H2-receptor Antagonist Cimetidine Research Articles

Management of Medication-Induced Psychiatric Disorders.

Management of Medication-Induced Psychiatric Disorders.

Histamine causes endothelium‐independent dilation of mouse bladder feeder arterioles

In addition to being highly vascularized, the urinary bladder vasculature has unique properties that help to maintain blood flow during voiding and filling. Unlike other vessels of similar size, however, bladder arterioles do not contract to increases in intraluminal pressure. Prolonged decreases in bladder blood flow are linked to many types of bladder dysfunction, including painful bladder syndrome and interstitial cystitis. Although the vasculature has an important role in bladder dysfunction, the mechanisms regulating vasculature diameter in the bladder are still widely unknown. We tested the hypothesis that histamine, an important pro-inflammatory compound released from mast cells in the bladder wall, also alters bladder arteriolar diameter. Using pressure myography with isolated bladder feed arterioles, concentration-response curves to histamine (1 nM – 10 µM) were performed in vessels constricted with the thromboxane mimetic U-46619 (10 nM). Histamine caused a concentration-dependent vasodilation that was inhibited by the histamine H2 receptor antagonist cimetidine (10 µM) but not the H1 receptor antagonist fexofenadine (10 µM). Histamine-dependent vasodilation was not inhibited by the NOS inhibitor L-NAME (200 µM), the inward rectifier K+ channel blocker BaCl2 (100 µM), or endothelial denudation, suggesting the dilation was endothelium-independent. Alternatively, increasing extracellular K+ (35 mM) or exposure to the KV channel blocker XE-991 (10 µM) attenuated dilations to histamine. These findings suggest the H2 receptors in bladder vascular smooth muscle, and not the endothelium, mediate histamine-induced dilation in bladder arterioles. Since H2 receptors are coupled to GaS, these findings also suggest that histamine dilation results from an increase in cAMP that may hyperpolarize smooth muscle cells via protein kinase A-mediated activation of smooth muscle KV channels.

On-chip ion pair-based dispersive liquid-liquid extraction for quantitative determination of histamine H2 receptor antagonist drugs in human urine

In the present work, an ion-pair based dispersive liquid-liquid microextraction was performed on a centrifugal chip for the first time. The entire DLLME procedure, including flow direction, desperation, and sedimentation of the extracting phase, can be fulfilled automatically on a solitary chip. The chip was made of Poly(methyl methacrylate) (PMMA) and was of two units for two parallel extractions, each consisting of three chambers (for the sample solution, extracting solvents, and sedimentation). As the chip rotated, fluids flowed within the chip, and the dispersion, mixing, extraction, and sedimentation of the final phase were performed on the chip by simply adjusting the spin speed. Determination of two histamine H2 receptor antagonist drugs, cimetidine and ranitidine, as the model analytes from the urine samples was done using the developed on-chip ion-pair based DLLME method followed by an HPLC-UV. The effective parameters on the extraction efficiency of the model analytes were investigated and optimized using the one variable at a time method. Under optimized conditions, the calibration curve was linear in the range of 15–2000 μg L−1 with a coefficient of determination (R2) more than 0.9987. The relative standard deviations (RSD %) for extraction and determination of the analytes were less than 3.7% based on five replicated measurements. LODs less than 10.0 μg L−1 and preconcentration factors higher than 39-fold were obtained for both of the model analytes. The proposed chip enjoys the advantages of both the DLLME method and miniaturization on a centrifugal chip.

Acupuncture for symptomatic gastroparesis.

Acupuncture for symptomatic gastroparesis.

Miscellaneous Drugs and Male Reproduction.

In addition to main categories of medications believed to have negative impacts on male reproduction, there are a number of miscellaneous drugs with some evidence for such adverse reactions. Because of its widespread use and over-the-counter availability, the H2 receptor antagonist cimetidine is most concerning. As a competitive antagonist at androgen receptors, it can impact the HPG axis and semen quality. In this chapter, we review the studies of this drug and other histamine H2 receptor antagonists in men and experimental species. Several other medications are concerning and the evidence for negative effects on reproduction are covered: colchicine, domperidone, hydroxyurea, metformin, metoclopramide, mifepristone, retinoids, and statins.

