Mepyramine Research Articles

Sex differences in mouse behavior following pyrilamine treatment: role of histamine 1 receptors in arousal

Arousal, the activation of brain and behavior, is a fundamental component of behavior. While sex differences in behavior are pervasive, it is unknown whether they could be due to an underlying dimorphism in arousal mechanisms. Because histamine (HA) acting through histamine 1 (H1) receptors is one essential component of arousal neural circuitry, the aim of the current experiment was to measure sex differences in behavioral arousal following treatment with the H1 receptor antagonist, pyrilamine (PYRL). Castrated male and ovariectomized female Swiss–Webster mice were treated subcutaneously with either 15 or 35 mg/kg of PYRL. The effect of drug treatment was determined in an array of behaviors: sensory responsiveness, running wheel activity, and fearfulness. Surprisingly, the lower dose of PYRL increased some aspects of arousal, sensory responsiveness, and anxiety-like behavior, while the higher dose of PYRL resulted in decreases in arousal across tests, indicating that antagonism of histamine receptors does not have a linear relationship with arousal. Females were more sensitive to the arousal-reducing effects of PYRL than males in sensory and running wheel tasks but not in tests of emotion. In conclusion, antagonism of H1 receptors can alter arousal in a sex-dependent manner, independent of circulating gonadal steroids, in mice.

Degranulation of mast cells located in median eminence in response to compound 48/80 evokes adrenocortical secretion via histamine and CRF in dogs.

The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.

A Role for Histamine in Active Vasodilation

0267 It has been established that nitric oxide (NO) is involved in cutaneous active vasodilation. Recent evidence suggests vasoactive intestinal peptide (VIP) may be involved in active vasodilation and we have recently shown that VIP-mediated dilation includes a substantial NO-dependent portion. Furthermore, VIP has been shown to induce histamine release from mast cells in human skin. Thus, it is possible that the NO portion of active vasodilation may be due to release of histamine. PURPOSE: To determine the relative contribution of NO and histamine during whole body heating. METHODS: Six subjects were instrumented with 4 microdialysis fibers. Site 1 served as a control and was infused with Ringer's solution. Site 2 received 10 mM L-NAME to inhibit NO synthase (NOS). Site 3 received the H1 receptor antagonist pyrilamine maleate (500 μM). Site 4 was infused with L-NAME combined with H1 receptor antagonist (final concentrations of 10 mM and 500 μM). All infusions were continuous beginning 30 minutes prior to whole body heating and throughout the duration of the heating period. Subjects wore a water-perfused suit and hot water was pumped through the suit to increase core temperature at least 0.8°C. Laser-Doppler flowmetery was used to monitor skin blood flow (SkBF) over each site. Cutaneous vascular conductance (CVC) was calculated as flux/mean arterial pressure and normalized to maximal values via infusion of 28 mM sodium nitroprusside. RESULTS: In control sites, CVC increased during whole body heating to 69±3 %CVCmax. CVC values were significantly reduced in sites receiving NOS inhibition (32±2 %CVCmax; p<0.001) and in sites receiving H1 antagonist only (51±3 %CVCmax; p<0.05). CVC in sites that received NOS inhibition combined with H1 antagonist was attenuated compared to control (33±3 %CVCmax; p<0.001). However, there was no difference between NOS inhibited sites and combined NOS inhibitor and H1 antagonist sites. Additionally, NOS inhibited sites and combined NOS inhibitor and H1 antagonist sites were significantly reduced compared to H1 antagonist only sites (p<0.05). CONCLUSION: The increase in SkBF during whole body heating contains both a histamine component. Furthermore, these data are consistent with a role for VIP in active vasodilation. Supported by NIH Grant HL 70928

CROSSING INTERACTION OF ADRENERGIC, CHOLINERGIC, HISTAMINERGIC AND OPIOIDERGIC SYSTEMS ON WATER INTAKE IN ADULT MALE RATS

Several lines of evidence have indicated that many nuclei in the brain including preoptic nucleus, AV3V, subfornical organ, septal area and lateral hypothalamus are the targets of efferents from chemo-sensitive and pressure-sensitive systems. These areas may concern with regulation of fluid homeostasis. In the present study, intracerebroventricular injections were carried out in all experiments. After a 24 h deprivation of water, the volume of consumed water was measured for 1 h. Administration of pilocarpine (0.5-1 ?g/rat), prazocin (2 ?g/rat), histamine (40-80 ?g/rat) and naloxone (0.5-1 ?g/rat) increased, while scopolamine (5-10 ?g/rat), phenylepherine (30 ?g/rat), morphine (2.5 ?g/rat), pyrilamine (25-50 ?g/rat) and ranitidine (10-20 ?g/rat) decreased water intake in isolated rats. The activation of muscarinic cholinoceptors by pilocarpine attenuated the inhibitory effect induced by phenylepherine. Blockade of muscarinic cholinoceptors did not change the phenylepherine-induced response. Pretreatment of rats with prazocin decreased the pilocarpine-induced response. Pharmacological blockade of muscarinic cholinoceptors by scopolamine decreased the prazocin –induced effect on water intake. Blockade of histamine H1 and H2 receptors attenuated the histamine-induced response. Furthermore, pyrilamine, but not ranitidine, increased the inhibitory effect induced by morphine. Pharmacological blockade of H1 and H2 receptors decreased the naloxone-induced effect on water intake. It is concluded that the histaminergic system may have a close interaction with morphine and naloxone regarding drinking behavior. Also, muscarinic cholinoceptors and adrenoceptors may have an interactive effect in this respect.

