Effects Of Histamine Receptor Antagonists Research Articles

Lack of incremental effect of histamine receptor antagonists over proton pump inhibitors on the risk of neoplastic progression in patients with Barrett's esophagus: a cohort study.

Long-term acid suppression reduces the risk of progression to esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). Given recent reports about the harmful effects of using chronic proton pump inhibitors (PPI) there is renewed interest in alternative methods of acid suppression. Hence, we studied the effect of H2 receptor antagonists (H2 RA) on the risk of progression to neoplasia in our BE cohort. This is a retrospective analysis of prospectively collected data of patients in our BE registry from 2002 to 2015. Patients' characteristics, endoscopic findings, such as the length of BE, hiatal hernia size and histological findings and patients' use of medications such as PPI, aspirin, H2 RA, metformin and antihyperlipidemic agents were studied. The cohort consisted of 1466 patients with a mean age of 61 ± 13 years. The patients had a predominance of male sex (76.7% [1118/1457]) and Caucasian race (96.6% [1209/1252]). After excluding prevalent high-grade dysplasia (HGD) or EAC, 1025 patients had a median follow up of 43.6 months during which 57 patients progressed to HGD or EAC. PPI use (56% in progressors vs 69% in non-progressors; P = 0.007) but not H2 RA use (12% progressors vs 19% in non-progressors P = 0.162) was associated with lower risk of neoplastic progression. On multivariate analysis, there was no synergistic effect of addition of H2 RA to PPI on risk of neoplastic progression to HGD or EAC (relative risk 0.33; confidence intervals 0.05-2.29, P = 0.262). H2 RA do not seem to have a chemopreventive role in patients with BE.

Identification of a Neuronal Receptor Controlling Anaphylaxis.

Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

Histamine in regulation of bone remodeling processes

Bone remodeling is under autocrine, paracrine, endocrine and central nervous system control. One of the potential endogenous factors affecting bone remodeling is histamine, an endogenous amine which acts as a mediator of allergic reactions and neuromediator, and induces production of gastric acid. Histamine H₁ receptor antagonists are widely used in the treatment of allergic conditions, H₂ receptor antagonists in peptic ulcer disease, and betahistine (an H₃ receptor antagonist and H₁ receptor agonist) is used in the treatment of Ménière's disease. Excess histamine release in mastocytosis and allergic diseases may lead to development of osteoporosis. Clinical and population-based studies on the effects of histamine receptor antagonists on the skeletal system have not delivered unequivocal results. Expression of mRNA of histamine receptors has been discovered in bone cells (osteoblasts and osteoclasts). Histamine synthesis has been demonstrated in osteoclast precursors. Histamine increases bone resorption both by direct effects on osteoclast precursors and osteoclasts, and indirectly, by increasing the expression of RANKL in osteoblasts. In in vivo studies, H₁ and H₂ receptor antagonists exerted protective effects on the bone tissue, although not in all experimental models. In the present article, in vitro and in vivo studies conducted so far, concerning the effects of histamine and drugs modifying its activity on the skeletal system, have been reviewed.

Ontogenetic Serotoninergic Lesioning Alters Histaminergic Activity in Rats in Adulthood

The aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats lesioned as neonates with the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At 3days after birth Wistar rats were pretreated with desipramine (20mg/kg ip) before bilateral icv administration of 5,7-DHT (37.5μg base on each side) or saline-ascorbic (0.1%) vehicle (control). At 10week levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were determined in frontal cortex, striatum, and hippocampus by an HPLC/ED technique. In the hypothalamus, frontal cortex, hippocampus and medulla oblongata, the level of histamine was analyzed by an immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped activity) were performed, and effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists S(+)chlorpheniramine (H(1)), cimetidine (H(2)), and thioperamide (H(3)) were determined. We confirmed that 5,7-DHT profoundly reduced contents of 5-HT and 5-HIAA in the brain in adulthood. Histamine content was also reduced in all examined brain regions. Moreover, in 5,7-DHT-lesioned rats the locomotor and oral activity responses to thioperamide were altered, and apomorphine-induced stereotype was intensified. From the above, we conclude that an intact central serotoninergic system modulates histamine H(3) receptor antagonist effects on the dopaminergic neurons in rats.

