Histamine H1 receptor antagonists enhance the efficacy of antibacterials against Escherichia coli.

BACKGROUND: H1 receptor antagonists are commonly used for the treatment of allergic diseases. The aim of this study was to find out, if antihistaminic compounds like mepyramine have the ability to influence the activity of antibacterials. Therefore, the checkerboard method was chosen to detect these possible effects in vitro. Studies were performed with two different Escherichia coli (E. coli) strains as test microbes, treated with antibacterials in combination with mepyramine. RESULTS: The minimum inhibitory concentration (MIC) of E. coli ATCC® 25922™ and E. coli PIG 01 was reduced by combinations of the tested antibacterials with mepyramine. CONCLUSIONS: These results have to be confirmed in vivo, before the use of antihistamines should be considered as potential way to minimize the amount of used antibacterials for treatment of E. coli infections.

Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions.

BACKGROUND: Food anaphylaxis is an acute and life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal and near-fatal reactions in North America. Because prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies. OBJECTIVE: To investigate the impact of blocking mast cell mediators in a mouse model of peanut-induced anaphylaxis. METHODS: Mice were sensitized with peanut protein and cholera toxin via oral gavage weekly for 4 weeks. One week after the last sensitization, separate groups of mice were treated with either a (1) 5-lypoxygenase inhibitor, (2) a platelet-activating factor (PAF) receptor antagonist, (3) histamine receptor antagonists, or (4) a PAF receptor antagonist along with histamine receptor antagonists before peanut challenge. RESULTS: Treatment targeting either leukotrienes or histamine alone had no beneficial effects. In contrast, PAF antagonism significantly attenuated the magnitude and duration of the anaphylactic reactions. Particularly, it prevented severe reactions. Moreover, 83% of PAF-treated versus 43% of untreated mice reached recovery within 120 minutes after peanut challenge. Notably, combined blockade of PAF and histamine had a clearly greater beneficial effect. In fact, all but 1 mouse developed mild, if any, anaphylactic reactions. In addition, combination therapy was associated with a significant decrease in vascular leakage and release of vasoactive mediators after peanut challenge. CONCLUSION: Combination therapy blocking both PAF and histamine markedly reduces the severity of peanut-induced anaphylaxis, and thus it may be a potential life-saving therapeutic approach in peanut and, likely, other food-induced anaphylaxis.

Pyrilamine in the horse: detection and pharmacokinetics of pyrilamine and its major urinary metabolite O-desmethylpyrilamine.

Pyrilamine is an antihistamine used in human and veterinary medicine. As antihistamines produce central nervous system effects in horses, pyrilamine has the potential to affect the performance of racehorses. In the present study, O-desmethylpyrilamine (O-DMP) was observed to be the predominant equine urinary metabolite of pyrilamine. After intravenous (i.v.) administration of pyrilamine (300 mg/horse), serum pyrilamine concentrations declined from about 280 ng/mL at 5 min postdose to about 2.5 ng/mL at 8 h postdose. After oral administration of pyrilamine (300 mg/horse), serum concentrations peaked at about 33 ng/mL at 30 min, falling to <2 ng/mL at 8 h postdose. Pyrilamine was not detected in serum samples at 24 h postdosing by either route. After i.v. injection of pyrilamine (300 mg/horse) O-DMP was recovered at a level of about 20 microg/mL at 2 h postdose thereafter declining to about 2 ng/mL at 168 h postdose. After oral administration, the O-DMP recovery peaked at about 12 microg/mL at 8 h postdose and declined to <2 ng/mL at 168 h postdose. These results show that pyrilamine is poorly bioavailable orally (18%), and can be detected by sensitive enzyme-linked immunosorbent assay tests in urine for up to 1 week after a single administration. Care should be taken as the data suggest that the withdrawal time for pyrilamine after repeated oral administrations is likely to be at least 1 week or longer.

Histaminergic system of the lateral septum in the modulation of anxiety-like behaviour in rats.

