Biased agonism at histamine H1 receptor: Desensitization, internalization and MAPK activation triggered by antihistamines.

Histamine H1 receptor ligands used clinically as antiallergics rank among the most widely prescribed and over-the-counter drugs in the world. They exert the therapeutic actions by blocking the effects of histamine, due to null or negative efficacy towards Gαq-phospholipase C (PLC)-inositol triphosphates (IP3)-Ca2+ and nuclear factor-kappa B cascades. However, there is no information regarding their ability to modulate other receptor responses. The aim of the present study was to investigate whether histamine H1 receptor ligands could display positive efficacy concerning receptor desensitization, internalization, signaling through Gαq independent pathways or even transcriptional regulation of proinflammatory genes. While diphenhydramine, triprolidine and chlorpheniramine activate ERK1/2 (extracellular signal-regulated kinase 1/2) pathway in A549 cells, pre-treatment with chlorpheniramine or triprolidine completely desensitize histamine H1 receptor mediated Ca2+ response, and both diphenhydramine and triprolidine lead to receptor internalization. Unlike histamine, histamine H1 receptor desensitization and internalization induced by antihistamines prove to be independent of G protein-coupled receptor kinase 2 (GRK2) phosphorylation. Also, unlike the reference agonist, the recovery of the number of cell-surface histamine H1 receptors is a consequence of de novo synthesis. On the other hand, all of the ligands lack efficacy regarding cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA regulation. However, a prolonged exposure with each of the antihistamines impaires the increase in COX-2 and IL-8 mRNA levels induced by histamine, even after ligand removal. Altogether, these findings demonstrate the biased nature of histamine H1 receptor ligands contributing to a more accurate classification, and providing evidence for a more rational and safe use of them.

Histamine H1 and H3 receptor activation increases the expression of Glucose Transporter 1 (GLUT-1) in rat cerebro-cortical astrocytes in primary culture.

Astrocytes take up glucose via the 45 kDa isoform of the Glucose Transporter 1 (GLUT-1), and in this work we have investigated whether histamine regulates GLUT-1 expression in rat cerebro-cortical astrocytes in primary culture. Cultured astrocytes expressed histamine H1 and H3 receptors (H1Rs and H3Rs) as evaluated by radioligand binding. Receptor functionality was confirmed by the increase in the intracellular concentration of Ca2+ (H1R) and the inhibition of forskolin-induced cAMP accumulation (H3R). Quantitative RT-PCR showed that histamine and selective H1R and H3R agonists (1 h incubation) significantly increased GLUT-1 mRNA to 153 ±â€¯7, 163 ±â€¯2 and 168 ±â€¯13% of control values, respectively. In immunoblot assays, incubation (3 h) with histamine or H1R and H3R agonists increased GLUT-1 protein levels to 224 ±â€¯12, 305 ±â€¯11 and 193 ±â€¯13% of control values, respectively, an action confirmed by inmunocytochemistry. The effects of H1R and H3R agonists were blocked by the selective antagonists mepyramine (H1R) and clobenpropit (H3R). The pharmacological inhibition of protein kinase C (PKC) prevented the increase in GLUT-1 protein induced by either H1R or H3R activation. Furthermore, histamine increased ERK-1/2 phosphorylation, and the effect of H1R and H3R activation on GLUT-1 protein levels was reduced or prevented, respectively, by MEK-1/2 inhibition. These results indicate that by activating H1Rs and H3Rs histamine regulates the expression of GLUT-1 by astrocytes. The effect appears to involve the phospholipase C (PLC) → diacylglycerol (DAG)/Ca2+→ PKC and PLC → DAG/Ca2+ → PKC → MAPK pathways.

Histaminergic Pharmacology Modulates the Analgesic and Antiedematogenic Effects of Spinally Injected Morphine.

BACKGROUND: Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine. METHODS: After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group. RESULTS: Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect. CONCLUSIONS: Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing.

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

Endothelin-1 induces itch and pain in the mouse cheek model.

