Histamine H2-binding studies in the guinea-pig brain

Using³H-mepyramine and³H-tiotidine to label, respectively, the histamine H₁- and H₂-receptors, we have assessed the distribution of these receptors in five distinct areas of guinea-pig brain.With regard to the H₂-receptor, we could detect no binding in either the cerebellum or pons-medulla, whereas the distribution in the other brain areas was corpus striatum > cortex > hippocampus. This was in contrast to the distribution of the H₁-receptor which was found to be in all areas studied but predominantly in the cerebellum.     

Classification and biological distribution of histamine receptor sub-types

The distribution and classification of histamine receptors in mammalian and avian tissues have been summarized in Tables 1–4. It is evident that histamine receptors are present on a number of morphologically distinct cell types and the proportion of cells bearing H₁- and H₂-receptors varies not only with the species but also with the cell source. The pharmacological receptors mediating mepyramine-sensitive histamine responses have been defined as H₁-receptors. Receptors mediating mepyramine-resistant, but burimamide or metiamide-sensitive histamine responses have been classified as H₂-receptors. Histamine responses mediated via H₂-receptors seem to involve the adenylcyclase system resulting in elevation of intracellular cyclic-AMP level, which is susceptible to burimamide blockade but insensitive to β-adrenergic blocking agents. This mode of action of histamine involving H₂-receptors and the adenyl cyclase system has been shown to stimulate the mammalian heart; promote gastric acid secretion; inhibit antigen-induced histamine release from leucocytes and inhibit lymphocyte-mediated cytotoxicity. It can further be concluded that both H₁- and H₂-receptors are widely distributed throughout the animal body in the gastro-intestinal, reproductive, respiratory and cardiovascular systems, nervous system and on mast cells and blood leucocytes. In these tissues, histamine receptors play an important role in physiological, immunological and immunopathological processes. Interaction of histamine with both H₁- and H₂-receptors in varying proportions modulates the overall manifestation of cardiovascular and respiratory syndromes during certain immunopathological conditions (e.g. inflammation, allergy and anaphylaxis). Histamine receptors also appear to play an important role in the development of immuno-competence and immunity.     

Classification and biological distribution of histamine receptor sub-types

The distribution and classification of histamine receptors in mammalian and avian tissues have been summarized in Tables 1–4. It is evident that histamine receptors are present on a number of morphologically distinct cell types and the proportion of cells bearing H₁- and H₂-receptors varies not only with the species but also with the cell source. The pharmacological receptors mediating mepyramine-sensitive histamine responses have been defined as H₁-receptors. Receptors mediating mepyramine-resistant, but burimamide or metiamide-sensitive histamine responses have been classified as H₂-receptors. Histamine responses mediated via H₂-receptors seem to involve the adenylcyclase system resulting in elevation of intracellular cyclic-AMP level, which is susceptible to burimamide blockade but insensitive to -adrenergic blocking agents. This mode of action of histamine involving H₂-receptors and the adenyl cyclase system has been shown to stimulate the mammalian heart; promote gastric acid secretion; inhibit antigen-induced histamine release from leucocytes and inhibit lymphocyte-mediated cytotoxicity. It can further be concluded that both H₁- and H₂-receptors are widely distributed throughout the animal body in the gastro-intestinal, reproductive, respiratory and cardiovascular systems, nervous system and on mast cells and blood leucocytes. In these tissues, histamine receptors play an important role in physiological, immunological and immunopathological processes. Interaction of histamine with both H₁- and H₂-receptors in varying proportions modulates the overall manifestation of cardiovascular and respiratory syndromes during certain immunopathological conditions (e. g. inflammation, allergy and anaphylaxis). Histamine receptors also appear to play an important role in the development of immuno-competence and immunity.     

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)     

Distribution of Serotonin 4(a) Receptors in the juvenile Rat Brain and Spinal Cord