The central histaminergic system is known to have modulatory influence on anxiety-related behaviour both in animals and humans through histamine H1 and/or H2 receptors. In the present study, the effects of intra-lateral septal microinjections of histaminergic agents on anxiety-related behaviours in male Wistar rats have been investigated. As a model of anxiety, the elevated plus-maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used. Intra-lateral septal administration of histamine (0.5 and 1 microg/rat) decreased the percentage of open arm entries and open arm time but not locomotor activity, showing an anxiogenic response. The intra-lateral septal injections of different doses of the histamine H1 receptor antagonist, pyrilamine (5, 10 and 20 microg/rat) or the histamine H2 receptor antagonist, ranitidine (5, 10 and 20 microg/rat) could not significantly alter the anxiety-like parameters in the plus-maze test. However, intra-lateral septal injections of different doses of pyrilamine (10 and 20 microg/rat) or ranitidine (10 and 20 microg/rat) significantly reversed histamine (1 microg/rat)-induced anxiogenic effect. The results may indicate that the histaminergic system of lateral septum modulate anxiety-like behaviour through histamine H1 and H2 receptors.

Antinociception induced by central administration of histamine in the formalin test in rats.

In the present study, effects of intracerebroventricular (icv) administration of histamine, mepyramine (H1-receptor antagonist) and famotidine (H2-receptor antagonist) have been investigated on the formalin test in rats. Subcutaneous injection of formalin (50 microl, 1%) into the ventral surface of the left hind paw produced a marked biphasic pain response (first phase: 0-5 min and second phase: 15-45 min). All the performed treatments did not significantly influence the first phase of pain. Histamine at the doses of 10 and 40 microg and mepyramine and famotidine at the same doses of 20 and 80 microg, significantly (P < 0.05) decreased the late phase of formalin-induced pain. Pretreatments with mepyramine and famotidine at the same dose of 80 microg, significantly (P < 0.05) prevented the histamine (40 microg)-induced antinociception. These results indicate that brain histamine produces antinociception, and both central H1 and H2 receptors may involve in the histamine-induced antinociception in the formalin test in rats.

Histamine H1 Receptor Antagonists Facilitate Electroacupuncture Analgesia.

This study investigated the influence of the histamine H1 receptor antagonists, chlorpheniramine (CHL) and pyrilamine, on the analgesic effects of acupuncture in mice. Nociceptive response was evaluated by the acetic acid-induced abdominal writhe test. Electroacupuncture (EA) at bilateral ST36 reduced the manifestations of acetic acid-induced abdominal writhing, whereas needle insertion without electrostimulation had no such effect. Notably, EA treatment was not associated with any analgesic effects in mice pretreated with naloxone. Low doses of CHL (0.6[Formula: see text]mg/kg; p.o.) or pyrilamine (2.5[Formula: see text]mg/kg; i.p.) as monotherapy did not affect acetic acid-induced abdominal writhing. However, when each agent was combined with EA, acetic acid-induced abdominal writhing was reduced by a greater extent when compared with EA alone. Interestingly, the effects of CHL on acupuncture analgesia were not completely reversed by naloxone treatment. Acetic acid induced increases of phospho-p38 expression in spinal cord, as determined by immunofluorescence staining and Western blot analysis. These effects were attenuated by EA at ST36 and by low doses of histamine H1 receptor antagonists, alone or in combination. Our findings show that relatively low doses of histamine H1 receptor antagonists facilitate EA analgesia via non-opioid receptors. These results suggest a useful strategy for increasing the efficacy of EA analgesia in a clinical situation.

Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non-sedating antihistamine; a time course study in the guinea pig.

BACKGROUND AND PURPOSE: The H(1) receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood-brain barrier in any delay in brain H1RO. EXPERIMENTAL APPROACH: Concentration-time profiles in plasma and brain were obtained after 0.1 and 1 mg kg(-1) oral doses of levocetirizine in guinea pigs. H1RO in brain was measured ex vivo using [3H]-mepyramine and, in the periphery, by measuring the degree of inhibition of histamine-induced contractions of isolated guinea pig ileum. KEY RESULTS: The concentration-time profile of levocetirizine indicated lower levels (partition coefficient, K(p)=0.06-0.08), higher t(max) (2-4 h vs 1-1.5 h) and longer terminal half-life (4-5.6 h vs 2.1-2.8 h) in brain than plasma. The H1RO at 0.1 and 1 mg kg(-1) were 75% and 97%, respectively, at 1 hr in the periphery and, in the brain, were <20% and 28-67% respectively, at all time points studied. Brain H1RO vs plasma concentrations profile showed a delay, but not when compared to brain concentrations. CONCLUSIONS AND IMPLICATIONS: This study demonstrates an effective peripheral antihistamine effect of levocetirizine without central adverse effects at the dose close to human therapeutic dose. The slow increase in H1RO in the brain with time was caused by slow blood-brain barrier transport of levocetirizine. This demonstrates the importance of measuring time course of brain H1RO in relation to brain concentrations of drugs.

Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine.

Histamine H(1) blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this H(1) antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine.

Histaminergic Receptors Modulate Spinal Cord Injury-Induced Neuronal Nitric Oxide Synthase Upregulation and Cord Pathology: New Roles of Nanowired Drug Delivery for Neuroprotection.

The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist α-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.

Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

Involvement of skin barrier dysfunction in itch-related scratching in special diet-fed hairless mice.

HR-1 hairless mice fed with a special diet develop atopic-like dry skin, characterized by increased transepidermal water loss, and prolonged bouts of spontaneous scratching. In this study, the role of the skin barrier dysfunction in the prolongation of scratching was evaluated. Although the prolonged scratching was dose-dependently inhibited by opioid receptor antagonist naloxone, neither H(1) receptor antagonist, mepyramine, nor 5-HT(1/2) receptor antagonist, methysergide, affected it. Thus, the prolonged scratching could be itch-related response independent of histamine and serotonin. The application of petrolatum ointment on the skin temporarily alleviated the increase of transepidermal water loss for 60 min after treatment. Due to this alleviation in barrier dysfunction, the prolongation of scratching was significantly suppressed. However, when the barrier dysfunction relapsed, the scratching worsened. Taken together, a skin barrier dysfunction is associated with the itch-related response.

Naproxen, paracetamol and pamabrom versus paracetamol, pyrilamine and pamabrom in primary dysmenorrhea: a randomized, double-blind clinical trial. / Naproxeno, paracetamol y pamabrom versus paracetamol, pirilamina y pamabrom en dismenorrea primaria: estudio aleatorizado, doble ciego.

INTRODUCTION: Dysmenorrhea is caused by the discharge of prostaglandins into the uterine tissue; therefore, non-steroidal anti-inflammatory drugs (NSAIDs) are the established initial therapy for dysmenorrhea. Dysmenorrhea therapy may include the administration of drug monotherapy or combination therapy. However, clinical scientific evidence on the efficacy of medications with two or three drugs combined is scarce or nonexistent. OBJECTIVE: To evaluate and compare the efficacy and safety of two oral fixed-dose combinations for the relief of the symptoms of primary dysmenorrhea among Mexican women. One of the combinations is widely used in Mexico (paracetamol, pyrilamine and pamabrom) and the selected comparison was a medication with naproxen sodium, paracetamol and pamabrom based on the pathophysiology of primary dysmenorrhea. METHODS: This was a single-centre, double blind, experimental, parallel group, randomized trial. Female patients with primary dysmenorrhea, older than 17 years and with pain intensity greater than 45 mm on a visual analogue scale, were included. The patients were then randomized to receive tablets with naproxen sodium, paracetamol and pamabrom or tablets with paracetamol, pyrilamine and pamabrom for one menstrual cycle. Patient evaluations of symptomatology and pain intensity were recorded throughout one menstrual period. Descriptive and inferential statistical analyses were utilized. RESULTS: An intention-to-treat population of 91 women, with a mean age of 21.3 ± 3.2 years, received paracetamol, pyrilamine and pamabrom tablets, and 98 participants, with a mean age of 21.0 ± 3.2 years, received naproxen sodium, paracetamol and pamabrom tablets. The participants’ assessments of pain on the Visual Analogue Scale during the menstrual cycle demonstrated a significant reduction in both treatment groups (p<0.05). There is no significant difference in efficacy between both groups (p>0.05). CONCLUSIONS: The results showed that both drug combinations were not different in reducing dysmenorrheic pain. Likewise, both treatments were well tolerated. Therefore, both treatments may be used for the treatment of primary dysmenorrhea.

