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PubMed1977

[Vasodilator action of (+/-)-1-(3, 4, 5-trimethoxybenzyl)-6-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride (CV-705) in anesthetized dogs (author's transl)].

The vasodilator action of CV-705 was investigated in a number of vascular regions of anesthetized mongrel dogs and this action was compared with that of papaverine. When CV-705 was administered intravenously the vertebral, common carotid and internal carotid blood flow was increased considerably and was long-lasting. These effects were most remarkable among the regions tested. Femoral, aortic and coronary blood flow were also increased. On the other hand, the blood flow through superior mesenteric artery and portal vein increased only slightly. Renal blood flow was decreased slightly after an intravenous administration, whereas an increase was observed after an intra-arterial administration. Such a regional distribution of blood flow after CV-705 was quite similar to that observed with papaverine. CV-705 was well absorbed through the digestive tract. CV-705 given intravenously showed a weak hypotensive and positive chronotropic action. The increase in common carotid blood flow induced by intra-arterial administration of CV-705 was not affected by pre-treatment with atropine or triprolidine, but was partially suppressed by pre-treatment with propranolol. These results suggest that CV-705 has a papaverine-like action as well as a weak beta-adrenoceptor stimulating action, consequently a vasodilator action occurs.

Anesthesia↗
PubMed2006

Histaminergic neurons protect the developing hippocampus from kainic acid-induced neuronal damage in an organotypic coculture system.

The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H1) and histamine 3 (H3) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 microM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 microM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H3 receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H1 receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors.

Animals↗
PubMedDate not supplied

Heterogeneity of drug susceptibility of mouse active anaphylactic shock.

To determine the main mediators for mouse anaphylactic shock, the suppression of active anaphylactic shock by cyproheptadine, an antagonist of histamine/serotonin, and CV-6209, an antagonist of platelet-activating factor (PAF), was systematically evaluated using various mouse strains. The suppression was quite heterogeneic depending on the mouse strain and method for sensitization. When sensitization was done with bovine serum albumin (BSA) plus Bordetella pertussis organisms, anaphylactic shock in C57BL/6N mice was suppressed by cyproheptadine but not by CV-6209. In contrast, shock in C3H/HeN and WBB6F1-W/Wv mice was suppressed by CV-6209 but not by cyproheptadine. Shock in BALB/c mice was suppressed by both agents but that in WBB6F1-(+)/+ mice was not at all by either one. DS and BDF1 mice showed differences due to the length of the sensitization period; shock was not suppressed by cyproheptadine with a shorter sensitization (9 to 11 days) but clearly suppressed with prolonged sensitization of 14 to 15 days. Shock in DS, WBB6F1-(+)/+ and BDF1 mice, which was not suppressed by either agent alone, was strongly suppressed by the combination of the two agents. In animals which had been sensitized with BSA emulsified with Freund's complete adjuvant (FCA) and given DL-propranolol as a shock potentiator, a similar pattern of drug susceptibility as that in the pertussis-vaccinated animals was obtained in general, although a discrepancy was seen with regard to the suppression of CV-6209 in C3H/HeN and BDF1 mice. Synergistic suppression by CV-6209 and cyproheptadine was also very clear with the WBB6F1-(+)/+ mice sensitized using FCA. In addition, results quite similar to those with cyproheptadine were obtained with the other two antihistamines, triprolidine almost devoid of antiserotonin activity and oxatomide, in testing with BDF1 mice sensitized using Bordetella pertussis organisms. From these findings, the conclusion is that histamine and PAF play major roles solely or in combination in mouse active anaphylactic shock.

Anaphylaxis↗
PubMed1998

Suppressive effects of antihistaminic and/or anti-PAF agents on passive anaphylactic shock in mice sensitized with allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum.