Molecular Encapsulation of Histamine H2-Receptor Antagonists by Cucurbit[7]Uril: An Experimental and Computational Study

The histamine H2-receptor antagonists cimetidine, famotidine and nizatidine are individually encapsulated by macrocyclic cucurbit[7]uril (CB[7]), with binding affinities of 6.57 (±0.19) × 103 M−1, 1.30 (±0.27) × 104 M−1 and 1.05 (±0.33) × 105 M−1, respectively. These 1:1 host-guest inclusion complexes have been experimentally examined by 1H-NMR, UV-visible spectroscopic titrations (including Job plots), electrospray ionization mass spectrometry (ESI-MS), and isothermal titration calorimetry (ITC), as well as theoretically by molecular dynamics (MD) computation. This study may provide important insights on the supramolecular formulation of H2-receptor antagonist drugs for potentially enhanced stability and controlled release based on different binding strengths of these host-guest complexes.

Efficacy of Sucralfate in Reflux Disease in comparison to H2 – Receptor Antagonist: A Meta-Analysis of Randomized Trials

Background and Aim: Reflux esophagitis is characterized by the erosions of esophagus due to gastric acids. H2-Recptor antagonists are considered as effective therapy. We compared sucralfate with H2-receptor antagonist for treatment of reflux esophagitis. Methods: Seven studies are selected from different databases (PUBMED, MEDLINE, COCHRANE LIBRARY, CINAHL etc.) comparing the treatment of sucralfate with H2-receptor antagonists (cimetidine and ranitidine). All studies selected are randomized controlled clinical trials. We applied inclusion and exclusion criteria for selection of studies. We also checked for heterogeneity and publication bias. We calculated odds ratio and 95% confidence interval for each study. We searched for national library of medicine’s clinical trial registry for any unpublished data. Results: Seven studies consisting of 319 patients finally selected for meta-analysis. We evaluated confidence interval and odds ratio for each study. None of the study show statistical significant result (p>0.05). The overall effect obtained by combining studies shows no statistical significant result (OR= 1.357, 95% CI=0.834 to 2.206, P-value=0.219, I2=0) between sucralfate and H2-recptor antagonist. There is no heterogeneity among the studies (I2=0, χ2 =4.8). Conclusion: We can conclude that sucralfate is an effective alternate for treatment of reflux disease.

Vitamin B12-induced spermatogenesis recovery in cimetidine-treated rats: effect on the spermatogonia number and sperm concentration.

The H2-receptor antagonist cimetidine is an antiulcer drug also used for the treatment of cancer due to its antiangiogenic effect. However, this drug has caused structural changes in the seminiferous tubules. Vitamin B12 has been used as a therapeutic agent for the treatment of male infertility. The supplementation of rats with vitamin B12 during cimetidine treatment has recovered the damaged seminiferous tubules, but how this vitamin restores the seminiferous epithelium has not been clarified. In this study, we evaluated whether vitamin B12 improves the number of spermatogonia, spermatocytes, and sperm concentration in cimetidine-treated rats. Adult male rats were treated for 50 days as follows: cimetidine group received 100 mg kg−1 b.w. of cimetidine, cimetidine-B12 group received cimetidine and 3 μg of vitamin B12-hydroxocobalamin, B12 group received only 3 μg of vitamin, and control group received saline. Sperm concentration was calculated and historesin-embedded testes sections were used for the quantitative analyses of spermatogonia (A; In/B) and spermatocytes. TUNEL method and PCNA immunofluorescence were performed. Cimetidine caused a significant reduction in sperm concentration. TUNEL-positive spermatogonia and spermatocytes were correlated to a significant reduction in the number of these cells. In cimetidine-B12 group, sperm concentration was higher than cimetidine group and a significant increase in the number of spermatogonia (stages II–VI) was correlated to a high incidence of PCNA-immunolabeled spermatogonia and spermatocytes. The results show that the supplementation of rats with vitamin B12 during cimetidine treatment increases sperm concentration and exerts a potential effect in the recovery of spermatogonia and spermatocytes.

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain.