In the last 20 years there have been many studies investigating the distribution of 5-HT₄-receptors in the brain of different species. Most studies are methodically based on RT-PCR or in situ hybridization and have analysed the receptors at the mRNA level.Furthermore there have been some autoradiographic studies using specific 5-HT₄-receptor antagonists like [³H]GR113808, [³H]BIMU-1 or [¹²⁵I]SB207710.This study investigates the topographical distribution of the 5-HT_4(a)-receptor in the juvenile rat brain and spinal cord, which is important for neuromodulation of cellular excitability and could be involved in various developmental processes of the central nervous system. We analysed the 5-HT_4(a)-receptor at protein level with a monospecific polyclonal antibody by using an immunohistochemical staining.We saw an intensive staining in some areas of the cortex, in the olfactory bulb, in most areas of the cerebellum, in hippocampal areas like the dentate gyrus and in several different areas of the brainstem, especially in the motor nuclei. Overall we have shown comparable results in accordance with the results of other studies investigating the distribution of 5-HT_4(a)-receptors.Some areas like the islands of Calleja, the preoptic nucleus or the medial habenular nucleus showed a lower intensity of 5-HT_4(a)-receptors in comparison with the results of other studies. As a novel result we found a higher intensity of 5-HT_4(a)-receptor in several brain areas associated with motor function than was shown by other studies, especially in the motor cortex, in different areas of the cerebellum, in the red nucleus, in the motor nuclei of the brainstem or in the ventral horn cells of the spinal cord.We conclude that the 5-HT_4(a)-receptor may play a more prominent role in the modulation of motor cortico-ponto-cerebellar, cortico-spinal, rubro-spinal, vestibulo-spinal and cortico-nuclear tracts during juvenile development.     

Histamine evokes excitatory response of neurons in the cerebellar dentate nucleus via H2 receptors

Previous studies have shown an excitatory effect of histamine on neurons in two cerebellar nuclei, the fastigial nucleus and the interposed nucleus. Here we investigated action of histamine on the dentate nucleus (DN), another nucleus of the cerebellum, and provided more evidence for motor control by histamine via the cerebellum. Spontaneous unitary discharge of neurons in the DN was extracellularly recorded by use of cerebellar slice preparations. In total 79-recorded neurons, which were from 53 cerebellar slices, 67 neurons (84.8%) had an excitatory response to histamine stimulation, and the rest (15.2%) were not reactive. The histamine-induced excitation of the DN neurons was not blocked by low-Ca²⁺/high-Mg²⁺ medium, demonstrating that this effect of histamine was postsynaptic. Triprolidine, an antagonist of histamine H₁ receptors, did not block the excitatory effect of histamine, but ranitidine, an antagonist for H₂ receptors, blocked the excitatory response to histamine in a concentration-dependent manner. Further, histamine H₁ receptor agonist 2-pyridylethylamine did not elicit any response of DN neurons, but H₂ receptor agonist dimaprit had an excitatory action on the DN cells and this action was blocked by ranitidine. These results indicate that histamine excites cerebellar DN neurons via histamine H₂ receptors. Since the DN receives hypothalamocerebellar histaminergic projections and plays a role in initiation and planning of somatic movement, the postsynaptic excitation of the DN neurons by histamine suggests the possibility that the initiation and planning of movement may be modulated by the histaminergic projections.     

Effects of the H1-antagonist promethazine and the H2-antagonist burimamide on chronotropic,inotropic and coronary vascular responses to histamine in isolated perfused guinea-pig hearts

On guinea-pig atria part of the inotropic response to histamine is attributable to a concomitant increase of the frequency [7]. Since the chronotropic effect of histamine is mediated by a stimulation of H₂-receptors a direct interaction of histamine with H₁-receptors mediating the inotropic response on heart may be overlooked. For this reason the ability of the H₁-antagonist promethazine and the H₂-antagonist burimamide to inhibit the positive chronotropic, inotropic and coronary vascular responses to histamine was determined in spontaneously beating and electrically driven perfused guinea-pig hearts.

1. Burimamide produced a competitive blockade of the positive chrono- and inotropic responses to histamine.
2. On the other hand, promethazine in concentrations that had no effect on cardiac function by itself, proved to be ineffective against the positive chrono- and inotropic responses produced by histamine on spontaneously beating and electrically driven heart preparations.
3. The predominant coronary vasodilation observed after infusion with histamine was competitively antagonized by promethazine and burimamide. This blockade was not attributable to an interaction with myocardial H₂-receptors mediating increases in heart rate and contractility and was, therefore, direct in nature.
4. Based upon the present study and former investigations [7] the following distribution of different histamine receptors in the guinea-pig heart does exist: H₁-receptors are present in the atrial muscle and the coronary vascular bed. H₂-receptors are located in the sinus node, the ventricular myocardium and the coronary vessels.

     

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.     