INTRODUCCIÓN: La dismenorrea primaria es causada por la descarga de las prostaglandinas en el tejido uterino. Por lo tanto, los fármacos antiinflamatorios no esteroideos son la terapia inicial para la dismenorrea. El tratamiento para la dismenorrea puede incluir la administración de monoterapia o la combinación de fármacos. Sin embargo, la evidencia clínica científica sobre la eficacia de los medicamentos con dos o tres fármacos combinados es escasa o ausente. OBJETIVO: Evaluar y comparar la eficacia y seguridad de dos combinaciones, en dosis fija y oral para el alivio de los síntomas de la dismenorrea primaria en mujeres mexicanas. Basados en la fisiopatología de la dismenorrea primaria, se utilizó una combinación comercializada en México de paracetamol, pirilamina y pamabrom. El comparador seleccionado fue un medicamento que contiene naproxeno sódico, paracetamol y pamabrom. MÉTODOS: Se realizó un estudio en un solo centro, a doble ciego, experimental, paralelo y aleatorizado. Las pacientes con dismenorrea primaria que se incluyeron fueron mayores de 17 años de edad y con una intensidad del dolor mayor a 45 milímetros en una escala visual analógica. Las pacientes fueron aleatorizadas para recibir tabletas con naproxeno sódico, paracetamol y pamabrom o tabletas con paracetamol, pirilamina y pamabrom para un ciclo menstrual. Se evaluó la intensidad de la sintomatología y el dolor de las pacientes a lo largo de un período menstrual. Se utilizó análisis estadístico descriptivo e inferencial. RESULTADOS: Se incluyó una población con intención de tratar de 91 mujeres, con una edad media de 21,3 ± 3,2 años la cual recibió tabletas de paracetamol, pirilamina y pamabrom. Otras 98 participantes, con una edad media de 21,0 ± 3,2 años, recibieron tabletas de naproxeno sódico, paracetamol y pamabrom. Las evaluaciones de dolor de las participantes con la escala visual analógica durante el ciclo menstrual demostraron una reducción significativa en ambos grupos de tratamiento (p<0,05). No hubo diferencia significativa en la eficacia entre los dos grupos (p>0,05). CONCLUSIONES: Los resultados mostraron que ambas combinaciones de fármacos no fueron diferentes en reducir el dolor dismenorreico. Del mismo modo, ambos tratamientos fueron bien tolerados. Por lo tanto, ambos tratamientos se pueden utilizar para el tratamiento de la dismenorrea primaria.

Prevention of brain infarction by postischemic administration of histidine in rats.

Focal cerebral ischemia for 2 h by occlusion of the right middle cerebral artery provoked severe brain infarction in the rat brain after 24 h. Intraperitoneal administration of histidine, a precursor of histamine, immediately and 6 h after reperfusion, alleviated brain infarction. The infarct size in the histidine (200 mg/kg, 500 mg/kg, and 1000 mg/kg, each time) groups was 71%, 39%, and 7% of that in the control group, respectively. Although intracerebroventricular administration of mepyramine (3 nmol), an H1 antagonist, did not affect the morphologic outcome in histidine-treated rats, ranitidine (30 nmol), an H2 antagonist, completely abolished the alleviation caused by histidine. These findings indicate that postischemic administration of histidine prevents development of brain infarction by stimulating central histamine H2 receptors.

Histaminergic and catecholaminergic interactions in the central regulation of vasopressin and oxytocin secretion.

Activation of histaminergic and noradrenergic/adrenergic neurons in the brain stimulates the release of the neurohypophysial hormones arginine vasopressin (AVP) and oxytocin (OT) and are involved the mediation of the hormone responses to physiological stimuli such as dehydration and suckling. We therefore investigated whether the two neuronal systems interact in their regulation of AVP and OT secretion in conscious male rats. When administered intracerebroventricularly (i.c.v.), histamine (HA) as well as the H1 receptor agonist 2-thiazolylethylamine or the H2 receptor agonist 4-methylHA stimulated AVP and OT secretion. Prior i.c.v. infusion of antagonists specific to alpha or beta adrenergic receptors or their subtypes did not significantly affect the hormone response to HA or the histaminergic agonists. Infused i.c.v. norepinephrine (NE) or epinephrine (E) increased AVP and OT secretion. Prior i.c.v. infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the AVP and OT responses to NE and the AVP response to E, whereas only cimetidine inhibited the OT response to E significantly. Systemic pretreatment with imetit, which by activation of presynaptic H3 receptors inhibits neuronal synthesis and release of HA, decreased the AVP and OT responses to NE and E significantly. In the doses used, HA and E had no significant effect on mean arterial blood pressure. NE increased mean arterial blood pressure 10% at 1 and 2.5 min, whereafter the blood pressure returned to basal level within 10 min. The results indicate that noradrenergic and adrenergic neurons stimulate AVP and OT secretion via an involvement of histaminergic neurons, which may occur at magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The stimulatory effect of the amines on neurohypophysial hormone secretion seems to be independent of a central action on blood pressure. In contrast, a functionally intact noradrenergic and adrenergic neuronal system seems not to be a prerequisite for a HA-induced release of AVP and OT. The present findings further substantiate the role of histaminergic neurons in the central regulation of neurohypophysial hormone secretion.