AIMS: To date, suggestions that endothelin-1 (ET-1) causes nociception and pruritus are based on results in preclinical models in which responses to pruritic and nociceptive stimuli cannot be distinguished. This study reexamines these sensory effects of ET-1 in the new mouse cheek model, in which pruritogens and algogens evoke distinct behavioral responses. MAIN METHODS: Mice received intradermal (i.d.) injections of test substances into the left cheek and bouts of hind limb scratches or forepaw wipes, directed to the injection site, were considered indicative of pruritus and nociception, respectively. KEY FINDINGS: Histamine and capsaicin selectively evoked scratching and wipes, respectively, whereas ET-1 (3-60 pmol) promoted dose-dependent bouts of both behaviors. While scratching and wipe responses to ET-1 (30 pmol) were potentiated by BQ-788 (an ET(B) receptor antagonist) and reduced by co-injection of BQ-788 plus BQ-123 (an ET(A) receptor antagonist), BQ-123 alone inhibited scratching responses only. CTOP (µ-opioid receptor selective antagonist) only augmented scratching responses to ET-1, whereas DAMGO (µ-opioid receptor selective agonist) reduced both behaviors. Loratadine (histamine H(1) receptor antagonist) marginally reduced scratching, but markedly suppressed wipes. SIGNIFICANCE: These results demonstrate that ET-1 evokes pruritic and nociceptive behaviors in the mouse cheek model. Both responses to ET-1 appear to be mediated via ET(A) receptors and subjected to limitation by simultaneous ET(B) receptor activation. Local endogenous opioids acting on µ-opioid receptors selectively modulate the pruritic response to ET-1, whereas histamine, possibly derived from mast cells and acting on H(1) receptors, contributes importantly to the nociceptive effect of ET-1 in this model.

Strain-dependent differences in electrogenic secretion of electrolytes across mouse colon epithelium.

Mice have proven to be powerful models for the study of human physiology and pathophysiology. With the advent of techniques for genomic manipulation, the possibilities for studying inherited diseases in this convenient laboratory mammal are increasing by the day. It has been reported that when knocking out or otherwise modifying genes of interest in mice, the phenotype obtained can vary markedly depending on the genetic background of the animals used in the study. The aim of this work was to study whether the genetic background can influence the characteristics of fluid and electrolyte transepithelial transport in the distal colon of three mouse strains most in use in our and other laboratories. Ussing chamber recordings revealed that the colons of C57Bl/6J, Sv 129 and Black Swiss animals have distinctive responses to the calcium agonists carbachol and histamine that are not explained by the presence of different types of muscarinic and histaminergic receptors in these tissues. We have also found differences in the cAMP-activated, KCNMA1-channel-dependent potassium secretion between the strains. We interpret this to indicate a unique distribution of KCNMA1 channels in lower parts of the crypt of Sv 129 colonic epithelium compared with that of C57Bl/6J and Black Swiss animals. The reported differences should be taken into account when choosing the genetic background of animals to be used for genetic modification.

New antihistamines: a critical view.

OBJECTIVES: To perform a critical evaluation of the more recent H1 antihistamines and the various terms used to describe them, based on a review of evidence on their role in the treatment of allergic disorders. SOURCES OF DATA: Original articles, reviews and consensus documents published from 1998 to 2006 and indexed in the MEDLINE and PubMed databases. Keyword: antihistamines. SUMMARY OF THE FINDINGS: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the central nervous system (CNS), having fewer sedative effects as a result. Whilst second-generation antihistamines are in general better tolerated than their predecessors, some adverse effects, principally cardiotoxicity, have been observed with some of them. Over the last 20 years, new compounds with different pharmacokinetic properties have been synthesized. The majority of these exhibit anti-inflammatory properties that are independent of their action on the H1 receptor. More recent improvements, generally in the form of active metabolites, led to the use of the term third-generation antihistamines. This term emerged spontaneously, with no clear definition of its meaning or clinical implications, creating great confusion among healthcare professionals. CONCLUSION: On the basis of the evidence on H1 antihistamines, none of them deserve the title "third-generation antihistamine." As the Consensus Group on New Generation Antihistamines concluded, to merit this definition, a new class of antihistamines would have to demonstrate distinct clinical advantages over existing compounds and fulfill at least three prerequisites: they should be free from cardiotoxicity, drug interactions and effects on the CNS.

