magnetic Resonance analysis of the ligand histamine. Results: The three-dimensional receptor model and mutagenesis studies suggest that the amine of the agonist histamine may form an ion pair with the TM III Asp, whereas the imidazole ring of histamine may associate with TM V Asp and Thr. Conclusions: Homology modeling studies confirms the absence of TM VIII in the H₁ receptor. According to the model the histamine in particular interacts with the transmembrane (TM) regions of the H₁ receptor structure, in particular TM helix III and V. This is in line with recent mutagenesis studies. Database search methods for ESTs have been used for electronic prediction of tissue distribution of H₁ receptor expression. The results indicate that the H₁ expression is highest in heart and skeletal muscle, which may be of importance for drug targeting.Received 3 June 2003; accepted by A. Falus 3 June 2003     

Flush induced by fluoroquinolones in canine skin

The flush induced by two fluoroquinolone antibacterial agents, balofloxacin and ofloxacin, was studied in beagle dogs. Intradermal injection of the fluoroquinolones at concentrations above 10^–5M produced a localized flushed area. The flush responses to fluoroquinolones were inhibited by co-administration with H₂-antagonist(s) (ranitidine or cimetidine), but not with H₁-antagonist(s) (mepyramine or chlorpheniramine). Similar inhibitory effects of these H₂-antagonists were observed for the response to histamine. The flush responses to fluoroquinolones were inhibited by a local pretreatment with compound 48/80 administered to deplete the local stores of mast cell-bound histamine. When the fluoroquinolones were orally administered at a dose of 400 mg/kg, the concentration of histamine in plasma was increased, being accompanied by systemic erythema. These results indicate that the flush induced by fluoroquinolones is mediated by histamine release from canine cutaneous mast cells and H₂-receptor stimulation.     

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 increases anti-CD3 induced IL-5 production of TH2-type T cells via histamine H2-receptors

Besides its proinflammatory functions histamine released from basophils and mast cells during immediate-type hypersensitivity reactions is known to inhibit several lymphocyte functions like IL-2 and -IFN production. Recently, it has been shown that T helper cells of type 2 phenotype (T_H2) represent the T cell fraction which may play a pivotal role in the promotion of the allergic inflammatory eosinophilic late-phase reaction by secretion of cytokines, especially IL-4 and IL-5. We have investigated the effect of histamine on anti-CD3 induced IL-4 and IL-5 production by T_H2 cells. Histamine in concentrations between 10^–7 and 10^–5 mol/l concentration-dependently increased anti-CD3 induced IL-5 production up to 120%, whereas IL-4 production was not affected. The activity of histamine in increasing IL-5 production was mimicked by the H₂-receptor agonist dimaprit. Histamine induced increase in IL-5 production was inhibited by histamine H₂-receptor antagonists, but remained unaffected by H₁- or H₃-receptor antagonists. Administration of forskolin which directly stimulates the production of cAMP, the second messenger of the H₂-receptor, also resulted in an increase in anti-CD3 induced IL-5 production. These results indicate that the histamine-mediated increase in anti-CD3 induced IL-5 production is mediated via H₂-receptors. Consequently, histamine released from mast cells and basophils during the early-phase allergic reaction may act as an important stimulatory signal for the initiation of the allergic inflammatory late-phase reaction by increasing local IL-5 production of allergen triggered T_H2 cells.     

Influence of prostaglandin-synthesis inhibitors on carbachol-and histamine-induced vasodilatation in perfused rat hindquarters