Interactions of eosinophil granule proteins with skin: Limits of detection, persistence, and vasopermeabilization

Background Eosinophil granule proteins, including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), eosinophil peroxidase (EPO), and major basic protein (MBP), are prominently deposited in skin in several cutaneous disorders and likely contribute to disease pathology. Objective We sought to determine the limit of detection, persistence, and vasopermeabilization activity of the eosinophil granule proteins in skin. Methods The eosinophil granule proteins were injected intradermally. Their minimum detectable concentrations in human surgical waste skin and their persistence in guinea pig skin were determined by indirect immunofluorescence. Vasopermeabilization activity in the guinea pig without and with H 1 antihistamine (pyrilamine maleate) pretreatment was assessed by extrusion of Evans blue dye—treated plasma. Results The lowest detectable cutaneous concentrations were 0.05 μmol/L EPO, 0.1 μmol/L MBP, 0.25 μmol/L ECP, and 1 μmol/L EDN. Granule proteins persisted in guinea pig skin in vivo for 1 week (EPO), 2 weeks (ECP), 2.5 weeks (EDN), and 6 weeks (MBP). Each of the eosinophil granule proteins increased cutaneous vasopermeability in a concentration-dependent manner. The potency of vasopermeabilization induced by each granule protein was comparable with that of histamine. Pyrilamine maleate pretreatment of guinea pigs did not alter increased vasopermeability induced by ECP and EDN but significantly inhibited that induced by EPO and MBP. Conclusions Micromolar concentrations of eosinophil granule proteins are often deposited in skin in eosinophil-associated cutaneous disorders such as atopic dermatitis. These pathophysiologically relevant concentrations of eosinophil granule proteins cause increased cutaneous vasopermeability (both by means of histamine-independent and histamine-dependent mechanisms) and might alter cutaneous function for days to weeks.

Regulation by Prostaglandin E2 and Histamine of Angiogenesis in Inflammatory Granulation Tissue

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regulation by prostaglandin E2 and histamine of angiogenesis in inflammatory granulation tissue.

In an air pouch-type carrageenin-induced inflammation model in rats, the selective cyclooxygenase (COX)-2 inhibitor NS-398 dose dependently inhibited the granulation tissue formation, angiogenesis and the level of vascular endothelial growth factor (VEGF) in the granulation tissue. In culture of the minced granulation tissue, PGE2 induced VEGF production in a concentration-dependent manner. Histamine also induced VEGF production in the granulation tissue in vitro. The H2 receptor antagonist cimetidine, the cAMP antagonist Rp-cAMP and the protein kinase A inhibitor H-89 suppressed the histamine-induced VEGF production in the granulation tissue. However, the H1 receptor antagonist pyrilamine maleate, the H3 receptor antagonist thioperamide, the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein showed no effect. Subcutaneous implantation of a cotton thread in the dorsum of histidine decarboxylase-deficient (HDC-/-) mice, but not in mast cell-deficient (WBB6F1-W/Wv) mice, induced less angiogenesis with lower levels of VEGF in the granulation tissue than in their corresponding wild-type (HDC+/+ and WBB6F1(-)+/+) mice. In HDC-/- mice, the topical injection of histamine or the H2 receptor agonist dimaprit rescued the defective angiogenesis and granulation tissue formation. In addition, cimetidine but not pyrilamine maleate and thioperamide inhibited the histamine-induced angiogenesis in the granulation tissue in HDC-/- mice. These findings suggest that PGE2 and histamine augment angiogenesis in the inflammatory granulation tissue by inducing VEGF production, and histamine induces VEGF production possibly through the H2 receptor--cAMP--protein kinase A pathway.

Roles of Prostaglandin E2 and Histamine in Angiogenesis in Inflammatory Granulation Tissue