BackgroundIt is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain.MethodsNeuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC−/− (histidine decarboxylase gene knockout) and IL-1R−/− (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1β production, respectively.ResultsHistidine (100 mg/kg, i.p.) administered throughout days 0–3, 0–7, or 0–14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2–3, 4–7, and 8–14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1β upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC−/− mice and IL-1R−/− mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia.ConclusionsThese results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1β production in the spinal cord following nerve injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0637-0) contains supplementary material, which is available to authorized users.

The ABCG2 efflux transporter from rabbit placenta: Cloning and functional characterization

In human placenta, the ATP-binding cassette efflux transporter ABCG2 is highly expressed in syncytiotrophoblast cells and mediates cellular excretion of various drugs and toxins. Hence, physiological ABCG2 activity substantially contributes to the fetoprotective placenta barrier function during gestation. Developmental toxicity studies are often performed in rabbit. However, despite its toxicological relevance, there is no data so far on functional ABCG2 expression in this species. Therefore, we cloned ABCG2 from placenta tissues of chinchilla rabbit. Sequencing showed 84–86% amino acid sequence identity to the orthologues from man, rat and mouse. We transduced the rabbit ABCG2 clone (rbABCG2) in MDCKII cells and stable rbABCG2 gene and protein expression was shown by RT-PCR and Western blot analysis. The rbABCG2 efflux activity was demonstrated with the Hoechst H33342 assay using the specific ABCG2 inhibitor Ko143. We further tested the effect of established human ABCG2 (hABCG2) drug substrates including the antibiotic danofloxacin or the histamine H2-receptor antagonist cimetidine on H33342 accumulation in MDCKII-rbABCG2 or -hABCG2 cells. Human therapeutic plasma concentrations of all tested drugs caused a comparable competitive inhibition of H33342 excretion in both ABCG2 clones. Altogether, we first showed functional expression of the ABCG2 efflux transporter in rabbit placenta. Moreover, our data suggest a similar drug substrate spectrum of the rabbit and the human ABCG2 efflux transporter.

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Histamine is a biogenic amine that is widely distributed and has multiple functions, but the role it plays in acute myocardial infarction (AMI) remains unclear. In this study, we investigated the origin and contribution of endogenous histamine to AMI. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine generation. Using HDC-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the HDC promoter, we identified HDC expression primarily in CD11b+Gr-1+ immature myeloid cells (IMCs) that markedly increase in the early stages of AMI. Deficiency of histamine in HDC knockout mice (HDC−/−) reduced cardiac function and exacerbated the injury of infarcted heart. Furthermore, administering either an H1 receptor antagonist (pyrilamine) or an H2 receptor antagonist (cimetidine) demonstrated a protective effect of histamine against myocardial injury. The results of in vivo and in vitro assays showed that histamine deficiency promotes the apoptosis of cardiomyocytes and inhibits macrophage infiltration. In conclusion, CD11b+Gr-1+ IMCs are the predominant HDC-expressing sites in AMI, and histamine plays a protective role in the process of AMI through inhibition of cardiomyocyte apoptosis and facilitation of macrophage infiltration.

Aldosterone Decreases Nitric Oxide Mediated Dilatation through a Histamine H2 Dependent Mechanism in Intracerebral Arteries from Human and Mice

Background Prolonged exposure to aldosterone has a contractile effect through inhibition of NO-mediated vasodilatation in mice mesenteric arteries. This effect involves histamine release from perivascular mast cells. Furthermore, high plasma aldosterone gives exacerbated outcome after stroke. It was hypothesized that aldosterone affects intracerebral vessels by histamine receptor H2 activation resulting in vasospasms. Method: Changes in luminal diameter were measured in perfused intracerebral arteries (size 25–45 μm) from humans with operable brain tumors and mice. Results: Secondary dilatation (recovery) in response to high K+ was observed in human (50.4 %) and mice intracerebral arteries (52.5 %). Pretreatment with aldosterone (10-9M, 60 min) significantly inhibited recovery in mice (12.3 %). The inhibition was fully reversible. Pretreatment with N(G)-nitro-L-arginine methyl ester (10-5M) significantly inhibited recovery in response to high K+ in mice (13.5 %). Similar tendencies were seen on human intracerebral arteries. The effect of aldosterone on recovery in mice arteries was inhibited by the histamine H2 receptor antagonist cimetidine (10-5M, 55.3 %). RT-PCR showed expression of the mineralocorticoid receptor in human cerebral cortex and human intracerebral arteries. Conclusion Aldosterone inhibits NO dependent dilatation in both human and mice intracerebral arteries. The inhibition is mediated through the histamine H2 receptor. This mechanism could potentially be involved in cerebral vasospasms occurring after stroke. Foundation: Danish Research Council and Danish Heart Foundation.