Effects of sympathetic histamine on vasomotor responses of blood vessels in rabbit ear to electrical stimulation

To investigate the effects of histamine receptor antagonists on vasoconstriction induced by electrical stimulation (ES) on posterior auricular nerve, and to explore the pre- and post-synaptic effects of sympathetic histamine on the vasomotor responses of vascular smooth muscle in rabbit ear. ES was applied to posterior auricular nerves of the whole rabbit ear at 10 Hz, 20 Hz and 40 Hz, respectively. Besides, the whole ear was perfused with different histamine receptor antagonists under constant perfusion pressure, and the changes in the flow rate of perfusate were observed. The flow rate of venous outflow was decreased by ES at all the 3 frequencies. The ES-induced vasoconstriction at 20 Hz and 40 Hz could be partly inhibited by H(1) receptor antagonist chlorpheniramine (P < 0.05). After exhaustion of histamine in mast cells by pretreatment with specific mast cell degranulator compound 48/80, chlorpheniramine could still inhibit the ES-induced flow rate reduction. In contrast, H(2) receptor antagonist cimetidine could enhance the 40-Hz ES-induced flow rate reduction (P < 0.05). Moreover, ES-induced vasoconstriction at the 3 frequencies could all be enhanced by H(3) receptor antagonist thioperamide (P < 0.05). Stimulation on the auricular nerve may evoke histamine release from sympathetic nerves rather than from mast cells. Moreover, the functions of sympathetic histamine vary from pre-synaptic modulation to post-synaptic vasoconstriction or vasodilatation, via activation of different histamine receptors.

Analgesic Effects Of H1 Receptor Antagonists In The Rat Model Of Formalin-Induced Pain

Histamine receptors mediate nociceptive pathways, especially in the central nervous system. Some studies have demonstrated the analgesic effects of histamine receptor antagonists in the peripheral nervous system. It is not clear whether the local analgesic effect is class-specific or drug-specific.To answer this question, we used three different H1 receptor antagonists (pyrilamine, promethazine, and cetirizine) administered directly in the paw of the rat, intraperitoneally, or in peripheral nerve blockade in the formalin-induced pain model. The effects of the drugs on the number of paw elevations were observed.In phase I, the local administration of pyrilamine caused a dose-dependent reduction on the number of paw elevations; in the highest dose, the number of paw elevations was reduced by 97.8%. Promethazine decreased it by 92%, while cetirizine decreased by 23.9%. In phase II, pyrilamine decreased the number of paw elevations by 93.5%, promethazine by 78.2%, and cetirizine by 80.1%. Intraperitoneal administration of drugs did not change painful behavior. When used in peripheral nerve block, in phase I pyrilamine reduced the number of paw elevations by 96.7%, promethazine by 73.3%, and cetirizine by 23.9%. In phase II, pyrilamine reduced the number of paw elevations by 86.6%, promethazine by 64.4%, and cetirizine by 19.9%.The results demonstrate that H1 receptor antagonists have local analgesic effects, different from the systemic effects, one of them an anti-inflammatory and class-specific effect and the other similarly to the local anesthetic effect, specific for promethazine and pyrilamine.

Histaminergic Activity in a Rodent Model of Parkinson’s Disease

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson's disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 microg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites L: -3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H(1); cimetidine, H(2); thioperamide, H(3) agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H(3) antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.

Histamine ameliorates anti-glomerular basement membrane antibody-induced glomerulonephritis in rats

Anti-glomerular basement membrane (anti-GBM)-induced glomerulonephritis involves T-helper type 1 (Th1) responses leading to rapid crescent formation. As many inflammatory and immune responses in general are affected by histamine, we examined the effects of histaminergic ligands on immune renal injury in the rat. Female Wistar-Kyoto rats were injected intraperitoneally with an antibody against the GBMs. Histaminergic ligands were then injected twice daily for 5 days after which renal function was assessed by proteinuria. Treatment with histamine led to significant dose-dependent reductions in proteinuria compared to the control antibody-injected group and markedly decreased the number of crescentic glomeruli and macrophage infiltration of the glomeruli. Furthermore, histamine significantly decreased the plasma concentration of interleukin-12, a Th1-type cytokine compared to the antibody-injected control animals. Dimaprit, an H(2)/H(4) agonist, mimicked the effects of histamine on proteinuria and crescent formation. Clozapine, an H(4) agonist, tended to mimic the effects of histamine, whereas an H(1), mepyramine, or an H(2) antagonist, ranitidine, did not reverse the protective effect of histamine. We suggest that histamine may alleviate renal injury in anti-GBM glomerulonephritis by suppressing the immune response.

