Histamine-induced microvascular permeability increases in hamster skin: a response predominantly mediated by H2-receptors

The pharmacology of histamine-induced increases in cutaneous microvascular permeability was investigated in the hamster by (a) examining the effects of cimetidine and pyrilamine on the increase in microvascular permeability evoked by graded doses of intradermally-injected histamine, and (b) comparing the cutaneous microvascular permeability responses to graded doses of impromidine (0.1–100 g), dimaprit (1–100 g) and -histine (0.1–100 g). Pretreatment with pyrilamine (0.1 mg/kg i.v. bolus injection) did not reduce the increase in microvascular permeability produced by any dose of histamine. In contrast, cimetidine (0.5 mg/kg/min i.v. infusion) significantly inhibited the microvascular permeability responses to 10 and 100 g histamine. Although neither cimetidine nor pyrilamine significantly altered the microvascular permeability response to 0.1 and 1g histamine, inhibition was afforded by a cimetidine-pyrilamine combination. These results suggest a predominantly H₂-receptor mediated phenomenon with a minor H₁-receptor mediated component. Studies with the H₂-receptor agonists impromidine and dimaprit and the H₁-receptor agonist -histine provide further support for this contention. Dimaprit and impromidine caused a dose-dependent increase in cutaneous microvascular permeability, but betahistine produced only a relatively modest response. In other laboratory species, increased cutaneous microvascular permeability appears to be mediated solely by H₁-receptors. Therefore, the hamster skin appears unique with respect to the pronounced H₂-receptor involvement in histamine-induced microvascular permeability changes.     

The role of histamine in wound healing. II. The effect of antagonists and agonists of histamine receptors (H1 and H2) on collagen levels in granulation tissue

The effects of mepyramine (H₁-receptor antagonist), cimetidine (H₂-receptor antagonist), IEM-813 (H₁-receptor agonist) and 4-Met-Hi (H₂-receptor agonist) on collagenogenesis processes in subcutaneous implanted sponges of rats were studied. Administration into sponges of cimetidine 30 min before histamine injection blocked both the stimulatory effect of low histamine doses and the inhibitory effect of high histamine doses on collagen formation. Low doses of 4-Met-Hi increased collagen levels but reduced the levels at high doses. Mepyramine and IEM-813 did not influence collagen biosynthesis.     

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.     

Selective disappearance of histamine H2-receptor activity in the human gastric cancer cell line HGT-1 after short-term or chronic treatment by histamine or its H2-antagonists

Homologous loss of histamine H₂-receptor activity (cAMP generation) was observed after short-term (10–20 min) or chronic treatment (6 days) of cultured HGT-1 cells with histamine (desensitization) or the H₂-receptor antagonist SKF 93479. This inactivation process was not observed when HGT-1 cells were exposed to the classical H₂-antihistamine cimetidine.The data show: (1) that the compound SKF 93479 has a very prolonged inhibitory action on histamine receptor activity, suggesting an irreversible interaction between the antagonist and the receptor; (2) that cimetidine is a reversible H₂-receptor antagonist which can be removed without changing the the efficacy and the potency of histamine on gastric cells; (3) that the H₂-receptor antagonists cimetidine and SKF 93479 specifically block histamine H₂-receptor activity in HGT-1 cells since cAMP generation induced by other hormones such as vasoactive intestinal peptide (VIP), glucagon or gastric inhibitory peptide (GIP) was unchanged after treatment; (4) the first evidence for time-dependent (half-life: 20 min) desensitization of gastric H₂-receptors.     

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

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

Naloxone antagonizes a central histaminergic stimulation of corticosterone secretion in rats

The interaction of central opioid receptors with histaminergic stimulation of the hypothalamo-pituitary-adrenocortical axis, evaluated indirectly through corticosterone secretion, was investigated in conscious unstressed rats. To avoid any possible direct action on the adrenal cortex, all drugs were given intracerebroventricularly (i.c.v.). Histamine, 2-pyridylethylamine (PEA), a histamine H₁-receptor agonist, and 4-methyl-histamine (MeHA) and dimaprit, the H₂-receptor agonists, considerably increased the serum corticosterone levels 1 h after adminstration. Naloxone, an opioid receptor antagonist, almost abolished the corticosterone response to PEA and considerably reduced the responses to MeHA, dimaprit and histamine. The maximum inhibitory effects of naloxone on corticosterone responses induced by histamine and histamine agonists were comparable with those of the H₁-and H₂-receptor antagonists, mepyramine and cimetidine.These results strongly suggest that a major part of the histaminergic stimulation of the hypothalamopituitary-adrenal axis is mediated by central opioid receptorsThe study was supported by the Polish Academy of Sciences, grant No 06.03.     