New antihistamines: a critical view

OBJETIVO: Avaliar criticamente os mais novos anti-histamínicos anti-H1 e os diferentes termos utilizados para denominá-los, com base na revisão de evidências sobre o papel dos anti-H1 no tratamento das doenças alérgicas. FONTES DOS DADOS: Artigos originais, revisões e consensos indexados nos bancos de dados MEDLINE e PUBMED de 1998 a 2006. Palavra chave: anti-histamínicos. SíNTESE DOS DADOS: Os anti-histamínicos de segunda geração diferenciam-se dos de primeira geração por sua elevada especificidade e afinidade pelos receptores H1 periféricos e pela menor penetração no sistema nervoso central (SNC), com conseqüente redução dos efeitos sedativos. Embora os anti-histamínicos de segunda geração sejam, geralmente, melhor tolerados do que seus predecessores, alguns efeitos adversos, principalmente cardiotoxicidade, surgiram com alguns deles. Nos últimos 20 anos, novos compostos, com diferentes farmacocinéticas, foram sintetizados. A maioria deles manifesta propriedades antiinflamatórias que independem de sua atividade no receptor H1. Aprimoramentos mais recentes, geralmente na forma de metabólitos ativos, levaram ao uso do termo anti-histamínico de terceira geração. Esse termo surgiu espontaneamente, sem uma descrição clara de seu significado e implicações clínicas, criando grande confusão entre os profissionais da saúde. CONCLUSÕES: Com base nas evidências sobre anti-histamínicos anti-H1, nenhum deles pode ser considerado como "anti-histamínico de terceira geração". Para tanto, seria preciso comprovar que a nova classe de anti-histamínicos possui vantagens clínicas distintas sobre os compostos existentes e preenche pelo menos três pré-requisitos: ausência de cardiotoxicidade, de interações medicamentosas e de efeitos sobre o SNC.

OBJECTIVE: To perform a critical evaluation of the more recent H1 antihistamines and the various terms used to describe them, based on a review of evidence on their role in the treatment of allergic disorders. SOURCES: Original articles, reviews and consensus documents published from 1998 to 2006 and indexed in the MEDLINE and PubMed databases. Keyword: antihistamines. SUMMARY OF THE FINDINGS: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the central nervous system (CNS), having fewer sedative effects as a result. Whilst second-generation antihistamines are in general better tolerated than their predecessors, some adverse effects, principally cardiotoxicity, have been observed with some of them. Over the last 20 years, new compounds with different pharmacokinetic properties have been synthesized. The majority of these exhibit anti-inflammatory properties that are independent of their action on the H1 receptor. More recent improvements, generally in the form of active metabolites, led to the use of the term third-generation antihistamines. This term emerged spontaneously, with no clear definition of its meaning or clinical implications, creating great confusion among healthcare professionals. CONCLUSIONS: On the basis of the evidence on H1 antihistamines, none of them deserve the title"third-generation antihistamine." As the Consensus Group on New Generation Antihistamines concluded, to merit this definition, a new class of antihistamines would have to demonstrate distinct clinical advantages over existing compounds and fulfill at least three prerequisites: they should be free from cardiotoxicity, drug interactions and effects on the CNS.

Antagonism by imidazoline-type drugs of muscarinic and other receptors in the guinea-pig ileum.