In perfused rat hindquarters, in which vascular tone was maintained by norepinephrine, carbachol-induced dilatations were blocked by atropine (10^–7 M), while histamine dilatations were inhibited as well by mepyramine (10^–6 M) as by cimetidine (10^–5 M) indicating a histamine effect through both H₁- and H₂-receptors. This double-receptor histamine effect was confirmed by the observation that speccific H₁- and H₂-receptor agonists, respectively PEA (2-pyridyl-ethylaminedihydrochloride) and dimaprit also produced a vasodilation.Carbachol- and histamine-induced dilatations were also inhibited by ETYA (5,8, 11,14-eicosatetraynoic acid) and quinacrine but not by indomethacin. The inhibition of the histamine vasodilatation appeared to rest on an interference with the H₁-receptor mechanism. It is concluded that metabolites of arachidonic acid possibly mediate the dilating effect of carbachol, acting through muscarine receptors, and of histamine, acting through H₁-receptors.Preliminary communication held at the meeting of the Belgian Society for Fundamental and Clinical Physiology and Pharmacology, June 5, 1982 (Arch Int Pharmacodyn 1982, 260:312–313)     

Histology of gastric biopsies from peptic ulcer patients before and after short-term treatment with omeprazole or H2-receptor antagonists

Summary Sixty patients with duodenal or prepyloric ulcers were given omeprazole (30 or 40 mg o.m.; average period of treatment: 2.9 weeks) or histamine H₂-receptor antagonists (cimetidine 400 mg b.i.d. or ranitidine 150 mg b.i.d.; average period of treatment: 3.5 weeks) for a single period ranging between 2 and 6 weeks. At the end of the treatment period fasting plasma gastrin levels were moderately increased in both groups in comparison with the pretreatment values. Endoscopic biopsies were taken from the oxyntic mucosa at the beginning and at the end of the treatment period. Light microscopy of the biopsies was aimed particularly at determining the number of endocrine cells. In addition, the mucosal thickness and the volume densities of the parietal cells, the lamina propria and the gland lumina were measured. There were no significant differences in the endocrine or parietal cell populations, between biopsies taken from the patients before and after treatment with omeprazole or histamine H₂-receptor antagonists. The mucosal thickness and the densities of the lamina propria and of the gland lumina remained unaffected by the treatment.     

The effects of H2-receptor antagonists on anaphylaxis in the guinea-pig

Histamine has been shown to inhibit a variety of immune responses including the antigen-induced, IgE mediated, release of histamine from sensitized human leucocytes and from sensitized monkey and dog mast cells. The inhibitory action of histamine appears to be mediated by action at a histamine H₂-receptor. In in vitro experiments the H₂-receptor antagonist metiamide has been shown to block this histamine effect and it has been suggested that H₂-receptor antagonists could intensify immediate hypersensitivity reactions in vivo.The effects of the H₂-receptor antagonist metiamide and cimetidine have been studied in in vitro and in vivo models of anaphylaxis in the guinea-pig. The amount of extracellular histamine found after antigen challenge is greater when an H₂-receptor antagonist is present during the incubation of mast cells with antigen. Bronchoconstriction induced by antigen in sensitized guinea-pig is exacerbated only by high doses of cimetidine. Possible explanations for the mechanism of action involved are discussed.     

Relationship between histamine-induced changes of cyclic AMP and mechanical activity on smooth muscle preparations of the guinea-pig ileum and the rabbit mesenteric artery

On guinea-pig ileum and rabbit mesenteric artery contracted by high potassium (100 mM) histamine produced relaxations which were inhibited by the H₂-receptor antagonist metiamide. These results are thus indicative for the role of H₂-receptors in mediating relaxation and for H₁-receptors in mediating contraction on smooth muscle.Time course studies for the relaxing and cyclic AMP responses to histamine showed that the cyclic AMP increase preceded the H₂-receptor mediated relaxation. The cyclic AMP increase in response to histamine was prevented by metiamide, but remained unaffected by mepyramine on both the guinea-pig ileum and the rabbit mesenteric artery.In addition, dose-response curves obtained on the mesenteric artery demonstrated that the H₂-receptor mediated depressor responses coincided with cyclic AMP increases. Thus, these results gave clear-cut evidence that cyclic AMP is an intracellular metabolic event only implicit in the H₂-receptor mediated relaxation, but not in the H₁-receptor mediated contraction on smooth muscle preparations.