Species differences in histamine receptors in the vas deferens

Histamine, specific H₁-and H₂-receptor agonists in conjunction with specific H₁-and H₂-receptor antagonists and other types of classical antagonists were used to characterize histamine receptors in the vasa deferentia of mice, rats and guinea pigs. The H₁-receptor mediates contraction while the H₂-receptor produces inhibition. There were marked qualitative and quantitative differences in the distribution of the two types of histamine receptors in the vas deferens of different species. Results indicate that mouse and rat vas deferens contain an inhibitory H₂-receptor, but virtually no excitatory H₁-receptor. In contrast, guinea pig vas deferens contained an excitatory H₁-receptor but was essentially devoid of an inhibitory H₂-receptor. The rank order of relative potencies of various agonists as well as the calculated pA ₂ values of cimetidine in the mouse and rat vas deferens suggest that the two species probably have the same H₂-receptor. High concentrations of histamine and 2-methyl histamine have a stimulant action in the mouse and rat vas deferens which was secondary to release of endogenous noradrenaline rather than to the stimulation of an excitatory H₁-receptor.     

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.     

Downward regulation of neutrophil infiltration by endogenous histamine without affecting vascular permeability responses in air-pouch-type carrageenin inflammation in rats

The role of histamine in neutrophil infiltration and vascular permeability response in carrageenin air pouch inflammation in rats was examined. Injection of carrageenin solution into an air pouch induced a gradual increase in histamine content in the pouch fluid and histidine decarboxylase activity of pouch wall tissues, with a maximum attained at 24 h. Local administration of the H₂ antagonists cimetidine and famotidine, but not the H₁ antagonist pyrilamine, induced an increase in neutrophil infiltration at 24 h. Both types of histamine antagonists failed to suppress the vascular permeability response. In addition, H₂ antagonists attenuated the inhibitory effect of indomethacin on neutrophil infiltration without affecting the indomethacin-induced suppression of vascular permeability response. These results suggest that histamine produced in the inflammatory locus exerts a downward regulation of neutrophil infiltration through H₂ receptors but does not play any significant role in the vascular permeability response. Furthermore, the inhibition by indomethacin of neutrophil infiltration might be ascribed to the increase in histamine level in the pouch fluid.     

Central histaminergic stimulation of hyperlipemic response in rats under stress

In rats subjected to a mild stress of immobilization histamine, the H₁-receptor agonist 2-pyridylethylamine (PEA), and the H₂-receptor agonists 4-methyl histamine (4-MeHA) and impromidine administered intracerebroventricularly (i.c.v.) 1 h prior to stress, intensified the stress-induced increase in serum free fatty acid (FFA) levels. Impromidine was far more potent than histamine and its agonists in increasing hyperlipemia in stressed rats. The hyperlipemic response to histamine was abolished by i.c.v. pretreatment of rats with mepyramine, a H₁-receptor antagonist, but was unchanged in rats pretreated with cimetidine or metiamide, H₂-receptor antagonists. The increase in serum FFA levels induced in stressed rats by PEA was abolished by mepyramine but the hyperlipemic responses to 4-MeHA and impromidine were not antagonized by cimetidine.These results suggest that central H₁-receptor mediate the histamine-stimulated hyperlipemic response in stressed rats.     

Antagonistic action of naloxone on central histamine receptors-stimulated corticosterone secretion in rats under stress

In rats under a mild stress of restraint the interaction between central opioid receptors and histaminergic stimulation of the pituitary-adrenocortical activity was investigated indirectly through corticosterone secretion. In order to avoid a possible direct action on adrenal glands, all the tested drugs were administered intracerebroventricularly (icv). Naloxone an opioid antagonist and cimetidine, a H₂- and mepyramine a H₁-receptor antagonists were given 15 min before histamine and histamine agonists. One hour after histaminergic drug injection the rats were restrained for 10 min and decapitated. Histamine, 2-pyridylethylamine (PEA), a histamine H₁-receptor agonist, and 4-methylhistamine (MeHA) and dimaprit, H₂-receptor agonists, significantly intensified the stress-induced increase in serum corticosterone levels. Naloxone, given alone icv or ip, did not substantially alter the stress-induced corticosterone response. Like mepyramine naloxone abolished the corticosterone response to PEA in stressed rats. Naloxone also decreased significantly, though not totally, the corticosterone response to MeHA, dimaprit and histamine, its efficiency being similar to that of cimetidine, a H₂-receptor antagonist. These results suggest that in stressed rats central opioid receptors are considerably involved in the histamine H₁-receptor — and, to a lesser degree, in the H₂-recepor stimulation of the hypothalamo-pituitary-adrenocortical axis.     

