The pharmacology of burimamide and metiamide, two histamine H2-receptor antagonists.

Burimamide and metiamide are two histamine H2-receptor antagonists. Evidence is presented that indicates the competitive nature and the specificity of the antagonism. Metiamide is about ten times more potent than burimamide and is also more effective than burimamide when given orally. Both compounds inhibit gastric secretion and the evidence is consistent with this inhibition being due to competitive antagonism of H2 receptors in the gastric mucosa. Burimamide, unlike metiamide, causes release of catecholamines even at dose levels that are just sufficient to produce H2-receptor antagonism. Burimamide, but not metiamide, has alpha-adrenoceptor blocking activity. In certain models for inflammation, particularly rat paw edema induced by compound 48/80, burimamide in combination with the H1-receptor antagonist mepyramine shows anti-inflammatory activity. This may, in part, be associated with the catecholamine-releasing properties of the compound. Metiamide is less active in this respect.     

H2 antihistamines augment antigen-induced histamine release from human basophils in vitro

H2 antihistamines, including cimetidine, burimamide, metiamide, and tiotidine, consistently augmented antigen-induced histamine release from human basophils in vitro when control histamine release was less than 20% of total. This effect was specific to the H2-receptor blocking activity of these drugs: equivalent degrees of receptor blockade by four different H2 antihistamines resulted in equipotent enhancement; H1-receptor antagonists did not alter histamine release; and aminoguanidine and amodiaquine, agents that inhibit histamine metabolism but do not block H2 receptors, did not enhance histamine release. Cimetidine did not enhance release when present a) when basophils were "activated" but did not release histamine ("first stage"), or b) when basophils were no longer susceptible to histamine inhibition ("second stage"). Thus, H2 antagonists enhanced histamine release by blocking the capacity of released histamine to act on H2 receptors to inhibit release. Because it is likely that only small percentages of histamine are released in vivo, it is possible that H2 antihistamines amplify the inflammatory process by blocking the inhibitory effects of the released histamine.     

Histamine H2 receptors and cyclic AMP in brain

The intravenous injection of histamine to 2–3 day old chicks resulted in a rapid and marked increase in the cyclic AMP content of the cerebral hemispheres that had been removed and frozen within 0.5s using a freeze-blowing technique. This response was not antagonized by pretreatment of the chicks with the histamine H₁-receptor antagonists mepyramine and diphenhydramine but was blocked by the H₂-receptor antagonists burimamide and metiamide. Parallel $\text{in vitro}$ experiments on slices of chick cerebral hemispheres demonstrated that the H₁ antagonists only produced a weak and non-competitive antagonism of the effects of histamine on cyclic AMP production. On the other hand the H₂ antagonists at low concentrations competitively blocked the histamine response. It is suggested that increased cyclic AMP formation in chick cerebral hemispheres can be mediated through stimulation of histamine H₂-receptors.     

On the specificity of histamine H2-receptor antagonists in the rat cerebral cortex.

The effects of iontophoretically applied histamine H2-receptor antagonists and their antagonism of various amines, acetylcholine (ACh), and adenosine 5'-monophosphate (5'-AMP) were studied on spontaneously active rat cerebral cortical neurons. Metiamide selectively blocked the depressant actions of histamine. Burimamide, in amounts necessary for histamine antagonism, also antagonized the depressant effects of noradrenaline, dopamine, and 5-hydroxytryptamine. Neither antagonist affected 5'-AMP-induced depressions, but both reduced or blocked the excitatory actions of ACh. It is concluded that metiamide may be useful as a reliable antagonist of H2 receptors on cerebral cortical neurons.     

Localization of histamine and histamine H2-receptor antagonists in the gastric mucosa.