Scratching behavior in NC/Nga mice with dermatitis: Involvement of histamine-induced itching

ABSTRACT Background Itching, a typical symptom in dermatitis, including atopic dermatitis (AD), leads to scratching. In the present study, we investigated whether histamine-induced itching is involved in scratching behavior seen in NC/Nga (NC) mice, in which AD-like dermatitis is induced spontaneously. Methods The severity score of dermatitis, the number of scratches, histamine content, activity of the histamine-forming enzyme histidine decarboxylase (HDC), the number of mast cells and the effect of histamine receptor antagonists were examined. Results We found two types of scratching behavior in NC mice, one of a short duration (0.3-1.0 s) and the other of a longer duration (over 1.0 s). The number of short scratchings and HDC activity increased with age (4–13 weeks) in parallel with the severity of dermatitis in NC mice raised in conventional surroundings. The number of longer-duration scratchings had increased before any apparent development of dermatitis and this type of scratching behavior increased at 13 weeks, as did histamine content and mast cell number in the skin. There were no changes in these parameters in NC mice raised in specific pathogen-free surroundings during the experimental period. Chlorpheniramine (a histamine H receptor antagonist), but not histamine H 2 and H 3/4 receptor antagonists, decreased the number of short scratchings. None of the histamine receptor antagonists decreased the number of long scratchings, whereas tacrolimus reduced both short and long scratching behavior. Conclusions The findings of the present suggest that histamine produced by enhanced HDC activity is involved in the induction of short scratchings in NC mice.

The effects of pyrilamine and cimetidine on mRNA C-fos expression and nociceptive flinching behavior in rats.

C-fos and Fos expression, frequently used as a neural nociceptive marker, is altered by many drugs. The effects of histamine receptor antagonists on c-fos messenger (m)RNA expression are unknown. We examined the effect of local and systemic administration of pyrilamine (H(1) receptor antagonist) and cimetidine (H(2) receptor antagonist) on the nociceptive flinching behavior elicited by injection of 50 micro L of 1% formalin into the dorsal region of the hind paw of rats. Nociceptive flinching behavior was observed for 45 min, and the rats were then killed and lumbar spinal cord obtained for c-fos mRNA expression, measured using the Northern blot hybridization technique. Systemic administration of pyrilamine and cimetidine did not elicit response in nociceptive behavior or in c-fos mRNA expression. When the drugs were locally administered, they affected behavior and c-fos mRNA expression in different patterns. Pyrilamine decreased the number of flinches in a dose dependent manner in both phases, whereas cimetidine did not affect Phase I and decreased the number of flinches in Phase II, but only partially. Pyrilamine 5 and 20 mM decreased c-fos mRNA expression, and cimetidine decreased the expression only at 100 mM. The systemic use of the drugs had no effect on c-fos mRNA expression. Histamine receptor antagonists present antinociceptive effects when administered peripherally. These effects are observed through a nociceptive flinching behavior test and mRNA c-fos expression. Pyrilamine (H(1) receptor antagonist) has a greater antinociceptive effect than cimetidine (H(2) receptor antagonist).

The effect of histamine receptor antagonists on incident colorectal adenomas

The effect of histamine receptor antagonists on incident colorectal adenomas

Standard treatment: the role of antihistamines.

Histamine-1 (H1) antihistamines are the first-line drug for the treatment of urticaria. Major progress has been achieved in recent years both in the understanding of their ligands, the H1-histamine receptors, and therefore in the mechanisms of their pharmacologic effects, as well as in the development of safer antihistamines with low or no sedating effects and no interactions on the level of potassium channels leading to QT-prolongations and interactions on the level of cytochrome P450 isoenzymes. This development has brought antihistamines very close to the ideal antihistamines that are desired by clinicians to treat most types of urticaria in patients who have to take these drugs for a long time.