A Murine Model of Asparaginase Allergy

In order to study interventions that influence the severity of symptoms and serum asparaginase activity following asparaginase-induced hypersensitivity reactions, we developed a murine model of asparaginase allergy that recapitulates key features of clinical hypersensitivity to native E. coli asparaginase. BALB/c mice received 10 μg ip doses of E. coli asparaginase formulated with aluminum hydroxide adjuvant on day 0 and 14 of treatment in order to sensitize mice to asparaginase. Asparaginase allergies were induced in sensitized mice by challenging with a 100 μg iv dose of E. coli asparaginase on day 24 of treatment. The severity of hypersensitivity was reflected by the decrease in rectal temperature following the asparaginase challenge. Pre-challenge plasma samples were collected for anti-asparaginase antibody levels before inducing asparaginase allergies, and post-challenge samples were collected at the end of the experiment for measuring anti-asparaginase antibody levels, asparaginase activity, and mouse mast cell protease 1 (mMCP-1) levels.Sensitized mice developed high levels of anti-asparaginase IgG antibodies (P = 1.1 x 10-7) and had immediate hypersensitivity reactions (P = 3.3 x 10-10) to asparaginase upon challenge compared to non-sensitized mice. Furthermore, sensitized mice had profoundly lower plasma asparaginase activity (P = 4.2 x 10-13) and elevated levels of mouse mast cell protease 1 (mMCP-1, P = 6.1 x 10-3) after the asparaginase challenge compared to non-sensitized mice.We investigated the influence of pretreatment with the H1 receptor antagonist triprolidine, the H2 receptor antagonist cimetidine, the PAF receptor antagonist CV-6209, or dexamethasone on the severity of asparaginase-induced allergies. Our studies showed that the combination of triprolidine and CV-6209 was best for mitigating asparaginase-induced hypersensitivity symptoms (i.e., temperature drop) compared to non-pretreated, sensitized mice (P = 1.2 x 10-5). However, pretreatment with oral dexamethasone (4 mg/L in drinking water starting 7 days before asparaginase sensitization) was the only agent capable of mitigating the severity of the hypersensitivity symptoms (P = 0.03) and also partially restoring asparaginase activity (P = 8.3 x 10-4) compared to sensitized mice.Dose adjustment strategies were investigated for rescuing asparaginase activity in sensitized mice without requiring pretreatment with dexamethasone, and a 5-fold greater dose of asparaginase was required to restore enzyme activity to a similar concentration as in non-sensitized mice. In the absence of pretreatment, we found that the severity of asparaginase-induced reactions increased in a dose-dependent manner and that mMCP-1 levels correlated to the severity of the reactions (R2 = 0.577, P = 3.0 x 10-16).Our results suggest a role of histamine and PAF in asparaginase-induced allergies and demonstrate possible strategies for mitigating the severity of asparaginase-induced reactions and maintaining targeted concentrations of asparaginase. Furthermore, our results indicate that mast cell-derived proteases released during allergic reactions to asparaginase may be a useful marker of hypersensitivity, as elevated levels of mMCP-1 were detected in all sensitized mice and correlated with the severity of the reaction. DisclosuresEvans:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.

Communication between mast cells and rat submucosal neurons.