Synopsis Histamine stimulates acid secretion by the parietal cell and this secretion is inhibited by the histamine H₂-receptor antagonists. Whole body autoradiography showed that radioactivity from¹⁴C-histamine was localized in the artery walls of the stomach and in the muscularis mucosae, but that the level in the fundic mucosa was the same as the blood.When the H₂-receptor antagonists burimamide, metiamide and cimetidine were labelled with³⁵S,¹⁴C or³H and dosed to rats, whole body autoradiography showed that the stomach was predominantly labelled in the glandular mucosa from 5 to 120 min after administration. Microautoradiography in the rat and dog after intravenous injection of [³H] metiamide or [³H] cimetidine demonstrated an uptake of tritium in the parietal cell cytoplasm that was 3- to 4-times greater than that found in adjacent peptic cells or areas of muscularis mucosa. The preferential labelling persisted at a low level up to 6 h after injection in the rat. The localization of radioactivity from the H₂-antagonists in the parietal cell cytoplasm correlates well with their pharmacological activity in preventing acid secretion from this cell.     

Histamine modulation of eosinophil migration.

Preincubation of eosinophils with 10(-5) M or higher concentrations of histamine inhibited the eosinophil chemotactic response to endotoxin-activated serum whether by using the nucleopore filter assay and counting the cells migrating through the filter, or by using the Zigmond-Hirsch assay and counting the cells at each 10-mum interval. When the H2-receptor sites on the eosinophils were blocked by metiamide, the inhibitory capacity of histamine was prevented. Preincubation of eosinophils with 10(-6) M histamine increased the number of responding eosinophils to endotoxin-activated serum and this enhancement was blocked by an H1-receptor antagonist. Isoproteronol and aminophylline inhibited eosinophil movement and increasing concentrations of dibutryl cyclic AMP inhibited eosinophil migration. Concentrations of histamine that consistently resulted in inhibition of eosinophil movement stimulated an increase in cyclic AMP that was prevented by blocking the H2-receptor but not the H1-receptor. Thus, histamine-dependent inhibition of the eosinophil chemotactic response to other agents is mediated through the H2-receptor and is associated with an increase in the intracellular level of cyclic AMP whereas histamine dependent enhancement of eosinophil migration to other agents appears to be mediated through the H1-receptor. Eosinophils behave as a heterogeneous population as assessed by the ability of histamine to augment or inhibit cell migration. This may reflect differences in H1 to H2 receptor density or cell responsiveness to receptor stimulation. The chemoattractant activity of histamine itself is not influenced by H1 or H2 receptor antagonists, thus it is possible that an eosinophil has a third type of histamine receptor.     

Bronchial vasodilation by histamine in sheep: characterization of receptor subtype.

Histamine has been shown to mediate features of pulmonary allergic reactions including increased tracheobronchial blood flow. To determine whether the increase in blood flow was due to stimulation of H1- or H2-histamine receptors, we gave histamine base (0.1 micrograms/kg iv) or histamine dihydrochloride as an aerosol (10 breaths of 0.5% "low dose" or 5% "high dose") before and after H1- or H2-receptor antagonists. Blood velocity in the common bronchial branch of the bronchoesophageal artery (Vbr) was continuously measured using a chronically implanted Doppler flow probe. Pretreatment with H2-receptor antagonists cimetidine, ranitidine, or metiamide did not affect the increase in Vbr induced by intravenous histamine [106 +/- 45% (SD)]. Addition of the H1-receptor antagonists diphenhydramine or chlorpheniramine, however, reduced the Vbr response to 16 +/- 22, 21 +/- 28, 23 +/- 23, and 37 +/- 32% of the unblocked responses (P less than 0.05) when intravenous histamine was given at 3, 10, 20, and 30 min, respectively, after the H1 antagonist. At 40, 50, and 60 min the H1-receptor blockade appeared to attenuate, but subsequent continuous infusion of chlorpheniramine (2 mg.kg-1.min-1) then blocked the histamine response for 60 min. Low-dose histamine aerosol did not change mean arterial or pulmonary arterial pressures, cardiac output, or arterial blood gases but increased Vbr transiently from 15.2 +/- 3.4 to 37.6 +/- 8.4 (SE) cm/s. After chlorpheniramine, the Vbr response to histamine, 16.3 +/- 2.2 to 22.6 +/- 3.6 cm/s, was significantly reduced (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of H1 and H2 receptor antagonists on Tetrahymena.