Histamine H1 and H2 Receptor Antagonists Accelerate Skin Barrier Repair and Prevent Epidermal Hyperplasia Induced by Barrier Disruption in a Dry Environment

Keratinocytes have histamine H1 and H2 receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H2 receptor antagonists famotidine and cimetidine accelerated the recovery of skin barrier function, but histamine and histamine H2 receptor agonist dimaprit delayed the barrier repair. Application of compound 48/80, a histamine releaser, also delayed the recovery. Imidazole, an analog of histamine, had no effect. The histamine H1 receptor antagonists diphenhydramine and tripelennamine accelerated the recovery. Histamine H3 receptor agonist Nalpha-methylhistamine and antagonist thioperamide had no effect. In addition, topical application of famotidine or diphenhydramine prevented epidermal hyperplasia in mice with skin barrier disrupted by acetone treatment in a dry environment (humidity < 10%) for 4 d. In conclusion, both the histamine H1 and H2 receptors in the epidermis are involved in skin barrier function and the cutaneous condition of epidermal hyperplasia.

H1 histamine receptor antagonist inhibits constitutive growth of Jurkat T cells and antigen-specific proliferation of ovalbumin-specific murine T cells

Histamine is produced from histidine by histidine decarboxylase (HDC) in many cells including normal and malignant lymphocytes. We examined the expression of HDC and the effect of histamine receptor antagonists on the proliferation of a human T cell line, Jurkat and on antigen-driven proliferation of lymphocytes from ovalbumin-immunized mice. Our results demonstrate that HDC is inducible in Jurkat cells by anti-CD3. The H1 receptor antagonist triprolidine dose dependently inhibits proliferation of both Jurkat cells and ovalbumin-stimulated murine lymphocytes, while the H2 antagonist ranitidine was ineffective. Alpha-fluoro-methyl-histidine blocking HDC activity did not inhibit the T cell proliferation, suggesting an existing pool of histamine in T cells.

The effect of histamine receptor antagonists on stress-induced catecholamine secretion: an adrenomedullary microdialysis study in the rat

The effects of pretreatment with selective histamine receptor antagonists on changes in sympathoadrenal activity and haemodynamics, induced by 60-min immobilization stress, were studied in conscious rats. Using adrenomedullary microdialysis, it was shown that ranitidine (5 mg/kg, i.v.), a histamine H 2 receptor antagonist, selectively suppressed stress-stimulated noradrenaline secretion without affecting adrenaline response, whereas triprolidine (10 mg/kg, i.v.), a histamine H 1 receptor antagonist, had little effect on stress-induced secretion of both catecholamines. Neither triprolidine nor ranitidine changed the pressor response to 60-min stress. The stress-induced increase in heart rate was not altered by triprolidine, whereas ranitidine reduced it after 30 min of stress. To test whether the anti-secretory effect of ranitidine could be of peripheral origin, in a separate experimental series, a local catecholamine secretion was stimulated by histamine (0.5 mM) perfused through the adrenomedullary dialysis probe. It appeared that triprolidine, but not ranitidine, reduced this effect of histamine. Thus, the present results suggest that during stress, the activity of the central histaminergic system, via histamine H 2-receptors, may selectively modulate noradrenaline secretion by the adrenal gland.

Effects of histamine receptor antagonists injected intrathecally on antinociception induced by opioids administered intracerebroventricularly in the mouse

The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by supraspinally administered μ-, ε-, δ-, and κ-opioid receptor agonists. The effects of intrathecal (i.t.) injections with cyproheptadine [a histamine-1 (H1) receptor antagonist], ranitidine (a H2 receptor antagonist), or thioperamide (a H3 receptor antagonist) injected i.t., on the antinociception induced by morphine (a μ-receptor antagonist), β-endorphin (an ε-receptor agonist), D-Pen2,5-enkephalin (DPDPE, a δ-receptor agonist) or trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohxyl] benzeocetamide (U50,488H, a κ-receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (from 0.31 to 62 nmole), ranitidine (from 0.28 to 56 nmole), or thioperamide (from 0.24 to 48 nmole) alone did not show any antinociceptive effect. The i.t. pretreatment with cyproheptadine or thioperamide dose-dependently attenuated the inhibition of the tail-flick response induced by i.c.v. administered morphine (0.6 nmole), b-endorphin (0.03 nmole), DPDPE (1.5 nmole), and U50,488H (130 nmole). In addition, the i.t. pretreatment with ranitidine dose-dependently attenuated the inhibition of the tail-flick response induced by morphine, b-endorphin and U50,488H without affecting DPDPE-induced response. Our results suggest that spinal histamine H1 and H3 receptors may involved in the production of antinociception induced by supraspinally applied morphine, b-endorphin, DPDPE and U50,488H. Spinal H2 receptors appear to be involved in supraspinally administered morphine, b-endorphin- and U50,488H-induced antinociception but not DPDPE-induced antinociception.