1 Several imidazolines were examined for the antagonism of muscarinic (M3) and other receptors on the isolated ileum of guinea-pig. The effect of the muscarinic agonist, carbachol was competitively antagonized by oxymetazoline at 10(-5) m. A dissociation constant (KB) of 3.6 microm for the antagonist was calculated. At higher concentrations, 3 x 10(-5) and 10(-4) m, of the antagonist, the agonist dose-response curve was shifted to the right with a decrease in the maximum effect. Thus, a non-competitive block occurred at higher concentrations of oxymetazoline. Blockade of histamine H, and serotonin receptor-mediated responses by oxymetazoline were also of a non-competitive type. 2 Naphazoline at 10(-4) m shifted the dose-response curves of carbachol and serotonin to the right by two- and 15-fold, respectively. The maximum contraction of the agonist was not affected. Tolazoline also had a weak antihistaminic activity. At similar concentration; tetrahydrozoline clonidine and phentolamine at 10(-5) m produced two-, three- and four-fold shift of the carbachol dose-response curve without significant changes in the maxima. Neither methoxamine, p-amino-clonidine nor cimetidine blocked the responses of carbachol. 3 The isosteric nature of the alpha-adrenoceptor agonist, oxymetazoline and some imidazolines with carbachol, in part, explains its molecular competition at the muscarinic M3 receptor of the guinea-pig ileum. Surprisingly, contractile effects of carbachol (M3), histamine (H1) or serotonin (5HT3/5HT4) were not influenced by methoxamine, tetrahydrozoline, p-amino clonidine and cimetidine.

Fasting duration influences the inhibition of food intake by histamine in chickens.

This work was performed to investigate the effect of duration of fasting in the responses of chickens peripherally injected with histamine on the regulation of food intake. The animals were 16-week-old male chickens from layer-strain and the doses of histamine used were 500 and 1000 microg/kg of body weight. The non fasted chickens showed no effect of histamine on the food intake. When the animals were fasted during 4 h, injected with the histamine and immediately refed, the results showed a reduction of food intake only the first 15 min of the experiments with the dose of 1000 mug. In chickens fasted during 16 h or 26 h and refed, the histamine inhibited significantly the food intake at all time with the two doses. When the animals were fasted 16 h and refed during 60 min before the administration of the histamine, there is no inhibition of food intake. No effect on water intake has been registered in all the experiments. The blockade of the action of histamine injected in chickens fasted during 16 h by cimetidine and promethazine, show that the inhibition of food intake occurs through the H1 but not through H2 receptors. The fasting used in paradigm to investigate the effect of drugs such as histamine on the appetite, can affect differently the responses according to its duration, as observed here in chickens.

Dual role of histamine in modulation of Leydig cell steroidogenesis via HRH1 and HRH2 receptor subtypes.

Although several reports indicate effects of histamine (HA) on female reproductive functions, scant literature exists to suggest a physiological role of HA in the male gonad. In the present study, we report a dual concentration-dependent effect of HA on steroidogenesis in MA-10 murine Leydig cells and purified rat Leydig cells. Although 1 nM HA can stimulate steroid production and significantly increase the response to LH/hCG in these cells, 10 microM HA exerts an inhibitory effect. We also provide confirming evidence for the existence of functional HRH1 and HRH2 receptors in both experimental models. The use of HRH1 and HRH2 selective agonists and antagonists led us to suggest that HRH2 activation would be largely responsible for stimulation of steroidogenesis, while HRH1 activation is required for inhibition of steroid synthesis. Our results regarding signal transduction pathways associated with these receptors indicate the coupling of HRH2 to the adenylate cyclase system through direct interaction with a Gs protein. Moreover, we show HRH1 activation mediates increases in inositol phosphate production, possibly due to coupling of this receptor to Gq protein and phospholipase C activation. The data compiled in this report clearly indicate that HA can modulate Leydig cell steroidogenesis in the testis and suggest a possible new physiological site of action for HA. Given that many drugs binding to HRH1, HRH2, or both, are widely prescribed for the treatment of diverse HA-related pathologies, it seems necessary to increase the knowledge regarding histaminergic regulation of testicular functions, to avoid possible unexpected side effects of such substances in the testis.

Neuroendocrine effects of quetiapine in healthy volunteers.