In Tetrahymena pyriformis the phagocytotic rate increases in response to histamine, but neither the H1 antagonist phenindamine nor the H2 antagonist metiamide stimulate phagocytosis. The H1 antagonist counteracts the effect of histamine, whereas the H2 antagonist does not. The histamine receptor of Tetrahymena is of H1-type, since it cannot distinguish between histamine and antagonists which are closely related to it chemically. It does, however, distinguish between histamine and the chemically unrelated H1 antagonist, phenindamine. The H2 antagonist does not interact with the receptor.     

Piperidino-hydrocarbon compounds as novel non-imidazole histamine H(3)-receptor antagonists

In search for novel non-imidazole histamine H(3)-receptor antagonists, piperidino-hydrocarbon compounds were synthesized using the known non-imidazole histamine H(3)-receptor antagonist FUB 637 (3-phenylpropyl 3-piperidinopropyl ether) as lead structure. Piperidino-alkyl derivatives containing highly flexible side chains (2, 4-7) were prepared via N-alkylation. Compounds containing unsaturated alkyl groups were synthesized in order to investigate the impact of rigidifying the side chain (8-16). Terminal alkynes were prepared by alkylation of lithium acetylide-ethylenediamine complex, disubstituted alkynes were synthesized by alkylation of the appropriate acetylene in the presence of n-butyllithium-N,N,N',N'-tetramethylene-ethylene-diamine complex. The novel compounds were investigated in an in vitro functional assay on the guinea-pig ileum, in which N-(7-phenylhept-3-ynyl)piperidine (14) proved to be of good potency in this class (pA(2)=7.21). In an in vivo assay the compounds were additionally screened for their abilities to influence central H(3)-histaminergic neuron activity in mice with regard to their oral availabilities and distribution properties. In this screening, N-pent-4-ynylpiperidine (9) and N-hex-5-ynylpiperidine (10) proved to be highly potent and orally available histamine H(3)-receptor antagonists. The ED(50) values for 9 and 10 were 1.3 and 1.4mg/kg po, respectively, which is in the potency range of the reference antagonist thioperamide.     

Histamine H1- and H2-receptors in canine renal artery in vivo and in vitro

The present work investigates (a) the modification by pretreatment with selective H1- and H2-receptor antagonists on the dose-response curves (DRC) to histamine for heart rate, blood pressure, renal arterial blood flow and renal vascular resistance in anesthetized dogs, and (b) the characteristics of the DRC to histamine in canine isolated renal artery. In vivo, pretreatment with metiamide (10 mg/kg i.v.) did not modify the DRC to histamine. In contrast, significant rightward shift of the DRC to histamine for all the hemodynamic parameters was observed after diphenhydramine (5 mg/kg i.v.). Combined pretreatment with metiamide and diphenhydramine resulted in further rightward displacement of the DRC to histamine. Analysis of the DRC to the relaxant effect of histamine in depolarized (K+ 67 mM) isolated canine renal artery yielded an ED50 of 3.3 x 10(-4) M and a Hill coefficient of 1.74. The results demonstrate the existence of the two types of histamine receptors, H1 and H2, in the renal artery of the dog, both mediating dilator responses, although the H1-receptor appears to predominate.     

Relief of duodenal ulcer sysmptons by oral metiamide.

Thirty patients with symptoms of duodenal ulceration were treated for five to eight weeks in a double-blind trial with either metiamide 1 g daily by mouth or a placebo. In the 15 patients receiving metiamide there were significant reductions in nocturnal pain and antacid consumption. Daytime pain was diminished. The results suggest that histamine H2-receptor antagonists are likely to be useful in the medical management of the symptoms of duodenal ulceration.     

H2 Histamine Receptors on the Epithelial Cells of Choroid Plexus

A major site of cerebrospinal fluid production in vertebrates is the choroid plexus. The epithelial cells of the choroid plexus accumulate intracellular cyclic AMP in response to several effectors, including histamine. Since histamine is known to regulate fluid secretion in the stomach via H2 histamine receptors, we asked whether H2 receptors might also be present on epithelial cells of bovine choroid plexus. Using agonists and antagonists of histamine, we show that an agonist and antagonist pair specific for the H2 subtype were clearly more effective than an H1 agonist and antagonist pair in mimicking or inhibiting histamine stimulation of cellular cyclic AMP. Analysis by Schild plot allowed assignment of an apparent dissociation constant to the H2 antagonist metiamide which was 34-fold lower than that of its H1 counterpart, diphenhydramine. These results indicate that epithelial cells of the choroid plexus possess H2 histamine receptors.     