For the immunopharmacological characterization of murine passive anaphylactic shock, the effects of antihistaminics and/or anti-platelet-activating factor (anti-PAF) agents were studied on the shock mediated by allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum. IgE antibody-mediated shock was strongly suppressed by cyproheptadine (10 mg/kg, ip) in every strain regardless of the age and sex of the mice and the presence or absence of a shock potentiator. As far as tested with CTS, DS, and B6D2F1 mice, IgE antibody-mediated shock was also suppressed by the other two antihistamines, triprolidine (10 mg/kg, ip) and oxatomide (100 mg/kg, po). This type of shock was not suppressed by an anti-PAF agent, CV-6209 (3.3 mg/kg, iv), when tested on aged CTS mice given no shock potentiator and young DS mice given a potentiator such as Bordetella pertussis organisms or DL-propranolol. IgG1 antibody-mediated shock was also suppressed by cyproheptadine in general except for CTS mice. Suppression in the DL-propranolol-treated DS and C3H/He mice was not very marked on sensitization with undiluted or slightly diluted IgG1 ascites but quite striking on sensitization with properly diluted ascites. In contrast with the effect of cyproheptadine, suppression by CV-6209 was obvious in aged CTS mice but not in young DL-propranolol-treated DS mice. The shock in DL-propranolol-treated DS mice sensitized with undiluted or slightly diluted ascites was completely abolished by the combined use of these two agents. These results suggest that histamine and/or PAF play a major role in IgE antibody- and IgG1 antibody-mediated shock. However, so far as tested in young DS mice, the shock mediated by hyperimmune serum differed in drug susceptibility from that mediated by the monoclonal antibodies. In the absence of shock potentiators, prevention was produced by cyproheptadine in the males which had been sensitized with the 1:4 or 1:8 dilution of the immune serum. In the presence of DL-propranolol, prevention was not produced even by the combined treatment with cyproheptadine and CV-6209. Therefore, it is likely that some mediators other than histamine and PAF, whose release is triggered by antibody isotypes other than IgE and IgG1, play a greater role for the shock mediated by hyperimmune serum than for the shock mediated by IgE or IgG1 antibody, especially in the presence of shock potentiators.

Anaphylaxis↗
PubMed2001

Role of mast cells in zymosan-induced peritoneal inflammation in Balb/c and mast cell-deficient WBB6F1 mice.

Zymosan-induced peritonitis was investigated in mast cell-deficient WBB6F1 mice and in Balb/c mice pretreated with mast cell stabilizer (cromolyn) or antagonists of histamine receptors (mepyramine, triprolidine, cimetidine, or ranitidine). The inherited mast cell deficiency in W/Wv knockouts of WBB6F1 mice impaired significantly the level of histamine and plasma exudation (measured 30 min after stimulation) as well as the influx of exudatory leukocytes, accumulation of plasma and exudate chemoattractants, and the release of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) measured at 6 h of inflammation. All of those factors were fully restored after selective intraperitoneal reconstitution of W/Wv mice with bone marrow-derived mast cells from their control +/+ counterparts. Cromolyn pretreatment of Balb/c mice reduced exclusively the early plasma exudation and histamine influx. Blocking of histamine receptors inhibited not only the early plasma exudation but also temporarily diminished primary leukocyte influx and levels of MCP-1 and IL-1beta. In conclusion, mast cells play an important role in the initiation of zymosan-induced peritonitis and modulate its further course.

Animals↗
PubMed1976

Prevention of secretagogue-induced ulcers in the rat.

An inhibitor of gastric secretion, Pfizer UK -9040, a derivative of the antihistamine triprolidine, was given orally 50 to 100 mg per kg 1 hr before and at various times during a 24-hr subcutanwous infusion of ulcerogenic secretagogues. The higher the dose and the more frequent the dosage, the lower was the incidence, severity, number, and perforations of duodenal ulcers. The mechanisms by which UK -9040 prevents these ulcers is probably inhibition of gastric secretion.

Animals↗
PubMed1981

[3H]Mianserin: differential labeling of serotonin and histamine receptors in rat brain.

Mianserin, a tetracyclic antidepressant, is a potent serotonin (5-HT) and histamine H1 antagonist in peripheral smooth muscle systems. Mianserin was found to possess high affinity for 5-HT2 and histamine H1 receptor binding sites in brain membranes. By using [3H]mianserin, both 5-HT2 and histamine H1 receptors can be specifically labeled in rat cerebral cortex membranes. Simultaneous incubation of brain membranes with 300 nM triprolidine or 30 nM spiroperidol enables the selective labeling of 5-HT2 or histamine H1 receptors, respectively. In the guinea-pig cerebellum, [3H]mianserin exclusively labels histamine H1 receptors, since 5-HT2 sites are virtually absent in this area.

Animals↗
PubMed2005

Delineation of receptor-ligand interactions at the human histamine H1 receptor by a combined approach of site-directed mutagenesis and computational techniques - or - how to bind the H1 receptor.

Histamine H(1) antagonists or "antihistamines" are one of the most prescribed drug families in Western countries. They exert their effect by binding to the histamine H(1) receptor, a receptor belonging to the class of rhodopsin-like G protein-coupled receptors (GPCRs). In this review, the binding of ligands to the human histamine H(1) receptor with respect to site-directed mutagenesis studies and molecular modeling techniques is described. The ligands described include agonists (histamine and histaprodifens), a stereoselective partial agonist (lisuride), and selected inverse agonists (mepyramine, acrivastine and triprolidine).