The present study measured prolactin, cortisol, ACTH and growth hormone in healthy male volunteers following an acute oral administration of quetiapine, an atypical antipsychotic with high affinity for H1 and moderate affinity for sigma, alpha1, 5-HT2, alpha2 and D2 receptors. Fifteen male volunteers entered this randomized double-blind, cross-over, placebo-controlled study. Blood samples were drawn every 30 min from 09:00 hours to 13:00 hours. The first samples were drawn immediately before the administration of 150 mg quetiapine or placebo. Mean results for each hormone and ANOVA for repeated measures were performed. The area under the curve (AUC) hormonal values were calculated and compared by paired t test. The ANOVA showed an increase of prolactin after quetiapine administration from time 60 min up to the end of the observation period. Cortisol decreased after quetiapine administration from time 150 min to time 240 min. ACTH secretion showed no difference compared to placebo. There was a late increase in growth hormone secretion, significant in comparison with placebo only at time 210 min. The AUC values were statistically different for prolactin and cortisol compared to placebo. A single dose of quetiapine (150 mg) increased prolactin secretion probably due to a transiently high D2 receptor occupancy at the anterior pituitary. Cortisol secretion decreased as was expected from quetiapine's pharmacodynamic profile. The lack of response of ACTH might be, at least in part, explained by the low hormonal assay sensitivity. The late growth hormone increase might have been due to quetiapine's antagonism of H1 receptors.

Histaminergic H1 and H2 receptors located within the ventromedial hypothalamus regulate food and water intake in rats.

The aim of the present study was to investigate the effect of the pharmacological blockade of histamine H1 and H2 receptors located within the ventromedial hypothalamus (VMH) on overnight food and water intake and on water intake elicited by two physiological stimuli: hyperosmolarity induced by an acute intragastric salt load and water deprivation. During the overnight period, the pharmacological blockade of both H1 and H2 VMH receptors significantly increased food intake and decreased water intake. In hyperosmotic rats, the blockade of H1 VMH receptors reduced water intake, while the blockade of H2 receptors in this same region yielded no significant effect. Additionally, in water-deprived rats, the blockade of both H1 and H2 receptors located within the VMH induced a significant decrease in water intake. The inhibitory effects on drinking behavior observed in this study do not seem to be a consequence of any "illness-inducing" effect provoked by the central administration of the antihistaminergic agents employed here, because an aversion test indicated that the injection of those compounds into the VMH does not induce any "illness-like" effect. In addition, the central administration of either mepyramine or cimetidine to dehydrated and hyperosmotic rats did not produce any reduction in locomotor activity measured in an open-field arena. Injections of the antihistaminergic agents used here into the regions that circumscribe the VMH produced no significant effects on water or food intake, indicating that the actions observed here may be specifically attributed to the set of histaminergic receptors situated within the VMH.

Acetylenic acids from the aerial parts of Nanodea muscosa.

The aerial parts of Nanodea muscosa, collected in Chile, yielded two new acetylenic acids. Their structures were elucidated by spectroscopic analyses, including 2D NMR techniques, as (13E)-octadec-13-en-11-ynoic acid (1) and (2E)-octadec-2-en-4-ynedioic acid (2). Compound 2 constitutes the first example of a conjugated ene-yne fatty diacid isolated from a natural source. Compounds 1 and 2 did not exhibit toxicity toward a panel of DNA damage checkpoint defective yeast mutants or show affinity for the 5-HT(1A), 5-HT(2A), D(2), and H(1) receptors.

Histamine H1 receptors in rat dorsal raphe nucleus: pharmacological characterisation and linking to increased neuronal activity.