Pharmacological interactions between ranitidine,cimetidine, metiamide and tiotidine at histamine H2-receptor sites in guinea-pig atria

Cumulative concentration-response curves to histamine or dimaprit were constructed on guinea-pig isolated right atria and agonist dose-ratios were determined following addition of ranitidine, cimetidine, metiamide or tiotidine alone or a combination of any two of these H₂-receptor blocking drugs. The observed histamine or dimaprit dose-ratios for combinations of any two of the H₂-antagonists tested were consistent with results predicted from the equation, DR₁₊₂=DR₁+DR₂–1, for two antagonists competing for the same receptor sites. Therefore we conclude that all four H₂-antagonists compete for the same histamine H₂-receptor.     

Studies on cutaneous vascular permeability in the rat: Increases caused by histamine and histamine-like agents

The pharmacology of histamine-induced increases in microvascular permeability has been studied in rat skin. Histamine caused dose-dependent increases in microvascular permeability, assessed as increases in extravascular albumin accumulation. The responses to histamine were inhibited in a dose-dependent manner by pretreatment with mepyramine and were not changed by cimetidine. 2-(2-Aminoethyl)pyridine also increased microvascular permeability whereas impromidine did not. These results suggest that H₁-receptors and not H₂-receptors are involved in the permeability response to histamine in rat skin. In contrast, dimaprit increased microvascular permeability and responses to dimaprit exceeded the maximum response to histamine. The response to dimaprit proved to be independent of H₂ receptors and was consistent with an indirect response due to mast cell degranulation.     

Pharmacological characterisation of cardiovascular histamine receptors in man in vivo

Summary Data from pharmacological studies carried out in healthy subjects using systemic histamine or impromidine and their antagonists are reviewed. Exogenous histamine by rapid injection appears to stimulate only H₁-receptors. Chlorpheniramine alone antagonised the responses to histamine.The effects of cardiovascular H₂-receptor stimulation are demonstrated best by a sustained and large dose of histamine given by infusion. If it be considered desirable to antagonise all the cardiovascular responses to endogenous histamine, the available pharmacological data in man suggest this would be achieved best by a combination of an H₁- and H₂-receptor antagonist.     

Hyperlipemic responses induced by centrally administered histamine H1- and H2-receptor agonists in rats

The H₁-receptor agonist 2-pyridylethylamine (PEA), and the H₂-receptor agonists dimaprit and impromidine administered intracerebroventricularly (i.c.v.) to conscious rats considerably increased the concentration of free fatty acids (FFA) in the blood serum.The hyperlipemic effect of PEA was abolished by mepyramine, a H₁-receptor antagonist. Responses to dimaprit and impromidine were not antagonized by cimetidine.These results suggest that central H₁-receptor stimulation elicits the hyperlipemic responses in rats. The role of central H₂-receptors in this reaction is not clear.     

Lipolytic responses induced by intracerebroventricular administration of histamine in the rat

Histamine (10–50 g) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30–60 min after administration. Histamine H₁-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H₂-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished the histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H₁-receptor antagonist, mepyramine, but not by the H₂-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H₁- than H₂-receptors.     

Binding of [3H]cimetidine to rat brain tissue

Binding of [³H]cimetidine to rat brain tissue was investigated, and a saturable binding with dissociation constant 0.22±0.05 M found. This binding is inhibited by a range of imidazole-derived histamine H₂-receptor antagonists, but not by a number of non-imidazole H₂-receptor antagonists. It is concluded that the [³H]cimetidine binding site in rat brain tissue that is labelled in these experiments is not the histamine H₂-receptor.     

Histamine H1- and muscarinic receptor antagonist activity of cimetidine and tiotidine in the guinea pig isolated ileum

The histamine H₂-receptor antagonists cimetidine and tiotidine were compared as antagonists for H₁- and muscarinic receptors in the guinea pig isolated ileum. Their interactions with histamine were evaluated on the phasic and tonic components of the histamine response. For carbachol, only the phasic component of the response was monitored.For their interactions with histamine, the type of antagonism, surmountable or nonsurmountable, depended upon the choice of response metameter. Evaluation of the antagonism produced by either tiotidine or cimetidine for histamine concentration-response curves based on the phasic response metameter showed an initial dextral shift with surmountable antagonism. With increasing antagonist concentrations the concentration-response curves were further shifted to the right and the maximum response was depressed. When this antagonism was evaluated for histamine concentration-response curves based on the tonic response metameter, cimetidine produced dextral shifts and nonsurmountable antagonism, and tiotidine exhibited only nonsurmountable antagonist activity. pA₂ values for cimetidine antagonism of the phasic and tonic components of the histamine response were 3.2 and 3.7 respectively, and pD₂ values for the phasic and tonic components were 1.8 and 2.3 respectively. The pA₂ value for tiotidine antagonism of the phasic component was 3.9 and the pD₂ values for the phasic and tonic components were 2.6 and 3.3 respectively.Cimetidine and tiotidine at concentrations which did not depress the phasic component of the histamine response produced surmountable antagonism to the contractile action of carbachol. The pA₂ values for cimetidine and tiotidine antagonism of carbachol were 3.8 and 3.6 respectively.     

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.     

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⁺.