Histamine is a mast cell mediator released e.g. during food allergy. The aim of the project was to identify the effect of histamine on rat submucosal neurons and the mechanisms involved. Cultured submucosal neurons from rat colon express H1, H2 and H3 receptors as shown by immunocytochemical staining confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) with messenger RNA (mRNA) isolated from submucosal homogenates as starting material. Histamine evoked a biphasic rise of the cytosolic Ca(2+) concentration in cultured submucosal neurons, consisting in a release of intracellularly stored Ca(2+) followed by an influx from the extracellular space. Although agonists of all three receptor subtypes evoked an increase in the cytosolic Ca(2+) concentration, experiments with antagonists revealed that mainly H1 (and to a lesser degree H2) receptors mediate the response to histamine. In coculture experiments with RBL-2H3 cells, a mast cell equivalent, compound 48/80, evoked an increase in the cytosolic Ca(2+) concentration of neighbouring neurons. Like the response to native histamine, the neuronal response to the mast cell degranulator was strongly inhibited by the H1 receptor antagonist pyrilamine and reduced by the H2 receptor antagonist cimetidine. In rats sensitized against ovalbumin, exposure to the antigen induced a rise in short-circuit current (I sc) across colonic mucosa-submucosa preparations without a significant increase in paracellular fluorescein fluxes. Pyrilamine strongly inhibited the increase in I sc, a weaker inhibition was observed after blockade of protease receptors or 5-lipoxygenase. Consequently, H1 receptors on submucosal neurons seem to play a pivotal role in the communication between mast cells and the enteric nervous system.

Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain.

The upregulation of Nav1.8 in primary afferents plays a critical role in the development and persistence of neuropathic pain. The mechanisms underlying the upregulation are not fully understood. The present study aims to investigate the regulatory effect of histamine on the expression of Nav1.8 in primary afferent neurons and its involvement in neuropathic pain. Histamine at 10(-8) M increased the expression of Nav1.8 in cultured DRG neurons. This effect could be blocked by H2 receptor antagonist cimetidine or famotidine, but not by H1 receptor antagonist pyrilamine or dual H3 /H4 antagonist thioperamide. Peri-sciatic administration of histamine increased Nav1.8 expression in the sciatic nerve and L4/L5 DRG neurons in a dose-dependent manner, accompanied with remarkable mechanical allodynia and heat hyperalgesia in the ipsilateral hindpaw. Famotidine but not pyrilamine or thioperamide inhibited Nav1.8 upregulation and pain hypersensitivity. In addition, famotidine (40 mg/kg, i.p.) not only suppressed autotomy behavior in the rat neuroma model of neuropathic pain but also attenuated mechanical allodynia and thermal hyperalgesia following partial sciatic nerve ligation. Moreover, famotidine inhibited Nav1.8 upregulation in the neuroma and ligated sciatic nerve. Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H2 receptor-mediated pathway and thereby contributes to neuropathic pain. H2 receptor antagonists may potentially be used as analgesics for patients with neuropathic pain.

Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults

Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke.

Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse

In arterioles, aldosterone counteracts the rapid dilatation (recovery) following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on cyclooxygenase (COX)-derived products and/or nitric oxide (NO) synthase (NOS) inhibition. Recovery of the response to high K(+) was observed in mesenteric arteries of wild-type and COX-2(-/-) mice but it was significantly diminished in preparations from endothelial NOS (eNOS)(-/-) mice. Aldosterone pretreatment inhibited recovery from wild-type and COX-2(-/-) mice. The NO donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS(-/-) mice, and this was inhibited by aldosterone. Actinomycin-D abolished the effect of aldosterone, indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10(-6) mol/l) or the TP-receptor antagonist S18886 (10(-7) mol/l). The effect of aldosterone on recovery in arteries from wild-type mice and the SNP-mediated dilatation in arteries from eNOS(-/-) mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries. The adventitia displayed granular cells positive for toluidine blue vital stain. Confocal microscopy of live mast cells showed loss of quinacrine fluorescence and swelling after aldosterone treatment, indicating degranulation. RT-PCR showed expression of mineralocorticoid receptors in mesenteric arteries and in isolated mast cells. These findings suggest that aldosterone inhibits recovery by stimulation of histamine release from mast cells along mesenteric arteries. The resulting activation of H2 receptors decreases the sensitivity to NO of vascular smooth muscle cells. Aldosterone may chronically affect vascular function through paracrine release of histamine.