Role of histamine H 1 and H 2 receptor antagonists in the prevention of intimal thickening

Vascular smooth muscle cell migration to the intima from the media and proliferation in the intima play key roles in atherosclerosis and restenosis after coronary angioplasty. Histamine released from adherent platelets at the injured artery and from mast cells in atheromas has stimulant actions on both smooth muscle cell migration and proliferation, and histamine receptor antagonists abolish the effect of histamine in vitro. The aim of this study was to examine the effect of histamine receptor antagonists on intimal thickening. Endothelial injury in the mouse femoral artery was induced by a photochemical reaction between localized irradiation by green light and intravenously administered rose bengal. The histamine H 1 receptor antagonist, diphenhydramine, at a dose of 30 mg/kg or the histamine H 2 receptor antagonist, cimetidine, at a dose of 200 mg/kg was intraperitoneally administered to mice for 21 days after endothelial injury. Twenty-one days after endothelial injury, morphometric analysis was performed to measure the cross-sectional areas of the intima and media. Diphenhydramine significantly reduced the intimal area to 1.1±0.3 (×10 −3 mm 2) compared with the value in the control group, which was 6.2±1.4 (×10 −3 mm 2), but cimetidine (5.5±1.9, ×10 −3 mm 2) did not. Similarly, the ratio of intimal area to medial area in the diphenhydramine-treated group but not in the cimetidine-treated group was significantly reduced (83%). In the in vitro study, cimetidine inhibited neither proliferation nor migration of mouse vascular smooth muscle cells stimulated by platelet-derived growth factor (PDGF). In contrast, diphenhydramine significantly ( P<0.05) inhibited proliferation in a dose-dependent manner, but did not inhibit migration. These results suggest that diphenhydramine, a histamine H 1 receptor antagonist, reduced the formation of intimal hyperplasia, at least in part due to inhibition of cell proliferation. However, cimetidine, a histamine H 2 receptor antagonist, was ineffective. Histamine may play a key role in intimal thickening, in part via histamine H 1 receptors in this model.

P-246 - Pharmacological studies on the respiratory Pharmacological studies on the respiratory tract (Rept. 186): The effects of histamine receptor antagonists on guinea pig rhinitis model.

P-246 - Pharmacological studies on the respiratory Pharmacological studies on the respiratory tract (Rept. 186): The effects of histamine receptor antagonists on guinea pig rhinitis model.

The differential effects of histamine receptor antagonists on morphine- and U-50,488H-induced antinociception in the mouse

The effects of thioperamide, an H 3 antagonist, and histamine H 1 and H 2 antagonists (s.c.) on morphine (s.c. or i.c.v.)- and U-50,488H (i.c.v.)-induced antinociception in male ddY mice were examined using the hot-plate (55°C) test. Thioperamide significantly inhibited morphine-induced antinociception, but not U-50,488H-induced antinociception. The suppressive effect of thioperamide on morphine-induced antinociception was reversed by the H 1 antagonist pyrilamine, but not by the H 2 antagonist zolantidine. On the other hand, pyrilamine significantly potentiated the antinociception induced by morphine, but not that induced by U-50,488H. Zolantidine significantly inhibited morphine-induced antinociception in a dose-dependent manner, but not U-50,488H-induced antinociception. Both astemizole, an H 1 antagonist, and ranitidine, an H 2 antagonist, which are known to barely cross the blood brain barrier, did not affect morphine-induced antinociception. These results suggest that morphine-induced antinociception may be potentiated by activation of H 2 receptors and suppressed by activation of H 1 receptors in the brain. Furthermore, neuronal histamine release induced by thioperamide may suppress morphine-induced antinociception through H 1 receptors.

P-209 - Effects of histamine receptor antagonists on diazepam-induced hyperphagia in rats

P-209 - Effects of histamine receptor antagonists on diazepam-induced hyperphagia in rats