The effects of cimetidine on histamine atrial chronotropic receptor activity

Clinically useful histamine antagonists have been reported to be specific for H₁-or H₂-receptors. However, data is accumulating that the specificity of those agents may be relative. This study was undertaken in an attempt to calrify this point. Histamine stimulates the chronotropic responses of rabbit atria by acting on both H₁- and H₂-receptors. Cimetidine (H₂-antagonist) and diphenhydramine (H₁-antagonist) both cause some inhibition of the histamine response, but there is no evidence of competitive blockade with these antagonists given separately or in combination. 4-Methylhistamine (H₂-agonist) stimulates chronotropic activity, and both H₁-and H₂-antagonists reduce this response to some degree. 2-Methylhistamine (H₁-agonist) is a less effective agonist (perhaps rabbit atria contain fewer H₁-receptors), but the response is also decreased by either H₁-or H₂-antagonists. These two ‘specific’ agonists were combined to stimulate the histamine responses, and the antagonists were given simultaneously. The results were qualitatively similar to those obtained with histamine. The question remains: (1) are these agonists and antagonists specific or (2) are the rabbit atrial chronotropic receptors not typical of the H₁-and H₂-type receptor?     

Identification of histamine H1- and H2-receptors by means of mepyramine,cimetidine and theophylline in the cardiovascular system of the dog

The haemodynamic effects of histamine infusions (0.5 to 8 g kg^–1 min^–1) were studied in anaesthetized dogs previously instrumented for measurements of left ventricular pressure (LVP),dP/dt _max, aortic and femoral blood pressure (P _AO;P _AF) and femoral blood flow (F _AF). Blockage of H₁- or H₂-receptors alone with either mepyramine (1 mg kg^–1 min^–1) or cimetidine (2 mg kg^–1 min^–1) did not prevent the dose-dependent decrease in contractility and blood pressure responses to histamine. Since, however, both antihistamines administered in combination competitively antagonized responses to histamine, it is concluded that peripheral and cardiac effects of histamine involve interaction with both H₁- and H₂-receptors. The potentiation ofdP/dt _max,P _AO andF _AF responses to histamine as produced by theophylline (4 mg kg^–1 min^–1) was completely reversed by cimetidine, which thus may be taken as an indication that also under in vivo conditions cyclic AMP serves as a mediator only for histamine H₂-responses. However, since these results do not allow clearly to separate between primary cardiac and peripheral responses in a further set of experiments blood pressure was held constant during histamine infusions. When peripheral mechanisms were excluded as responsible for cardiac actions of histamine by this procedure histamine evoked small positive inotropic responses which were prevented by cimetidine. These findings suggest that on ventricular muscle of dogs there exists a small fraction of H₂-receptors mediating positive inotropic effects which, however, were masked on intact animals by negative inotropic responses due to a pronounced fall in blood pressure.     

Effect of histamine and NαNα-dimethylhistamine on gastric acid secretion and mucosal blood flow in Heidenhain-pouch dogs

Conclusions It is concluded that in accordance with numerous previous reports acid secretion in response to histamine is mediated by H₂-receptors. The powerful effect of histamine on GMBF is at least in part mediated by H₁-receptors. Since NDMH is much less effective than histamine in increasing GMBF and is not inhibited by mepyramine, this compound is more selective in stimulating histamine H₂-receptors than histamine.     

Altered calcium concentration and rabbit atrial H1-receptors

Rabbit atria were incubated in various concentrations of calcium (0.9, 1.8 and 3.6 mM) and then homogenized and histamine H₁-receptors analysed by radioligand binding using (³H)-pyrilamine. Only atria incubated in 3.6 mM calcium showed an alteration in (³H)-pyrilamine binding. In these tissues theK _d of H₁-receptors for (³H)-pyrilamine was increased suggesting a decrease in the affinity of the H₁-receptor. That this decreased affinity is due to altered calcium concentrations was demonstrated by showing that no change in histamines' chronotropic effects were produced by decreasing the sodium concentration to produce the same calcium/sodium ratio compared to high calcium alone. We conclude that calcium has effects directly on H₁-receptor affinity and appears to produce a decrease in the ability of histamine to bind.     

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     

Is airway hyperactivity in asthma due to histamine H2-receptor deficiency?

The underlying biochemical and physiological changes responsible for remarkable airway hyperreactivity to histamine and other non-specific stimuli in asthmatics are poorly understood. Based on some experimental observations, a hypothesis “Deficiency of histamine H₂-receptors in asthma” is proposed. The deficiency of histamine H₂-receptor (histamine-sensitive adenyl cyclase) on leukocytes (mast cells, basophils, neutrophils and eosinophils) and in the airway smooth muscles during the process of hypersensitization, immunization, infectious diseases as well as in atopic bronchial asthmatics could occur. The H₂-receptor deficiency or physiological imbalance of histamine H₁- and H₂-receptors in the airways may at least, in part, explain the most commonly observed phenomenon of remarkable airway hyperreactivity to histamine in asthmatics.     