An Overview of Analytical Determination of Diltiazem, Cimetidine, Ranitidine, and Famotidine by UV Spectrophotometry and HPLC Technique

This review article recapitulates the analytical methods for the quantitative determinations of diltiazem and three H2 receptor antagonists (cimetidine, ranitidine, and famotidine) by one of the spectroscopic technique (UV spectrophotometery) and separation technique such as high‐performance liquid chromatography (HPLC). The clinical and pharmaceutical analysis of these drugs requires effective analytical procedures for quality control, pharmaceutical dosage formulations, and biological fluids. An extensive survey of the literature published in various analytical and pharmaceutical chemistry‐related journals has been compiled in its review. A synopsis of reported spectrophotometric and high‐performance liquid chromatographic methods for individual drug is integrated. This appraisal illustrates that majority of the HPLC methods reviewed are based on the quantitative analysis of drugs in biological fluids, and they are appropriate for therapeutic drug monitoring purpose.

Carnosine protects brain microvascular endothelial cells against rotenone‐induced oxidative stress injury through histamine H1 and H2 receptors in vitro

Although it is believed that carnosine has protective effects on various cell types, its effect on microvascular endothelial cells has not been well defined. In the present study, we investigated the protective effects of carnosine in microvascular endothelial cells using an in vitro rotenone-induced oxidative stress model. Mouse brain microvascular endothelial cells were exposed to 1μmol/L rotenone for 18h. In some experiments, carnosine (100nmol/L-1mmol/L) was added 30min prior to rotenone exposure. When used, histamine receptor antagonists (100nmol/L-10μmol/L) were added 15min before carnosine treatment. After rotenone exposure, apoptosis of microvascular cells was analysed by Hoechst 33342 staining, whereas mitochondrial membrane potential was assessed by JC-1 staining. Intracellular carnosine and histamine levels were determined using HPLC or ultra-HPLC. Over the range 1μmol/L-1mmol/L, carnosine concentration-dependently decreased the number of apoptotic cells after 18h exposure to rotenone. This effect was reversed by the histamine H1 receptor antagonists pyrilamine and diphenhydramine (1 and 10μmol/L) and the H2 receptor antagonists cimetidine (100nmol/L-10μmol/L) and zolatidine (10μmol/L). α-Fluoromethylhistidine (100μmol/L), a selective and irreversible inhibitor of histidine decarboxylase, also significantly inhibited the protective effects of carnosine. At 0.1mmol/L, carnosine restored the decrease in mitochondrial membrane potential after 6h exposure to 1μmol/L rotenone and this effect was also reversed by the H1 and H2 receptor antagonists. Moreover, intracellular carnosine levels increased as early as 1h after carnosine treatment, whereas intracellular histamine levels increased 18h after carnosine treatment. The results of the present study indicate that carnosine protects brain microvascular endothelial cells against rotenone-induced oxidative stress injury via histamine H1 and H2 receptors. The findings suggest that carnosine may be beneficial in the treatment of microvascular endothelial dysfunction induced by oxidative stress.

Histamine at low concentrations aggravates rat liver BRL-3A cell injury induced by hypoxia/reoxygenation through histamine H2 receptor in vitro

AimHistamine released from mast cell degranulation participates in the pathogenesis of ischemia/reperfusion injury. The purpose of our study was to define the role of histamine in hypoxia/reoxygenation mediated liver cell injury and to elucidate the underlying mechanism in vitro. MethodsHistamine alone or in combination with H1 receptor antagonist (pyrilamine), H2 receptor antagonist (cimetidine) or H3/4 receptor antagonist (thioperamide) at different concentrations before hypoxia was added to rat liver BRL-3A cell which was subjected to 24h hypoxia followed by 4h reoxygenation. Cell proliferation, apoptosis and the changes of ultrastructure were assessed, and MDA contents, SOD activities and ALT levels were quantified as well. ResultsHistamine (from 10−3 to 10−9M) did not affect the growth of BRL-3A cells without hypoxia treatment. However, histamine 10−8M significantly lowered the growth of BRL-3A cells challenged by hypoxia/reoxygenation, accompanied with concomitant elevations in MDA contents and decreases in SOD activities, all these changes were blocked by cimetidine, not by pyrilamine or thioperamide. However, histamine (above 10−6M) did not show exacerbating effects in BRL-3A cell subjected to hypoxia/reoxygenation. ConclusionHistamine at low concentrations (10−7–10−9M) aggravates hypoxia/reoxygenation mediated BRL-3A damage through histamine H2 receptor.