Failure of histamine antagonists to prevent hypoxic pulmonary vasoconstriction in dogs.

The role of histamine as a mediator of hypoxic pulmonary vasoconstriction was examined in intact anesthetized dogs. Antagonism of histamine vasoconstrictor (H1) receptors with a classic antihistaminic drug (chlorpheniramine) failed to prevent or modify the pulmonary vascular responses to hypoxia (10% O2). Blockade of histamine vasodilator (H2) receptors with a newly synthesized blocking agent (metiamide) potentiated the vasoconstriction induced by hypoxia and prevented the normal increase in heart rate. Combined H1- and H2-receptor blockade also did not prevent or reduce the hypoxic pulmonary pressor response, although it did effectively abolish the cardiovascular actions of infused histamine. In other dogs, histamine infused (3.6 mug/kg per min) during hypoxia attenuated the pulmonary vasoconstriction induced by hypoxia. The results imply that, in the dog, histamine does not mediate hypoxic pulmonary vasoconstriction. However, histamine does appear to be released during hypoxia, and it may play a role in modulating the pulmonary vascular responses to hypoxia by opposing the hypoxia induced vasoconstriction. The results also imply that histamine may be responsible for the increase in heart rate during hypoxia.     

Synthesis and biological evaluation of new non-imidazole H3-receptor antagonists of the 2-aminobenzimidazole series

A novel series of non-imidazole H(3)-receptor antagonists was developed, by chemical modification of a potent lead H(3)-antagonist composed by an imidazole ring connected through an alkyl spacer to a 2-aminobenzimidazole moiety (e.g., 2-[[3-[4(5)-imidazolyl]propyl]amino]benzimidazole), previously reported by our research group. We investigated whether the removal of the imidazole ring could allow retaining high affinity for the H(3)-receptor, thanks to the interactions undertaken by the 2-aminobenzimidazole moiety at the binding site. The imidazole ring of the lead was replaced by a basic piperidine or by a lipophilic p-chlorophenoxy substituent, modulating the spacer length from three to eight methylene groups; moreover, the substituents were moved to the 5(6) position of the benzimidazole nucleus. Within both the 2-alkylaminobenzimidazole series and the 5(6)-alkoxy-2-aminobenzimidazole one, the greatest H(3)-receptor affinity was obtained for the piperidine-substituted compounds, while the presence of the p-chlorophenoxy group resulted in a drop in affinity. The optimal chain length was different in the two series. Even if the new compounds did not reach the high receptor affinity shown by the imidazole-containing lead compound, it was possible to get good H(3)-antagonist potencies with 2-aminobenzimidazoles having a tertiary amino group at appropriate distance.     

Determination of the antihistaminic properties of histidine derivatives on models of guinea pig T- and B-lymphocyte rosette formation

It was found that carnosine, like metiamide, an H-2 antagonist of histamine, is capable of inhibiting the histamine caused suppression of T rosette-formation by guinea-pig blood and spleen lymphocytes. The other histidine derivatives, imidazole lactate, imidazole pyruvate and N-acetyl histidine did not exhibit such properties. The data obtained allow classifying carnosine with H-2-histamine blockers and serve as one of the explanations of the mechanism of its antiallergic action.     

Effects of biogenic amines on the formation of adenosine 3',5'-monophosphate in human thyroid slices.