Computational Biology↗
PubMed2005

Carrier mediated transport of chlorpheniramine and chlorcyclizine across bovine olfactory mucosa: implications on nose-to-brain transport.

Delivery to the CNS via the nasal cavity has been pursued as a means to circumvent the blood-brain barrier (BBB), yet the mechanism of drug transport across this novel route is not well understood. Hydroxyzine and triprolidine have been reported to readily reach the CNS following nasal administration, whereas no measurable amounts of chlorcyclizine or chlorpheniramine, structurally similar antihistamines, were observed in the CSF. The permeation of chlorpheniramine and chlorcyclizine in vitro across the bovine olfactory mucosa was studied to investigate the biological and physicochemical characteristics that contribute to the limited CNS disposition of these compounds following nasal administration. The submucosal to mucosal fluxes (J(s-m)) of chlorcyclizine and chlorpheniramine across the olfactory mucosa were significantly greater than the mucosal to submucosal fluxes (J(m-s)). Moreover, the submucosal-mucosal permeability of both compounds was temperature dependent and saturable. In the presence of metabolic inhibitors (ouabain and 2,4-dinitrophenol) and P-glycoprotein (P-gp)/multidrug resistance protein 1 (MRP1) inhibitors (quinidine and verapamil), the J(m-s) increased and J(s-m) decreased significantly. These results indicate that chlorpheniramine and chlorcyclizine are effluxed from the olfactory mucosa by efflux transporters such as P-gp and MRP1. Transport studies across inert polymeric membranes demonstrated that the permeability of chlorpheniramine and chlorcyclizine decreased at donor concentrations higher than 3 mM suggesting that physicochemical properties such as self-aggregation also play a role in the reduced olfactory mucosal permeability of these compounds at higher concentrations.

Animals↗
PubMed2006

Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.

Ten antihistamine drugs, diphenhydramine, orphenadrine, chlorpheniramine, diphenylpyraline, triprolidine, promethazine, homochlorcyclizine, cyproheptadine, cloperastine and clemastine, have been found to be extractable from human plasma samples using MonoTip C18 tips, inside which C18- bonded monolithic silica gel was fixed. Human plasma (0.1 mL) containing the ten antihistamines was mixed with 0.4 mL of distilled water and 25 microL of a 1 M potassium phosphate buffer (pH 8.0). After centrifugation of the mixture, the supernatant fraction was extracted to the C18 phase of the tip by 25 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C18 phase were then eluted with methanol by five repeated aspirating/dispensing cycles. The eluate was injected into a gas chromatography (GC) injector without evaporation and reconstitution steps, and was detected by a mass spectrometer with selected ion monitoring in the positive-ion electron impact mode. The separation of the ten drugs from each other and from impurities was generally satisfactory using a DB-1MS column (30 m x 0.32 mm i.d., film thickness 0.25 microm). The recoveries of the ten antihistamines spiked into plasma were 73.8-105%. The regression equations for the ten antihistamines showed excellent linearity with detection limits of 0.02-5.0 ng/0.1 mL. The within-day and day-to-day coefficients of variation for plasma were not greater than 9.9%. The data obtained from determination of diphenhydramine and chlorpheniramine in human plasma after oral administration of the drugs are also presented.

Administration, Oral↗
PubMed1996

Relative contribution of the selectins in the neutrophil recruitment caused by the chemokine cytokine-induced neutrophil chemoattractant (CINC).

Rat CINC induced a dose- and time-dependent accumulation of neurophils into murine air-pouches, a response which was inhibited by two selective H1-antagonists, mepyramine and triprolidine (approximately 60%). As pretreatment with fucoidin abolished CINC effect, the relative time-related contribution of selectins on this process was then investigated by using specific monoclonal antibodies (mAb). Anti-CD62L mAb gave a similar degree of inhibition of CINC-induced cell accumulation both at the 2h and 4h time-point (approximately 75%). Anti-CD62P mAb, but not the anti-CD62E mAb, inhibited PMN accumulation at 2h (65%), but only co-administration of these two mAbs inhibited the cell response to CINC at the 4h time-point (90%). Thus endogenous histamine, CD62L, CD62P, and CD62E, though to a different degree, are required for PMN extravasation observed in response to CINC administration.

Animals↗
PubMed2000

Biosynthesis of interleukin-6, an autocrine growth factor for melanoma, is regulated by melanoma-derived histamine.