Stimulation and suppression of rat stomach histidine decarboxylase activity

Conclusions The results suggest that histamine (via H₂-receptors) reduces the sensitivity of the histamine-storing cells to gastrin and that H₂-receptor blockade induces the opposite effects. We propose that the histamine-storing cells in the rat stomach are endowed with H₂-receptors and that exogenous histamine is capable of acting directly on the histamine cells. This may reflect a physiological control mechanism where by mobilized endogenous histamine modifies its own synthesis and release.     

Regulation of membrane histamine H1-Receptor binding sites by guanine nucleotides,mono- and divalent cations

Agonist interaction with histamine H₁-receptor in [³H] mepyramine bovine aortic membranes labeled with [³H] mepyramine is selectively regulated by cations and guanine nucleotides. GTP and his nonhydrolisable analog Gpp(NH)p' markedly decrease histamine affinity for [³H] mepyramine binding sites. The effect of GTP is reversed in the presence of divalent cation, magnesium. Calcium and sodium ions have little effect on histamine binding whereas magnesium ions decrease the affinity of histamine for the radioantagonist binding sites about tenfold.GTP has little effect on [³H] mepyramine binding and the interaction of H₁-antagonist triprolidine with histamine H₁-receptors. The above results indicate that the effect of guanine nucleotides, mono and divalent cations involves the effect on membrane signal transducing mechanism probably GTP-binding protein(s) cation regulatory site(s) rather than receptor binding site directly.     

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.     

Liberation of histamine by compound 48/80, tolazoline,betahistine and burimamide from isolated spontaneously beating guinea pig and rabbit atrial pairs

Tolazoline, betahistine, burimamide and compound 48/80 release histamine from isolated guinea pig atria resulting in histamine concentrations that will stimulate H₂-receptors. Tolazoline, burimamide and 48/80 also release histamine from rabbit atria but do not result in histamine concentrations that will stimulate either H₁- or H₂-receptors. However, betahistine (which does not release histamine from rabbit atria) and tolazoline stimulate the rabbit atrial chronotropic response by releasing catecholamines.     

H1-receptor reserves in guinea-pig left atria,trachea and pig coronary artery as identified by phenoxybenzamine

H₁-receptor reserves in guinea-pig left atria, trachea and pig coronary arteries were calculated by the use of phenoxybenzamine (Pba), a β-haloalkylamine that irreversibly blocks the H₁-receptor response to histamine or 2-(2-pyridyl)-ethylamine (PEA). Equieffective concentrations of the H₁-agonist in the absence (A) and presence (A′) of Pba were evaluated from concentration-response curves. By plotting the reciprocal values 1/A versus 1/A′ the amount of H₁-receptors not occupied by the agonist was calculated. The size of the H₁-receptor reserve could be estimated by comparison of the receptor occupation with the corresponding effect. Furthermore, the dissociation constants for histamine, PEA, Pba and the pD′₂-values for Pba were determined for the different tissues. 5% and 6% H₁-receptor occupation is necessary to achieve a half maximal contraction of the trachea with the agonists histamine and PEA, respectively. Only 0.5% H₁-receptor occupation is needed for the half maximal positiv inotropic effect of histamine in left atria, while 5.5% of the H₁-receptors have to be accupied using PEA as an agonist in this tissue. In the coronary artery of the pig 50% of the maximal contraction can be achieved by stimulation of 15.1% of the H₁-receptors with histamine.     

Effects of histamine agonists and antagonists on luminol-dependent chemiluminescence of granulocytes

Histamine inhibited luminol-dependent chemiluminescence (CL) of granulocytes in a dose-dependent manner, with an ID₅₀ of about 3×10^–5 M. Dimaprit, a selective H₂-agonist, produced a histamine-like effect. Furthermore, cimetidine, ranitidine, and TZU 0460, which are selective H₂-antagonists, but not mepyramine, a selective H₁-antagonist, blocked the inhibitory effect of histamine on CL. Thus it may be concluded that the inhibitory effect of histamine is mediated via histamine H₂-receptors. H₁- and H₂-antagonistsper se, except at extremely high concentrations, had no effect on CL of granulocytes.