Hippocampal somatostatin receptors and modulation of adenylyl cyclase activity in histamine-treated rats.

In the present study, the effects of an intracerebroventricular (i.c.v.) dose of histamine (0.1, 1.0 or 10.0 micrograms) on the hippocampal somatostatin (SS) receptor/effector system in Wistar rats were investigated. In view of the rapid onset of histamine action, the effects of histamine on the somatostatinergic system were studied 2 h after its administration. Hippocampal SS-like immunoreactivity (SSLI) levels were not modified by any of the histamine doses studied. SS-mediated inhibition of basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity was markedly increased in hippocampal membranes from rats treated with 10 micrograms of histamine (23% +/- 1% vs. 17% +/- 1% and 37% +/- 2% vs. 23% +/- 1%, respectively). In contrast, neither the basal nor the FK-stimulated enzyme activities were affected by histamine administration. The functional activity of the hippocampal guanine-nucleotide binding inhibitory protein (Gi protein), as assessed by the capacity of the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC activity, was not modified by histamine administration. These data suggest that the increased response of the enzyme to SS was not related to an increased functional activity of Gi proteins. In fact, the increased AC response to SS in hippocampal membranes from histamine (10 micrograms)-treated rats was associated with quantitative changes in the SS receptors. Equilibrium binding data obtained with [125I]Tyr11-SS indicate an increase in the number with specific SS receptors (541 +/- 24 vs. 365 +/- 16 fmol/mg protein, P < 0.001) together with a decrease in their apparent affinity (0.57 +/- 0.04 vs. 0.41 +/- 0.03 nM, P < 0.05) in rat hippocampal membranes from histamine (10 micrograms)-treated rats as compared to control animals. With the aim of determining if these changes were related to histamine binding to its specific receptor sites, the histaminergic H1 and H2 receptor antagonists mepyramine and cimetidine, respectively, were administered 1 h before histamine injection. The pretreatment with mepyramine or cimetidine induced an increase in the number and affinity constant of the SS receptors whereas the simultaneous pretreatment with both histamine antagonists prevented the histamine-induced changes in SS binding to its receptors. Since the hippocampal SS receptor/effector system is modulated by histamine, it is tempting to speculate that in the hippocampus, SS could be involved as a mediator of the histamine effects on behaviors such as learning and memory.

Histamine H1 receptors in the ventromedial hypothalamus mediate the anorectic action of the pancreatic hormone amylin.

In the present study we investigated the role of hypothalamic histamine H(1) receptors in the mediation of peripheral amylin's anorectic effect. Rats with chronically implanted bilateral cannulas were infused into the ventromedial hypothalamus (VMH) with the specific histamine H(1) receptor antagonists pyrilamine (PYR, 104 nmol/rat) or chlorpheniramine (CPA, 52 nmol/rat), respectively, combined with an intraperitoneal (IP) injection of amylin (5 microg/kg). Amylin's inhibitory effect on food intake (i.e. 50% reduction in cumulative food intake 30 min after ingestion) was markedly reduced by CPA and PYR (e.g. amylin and CPA: 5% reduction versus control). We therefore suggest an important role of hypothalamic H(1) receptors in the signal transduction of peripheral amylin's anorectic action.

The role of sensorial neuropeptides in the edematogenic responses mediated by B(1) agonist des-Arg(9)-BK in rats pre-treated with LPS.