The effects of various concentrations of biogenic amines on the formation of adenosine-3', 5'-monophosphate (cyclic AMP) and their interactions with other thyroid stimulators were investigated in human thyroid slices from normal and Graves' disease. Most of biogenic amines were found to have the stimulatory effects to some extent. Among the biogenic amines tested, histamine was the most potent thyroid stimulator, norepinephrine and serotonin, the intermediate in terms of cyclic AMP formation. The effect of histamine was almost as potent as TSH in thyroid slices from Graves' disease. This stimulatory effect of histamine was blocked by metiamide, a histamine H2-receptor antagonist, but not by chlorpheniramine, a histamine H1-receptor antagonist. The effect of norepinephrine was completely inhibited by propranolol, but not by phentolamine. Polyphloretin phosphate did not inhibit norepinephrine- or histamine-induced cyclic AMP formation, while it significantly depressed cyclic AMP formation induced by prostaglandin E2. The maximal effect of histamine was additive to that of TSH. It is suggested that biogenic amines, histamine and norepinephrine, in particular, have the thyroid receptors different from that of TSH or prostaglandin E2 and could play an important role in thyroid physiology.     

Effects of biogenic amines on the formation of adenosine 3', 5'-monophosphate in human thyroid slices.

The effects of various concentrations of biogenic amines on the formation of adenosine-3', 5'-monophosphate (cyclic AMP) and their interactions with other thyroid stimulators were investigated in human thyroid slices from normal and Graves' disease. Most of biogenic amines were found to have the stimulatory effects to some extent. Among the biogenic amines tested, histamine was the most potent thyroid stimulator, norepinephrine and serotonin, the intermediate in terms of cyclic AMP formation. The effect of histamine was almost as potent as TSH in thyroid slices from Graves' disease. This stimulatory effect of histamine was blocked by metiamide, a histamine H2-receptor antagonist, but not by chlorpheniramine, a histamine H1-receptor antagonist. The effect of norepinephrine was completely inhibitied by propranolol, but not by phentolamine. Polyphloretin phosphate did not inhibit norepinephrine- or histamine-induced cyclic AMP formation, while it significantly depressed cyclic AMP formation induced by prostaglandin E2. The maximal effect of histamine was additive to that of TSH. It is suggested that biogenic amines, histamine and norepinephrine, in particular, have the thyroid receptors different from that of TSH or prostaglandin E2 and could play an important role in thyroid physiology.     

Action of histamine and its receptor blockers on uterine circulation in sheep.

Effects of iv and ia administration of histamine and its H1 and H2 blockers (diphenhydramine and metiamide) on systemic arterial pressure, heart rate, and uterine and iliac blood flows were investigated in unanesthetized, chronically instrumented nonpregnant ewes. Intravenous histamine produced tachycardia, hypotension, and decreased iliac and uterine blood flows. In contrast, ia injections produced a significant increase in blood flows in these vascular beds which was dose-dependent. Evidence is presented to show that some of the circulatory actions of histamine may be related to stimulation of H1 while others may be related to H2 receptors. The peripheral circulatory action produced by iv histamine is probably secondary to its effects on reducing cardiac output. The uterine and iliac vascular beds contain mostly H1 receptors since their response to histamine can be blocked almost totally by Benadryl and not by H2 antagonist metiamide.     

Antimycobacterial and H1-antihistaminic activity of 2-substituted piperidine derivatives

2-Substituted derivatives of the antihistaminic agents Bamipine, Diphenylpyraline and of their 1-phenyl analogues were tested for their antimycobacterial and H(1)-antagonistic activities. They are strong H1-receptor antagonists and also inhibit the growth of mycobacterials with a maximum MIC of 6.25 microg/mL against Mycobacterium tuberculosis H(37)Rv. H1-receptor antagonistic potency was slightly decreased by substitution in ring position 2 and distinctly diminished by N-aryl substitution. The antimycobacterial potency of Diphenylpyraline was in general increased by substitution in ring position 2, whereas only a few Bamipine derivatives showed markedly improved activity. A correlation between the two activities was not detected for those compounds.     

Side-chain modified analogues of histaprodifen: asymmetric synthesis and histamine H1-receptor activity

New analogues of histaprodifen with polar side chains have been stereoselectively synthesized and evaluated as histamine H(1)-receptor agonists. As a key transformation the asymmetric aminohydroxylation has been used, which was successfully realized for the first time on an imidazolyl derivative. While all chiral analogues proved to be weak H(1)-receptor antagonists, an achiral keto derivative of histaprodifen turned out to be the first 2-acylated histamine congener displaying partial H(1)-receptor agonism (relative potency 12%).