In this work we studied the presence of histamine H(1) receptors in the rat dorsal raphe nucleus (DRN) and the effect of their activation on the activity of presumed serotonergic DRN neurones. [(3)H]-Mepyramine bound to DRN membranes with best-fit values of 107+/-13 fmol/mg protein for maximum binding (B(max)) and 1.2+/-0.4 nM for the equilibrium dissociation constant (K(d)). In DRN slices labelled with [(3)H]-inositol and in the presence of 10 mM LiCl, histamine stimulated the accumulation of [(3)H]-inositol phosphates ([(3)H]-IPs) with maximum effect 172+/-6% of basal and EC(50) 3.2+/-1.3 microM. [(3)H]-IPs accumulation induced by 100 microM histamine (162+/-5% of basal) was markedly, but not fully blocked by the selective H(1) antagonist mepyramine (300 nM; 64+/-6% inhibition). The simultaneous addition of mepyramine and the selective H(2) antagonist ranitidine (10 microM) abolished histamine-induced [(3)H]-IPs accumulation. The presence of H(2) receptors was confirmed by [(3)H]-tiotidine binding and by the determination of histamine-induced [(3)H]-cyclic AMP formation. Extracellular single-unit recording in brain stem slices showed that the exposure to histamine resulted in a marked increase in the firing rate of DRN presumed serotonergic neurones (471+/-10% of basal), that was dependent on the concentration of the agonist (EC(50) 4.5+/-0.3 microM). The action of histamine was not affected by the H(2) antagonist tiotidine (2 microM) but was fully prevented by 1 microM mepyramine. Taken together, our results indicate that histamine modulates the firing of DRN presumed serotonergic neurones through the activation of H(1) receptors coupled to phosphonositide hydrolysis.

Participación de receptores histaminérgicos involucrados en la permeabilidad vascular / Participation of histaminergic receptors involved in vascular permeability

La permeabilidad vascular puede ser modificada por la liberación de histamina endógena como resultado de la presencia de ciertos tiobarbitúricos (tiopental) en el organismo. Esta modificación en la permeabilidad es mediada por la activación del receptor histaminérgico H1, pero es incierta la participación del receptor H2. En este trabajo se evalúa la participación de receptores H1 y H2 durante los cambios de permeabilidad vascular inducidos por histamina, a través de la determinación de concentraciones séricas de albúmina, proteínas totales y globulinas, que indirectamente lo indican. Se formaron 5 grupos de organismos; un control y 4 experimentales denominados grupo A, B, C y D. A los organismos del grupo A se les aplicó histamina IV, 10 µg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso; al grupo C se le inyectó ranitidina IV, 0.13 mg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso y 0.13 mg/Kg de peso de astemizol y ranitidina IV, respectivamente. El grupo A mostró un decremento significativo en las concentraciones de albúmina, proteínas totales y globulinas. En los grupos B, C y D se observó una disminución en la concentración de proteínas totales y globulinas, pero no de albúmina. Estos resultados muestran que los receptores H1 y H2 están involucrados en el aumento de permeabilidad vascular a la albúmina, pero tal vez exista un proceso de permeabilidad diferencial en el cual el paso de globulinas desde la luz vascular hasta el intersticio esté regulado por otro mecanismo

This histamine-like effects of Phallusia nigra extract: evidences for direct activity at H1 receptors.

The methanol extract (mol. wt lower than 3,000 Da) of the sea squirt Phallusia nigra has stimulatory activity on guinea-pig ileum preparations. This effect was inhibited by cyproheptadine and mepyramine, but not be atropine. Mepyramine antagonized competitively the extract activity with a pA2 of 10.09 +/- 1.12, suggesting a direct activity on H1 histamine receptors. The extract was also assayed on guinea-pig right atria, however, only a mild increase in spontaneous contractions was observed compared to histamine, showing that the extract was a rather poor activator of cardiac H2 receptors. Histamine was not detected upon TLC analysis of the extract by comparison with an authentic standard.

[Antihistaminics]. / Antihistamínicos.

The antihistamines are drugs who compete for the histamine receptor H-1, blocking the liberation of autacoid mediators, that is the reason for their action in allergic diseases. It's important to know the pharmacodynamics and pharmacokinetics of these drugs in order to choose the best one for the patient, looking for the ones who have less side effects and work better. We show a summary of the principal antihistamines, their actions and side effects.