In the present study we have investigated some of the mechanisms underlying B(1) kinin receptor-induced paw edema formation in rats that had been treated with LPS, paying special attention to the involvement of neurogenic inflammation. Intradermal (i.d.) injection of the B(1) receptor agonist des-Arg(9)-BK (100 nmol/paw) resulted in a marked increase in paw volume in animals pre-treated with LPS (0.40+/-0.06 ml). The co-injection of the selective NK(1) FK888 (1 nmol/paw) or NK(2) SR 48968 (3 nmol/paw) receptor antagonists resulted in a significant inhibition of the edema induced by des-Arg(9)-BK (30+/-4 and 25+/-7%, respectively). The NK(3) SR 142801 (3 nmol/paw) antagonist did not demonstrate any significant effect on B(1) receptor-mediated paw edema. The edema induced by des-Arg(9)-BK was also significantly inhibited (33+/-5%) by the co-injection of the CGRP-receptor antagonist CGRP 8-37 (1 nmol/paw) or by treatment of animals with capsaicin (50 mgkg(-1), s.c., 48 h, prior) (45+/-4%). The pre-treatment of animals with methysergide or with mianserin, 5-HT(1) and 5HT(2) antagonists, respectively (both 10 mgkg(-1), i.p. 30 min), resulted in a significant reduction of the edema mediated by B(1) receptors (23+/-5 and 20+/-3%, respectively). In addition, compound 48/80 (12 microg/paw, 24 h) significantly reduced des-Arg(9)-induced paw edema in rats pre-treated with LPS (23+/-3%), while the treatment of animals with the H(1) receptor antagonist pyrilamine (10 mgkg(-1), i.p., 30 min) failed to affect the edematogenic responses involving B(1) receptors. Finally, the co-injection of NOS inhibitors L-NAME (100 nmol/paw) or 7-NINA (10 nmol/paw) did not affect the rat paw edema caused by des-Arg(9)-BK, whereas they significantly inhibited BK-induced paw edema. Jointly, the results of the present study show that the edematogenic response mediated by the activation of B(1) receptors, in animals pre-treated with LPS, involves the release of tachykinins and CGRP, as well as serotonin, while NO and histamine seem not to be involved. Therefore, these data further support the notion that B(1) receptors have an important role in modulating the inflammatory processes.

Epileptogenic activity induced by histamine H(1) antagonists in amygdala-kindled rats.

The epileptogenic activities induced by histamine H(1) antagonists in amygdala-kindled rats were studied in comparison with activities in nonkindled rats (sham rats). Intraperitoneal injection of pyrilamine, diphenhydramine and ketotifen resulted in behavioral and electroencephalogram (EEG)-detected seizures in amygdala-kindled rats at doses which caused no or negligible seizures in sham rats. On the other hand, loratadine and cetirizine caused no behavioral or EEG seizures in either amygdala-kindled or sham rats even at a dose of 40 mg/kg. In conclusion, first-generation H(1) antagonists likely elicit epileptogenic activity in amygdala-kindled rats more potent than that in sham rats.

No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats.

In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 mug), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 mug), but induced marked behavioural changes. Central pretreatment with mepyramine (200 mug, i.c.v.) or procaine (600 mug i.c.v.), reduced the hypotension evoked by clonidine (25 mug), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 mug, i.c.v.) or tolazoline (200 mug, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.

Collagenase-induced oedema in the rat paw and the kinin system.

Collagenase (100 micrograms) induced a large plasma extravasation, during the first 15 min after its injection in rat paw, associated with the rapid development of oedema which subsided after 6 h. The extent of the oedema was similar in normal and kininogen-deficient rats. The swelling induced in normal rats was reduced by HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and by three serine protease inhibitors, soybean trypsin inhibitor (SBTI), Leucaena leucocephala trypsin inhibitor 1 (LLTI-1) and Leucaena leucocephala trypsin inhibitor 2 (LLTI-2). These agents had no effect on the oedema induced in kininogen-deficient rats. The swelling was also reduced by methysergide, indomethacin, ketoprofen and methylprednisolone. It was increased by heparin, but it was not modified by mepyramine, WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo- [4,3-a][1,4]-diazepine-2-yl]-1-(4-morpholinyl)-1-propanone) and NG-nitro-L-arginine. In vitro, collagenase did not release kinins from rat plasma or from purified T-kininogen. LLTI-1 and LLTI-2 did not inhibit collagenase activity for one of its specific substrates. Kinins are thus involved in the development of collagenase oedema in normal rats. Their generation would be indirect following changes in matrix proteins in extravascular spaces. Nevertheless, kinins are not the decisive mediators of the swelling. Serotonin, possibly released from platelets, and prostanoids participate in the inflammatory process.