Interleukin-6 is an autocrine growth factor in advanced stage melanoma and biosynthesis of IL-6 is increased by histamine in various cell lines. In our study we analysed the direct relation of histamine and IL-6 synthesis in human melanoma cell lines. All melanoma cells contained IL-6 mRNA, but only metastatic melanoma cells secreted the IL-6 protein. The H1 histamine receptor antagonist triprolidine decreased gene expression and biosynthesis of IL-6, while other histamine receptor antagonists had no effect. These data indicate that endogenous histamine has a definite role in the regulation of local IL-6, suggesting that histamine and IL-6 could be part of autocrine growth regulation of the tumor.

Glucose-6-Phosphate Isomerase↗
PubMed1994

Biphasic increase in cytosolic free calcium induced by bradykinin and histamine in cultured tracheal smooth muscle cells: is the sustained phase artifactual?

The effects of bradykinin (BK) and histamine on intracellular Ca2+ ([Ca2+]i) were studied in fura-2-loaded guinea-pig tracheal smooth muscle cells in culture. BK, at 10 nM, and histamine, at 100 microM, induced a rise in [Ca2+]i which was inhibited by the B2 antagonist Hoe 140 and by the H1 antagonist triprolidine, respectively. This rise in [Ca2+]i is biphasic, consisting of a rapid transient phase followed by a sustained phase. The transient phase, induced by either BK or histamine, was strongly inhibited by thapsigargin, a microsomal Ca(2+)-ATPase inhibitor, usually used to deplete certain intracellular Ca(2+)-stores. Ni2+ (4 mM) did not affect the transient phase but abolished the sustained phase when cells were stimulated by BK, further supporting the fact that the transient phase was only dependent on intracellular Ca2+ pools. The sustained phase was partially (for BK) and completely (for histamine) inhibited by 30 microM Mn2+. This effect could be completely reversed by the addition of DTPA, a cell-impermeant chelator of Mn2+, indicating that the Mn2+ exerted its effect extracellularly. The presence of 1 mM probenecid (an inhibitor of a membrane organic anion transporter that extrudes fura-2) drastically inhibited the sustained phase by more than 77% for BK and 88% for histamine. Our results suggest that the effects of BK and histamine on airway smooth muscle cells are mediated via bradykinin B2 receptors and histamine H1 receptors, respectively whose activation allows the rapid transient rise in [Ca2+]i from thapsigargin-sensitive intracellular Ca2+ pools. The sustained phase is proposed to be drastically influenced by an acceleration of fura-2 extrusion during the increase of [Ca2+]i via a probenecid-sensitive mechanism.

Animals↗
PubMed1994

Bradykinin-induced contraction of guinea pig lung in vitro.

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Studies on the central effects of the H1-antagonist, loratadine.

Effects of loratadine (10, 20 and 40 mg) on visuo-motor coordination, dynamic visual acuity, short-term memory, digit symbol substitution, and on subjective assessments of mood were tested before, and 0.5, 1.5, 3.5 and 5.5 h after ingestion by 6 healthy female adults. There were no effects of 10 or 20 mg loratadine. With 40 mg loratadine the number of substitutions on the digit symbol test was reduced 5.5 h after ingestion, and on dynamic visual acuity response time was increased at 3.5 h and the number of responses missed was increased at 5.5 h. Triprolidine (10 mg) which was used as active control impaired performance on all the tasks and impaired performance was observed at all times after ingestion. Loratadine is a promising antihistamine for individuals involved in skilled activity. The anticipated single daily dose of 10 mg is unlikely to impair performance.

Adult↗
PubMed1982

H1- and H2-receptors in the guinea-pig heart: an electrophysiological study.

The mechanical and electrophysiological effects of 2-pyridylethylamine (PEA) and 4-methylhistamine (4MeH) in different sections of guinea-pig heart were examined. 4MeH produced a dose-dependent increase in contractility in the right ventricle and the right atrium, and a decrease in functional refractory period (FRP) in all the sections studied; the action potential duration was decreased and the plateau phase was usually heightened in both atria and the ventricle. These effects were consistently antagonized by cimetidine. PEA-induced changes in contractility, FRP and the action potential profile were studied in the presence of cimetidine. Triprolidine antagonized PEA effects on FRP and the action potential profile only in the left atrium. The results obtained are discussed in terms of the functional role of both H1 and H2 receptors in the various guinea-pig heart sections.

Action Potentials↗
PubMed1983

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 degrees C. SCATCHARD'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 greater than triprolidine greater than promethazine much greater than cimetidine. Binding data are in correlation with the previous pharmacological studies.

Aminopyridines↗
PubMed1986

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.

Animals↗