In an air pouch-type carrageenin-induced inflammation model in rats, the selective cyclooxygenase (COX)-2 inhibitor NS-398 dose dependently inhibited the granulation tissue formation, angiogenesis and the level of vascular endothelial growth factor (VEGF) in the granulation tissue. In culture of the minced granulation tissue, PGE2 induced VEGF production in a concentration-dependent manner. Histamine also induced VEGF production in the granulation tissue in vitro. The H2 receptor antagonist cimetidine, the cAMP antagonist Rp-cAMP and the protein kinase A inhibitor H-89 suppressed the histamine-induced VEGF production in the granulation tissue. However, the H1 receptor antagonist pyrilamine maleate, the H3 receptor antagonist thioperamide, the protein kinase C inhibitors Ro31-8425 and calphostin C or the tyrosine kinase inhibitor genistein showed no effect. Subcutaneous implantation of a cotton thread in the dorsum of histidine decarboxylase-deficient (HDC-/-) mice, but not in mast cell-deficient (WBB6F1-W/Wv) mice, induced less angiogenesis with lower levels of VEGF in the granulation tissue than in their corresponding wild-type (HDC+/+ and WBB6F1-+/+) mice. In HDC-/- mice, the topical injection of histamine or the H2 receptor agonist dimaprit rescued the defective angiogenesis and granulation tissue formation. In addition, cimetidine but not pyrilamine maleate and thioperamide inhibited the histamineinduced angiogenesis in the granulation tissue in HDC-/- mice. These findings suggest that PGE2 and histamine play a significant roles in angiogenesis in the inflammatory granulation tissue via induction of VEGF production, and histamine augments VEGF production possibly through the H2 receptor-cAMP-protein kinase A pathway.

Non-adrenergic non-cholinergic excitatory innervation in the airways: role of neurokinin-2 receptors.

1 The hypothesis that the non-adrenergic, non-cholinergic excitatory (NANC-e) innervation is involved in the induction of asthma and that antagonists of NANC-e neurotransmitter could reduce bronchoconstriction during asthma was tested. 2 The first objective was to identify the neurotransmitter(s) of NANC-e innervation from a group of selected putative neurotransmitters. The second objective was to use the antagonist of the identified neurotransmitter(s) to determine its effectiveness against bronchoconstriction to ovalbumin (OVA) in sensitized guinea-pigs. 3 Neurotransmitter identification was performed using the "tracheal pouch"', a surgical preparation established for demonstrating NANC innervation, in anaesthetized guinea-pig airways. A segment of trachea was cannulated and clamped at one end and the other end was connected to a pressure transducer. The stump of the trachea was connected to a ventilator to keep the blood gas values within the normal range. The vagus nerve and the sympathetic nerves were isolated bilaterally and cut. The left carotid artery was cannulated to monitor blood pressure and for sampling blood for blood gas analysis. The jugular vein was cannulated for administration of test agents. 4 Both NANC-e and NANC-i (inhibitory) control responses of airways were obtained by bilateral vagal stimulation after complete autonomic blockade with atropine, propranolol and prazosin. The relaxation of the tracheal pouch was indicative of the NANC-i response and the increase in insufflation pressure of the ventilated peripheral airways was due to NANC-e stimulation. 5 The involvement of the putative neurotransmitters such as neurokinin-A (NK-A), histamine, serotonin and endothelin (ET) was investigated by using the respective antagonists, MEN-10376, pyrilamine maleate, cyproheptadine hydrochloride, and two ET receptor antagonists (BQ-123 and IRL-1038), respectively. The antagonists were administered at the dose rate of 4 mg kg-1 i.v. which was determined from preliminary studies by testing against the respective agonists. 6 MEN-10376 (neurokinin-2 receptor antagonist) significantly inhibited the insufflation pressure (peripheral airway pressure) increase caused by NANC-e stimulation. MEN-10376 also inhibited the fall in blood pressure caused by bilateral vagal stimulation. The 5-HT antagonist, cyproheptadine, significantly enhanced the NANC-e response. 7 After identifying the NANC-e neurotransmitter as NK-A, the effectiveness of its antagonist, MEN-10376, was evaluated for its ability to attenuate the increase in insufflation pressure (bronchoconstriction) induced in guinea-pigs sensitized by OVA. Guinea-pigs were sensitized to OVA (200 mg i.p.) and 10 days later prepared for the determination of tracheal pouch and insufflation responses to 100 microg of OVA administered i.v. (challenge dose). This caused an increase in insufflation pressure in the presence of adrenergic and cholinergic blockade, which was significantly attenuated by MEN-10376. 8 These studies indicated that neurokinin-2 receptors were involved in the vagally mediated efferent neurotransmission of NANC-e and that NANC-e plays a role in allergen-induced bronchoconstriction.

Neurochemical regulation of cough response to capsaicin in guinea‐pigs

1. Although monumental efforts have been made to define the action sites of cough, the importance of neurotransmitter systems in the cough reflex has received limited attention. We studied the roles for four major neurotransmitters [acetylcholine, histamine, serotonin (5-hydroxytryptamine, 5-HT) and dopamine] in the modulation of the cough reflex. 2. Atropine (muscarinic cholinergic blocking agent), pyrilamine maleate (PM, histamine H1 blocker), cimetidine (histamine H2 blocker), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, specific 5-HT1A receptor agonist) and SCH-23390 (selective dopamine D1 receptor antagonist) were examined on the cough response to inhaled capsaicin in conscious guinea-pigs. 3. All the drugs significantly decreased the number of capsaicin-induced coughs in a dose-dependent manner. To compare the sensitivity of these drugs on cough response, we calculated the effective doses for 50% inhibition of cough (ED50) when the animals were exposed to 3 x 10-4 m capsaicin. The ED50 values were 0.03 microm kg-1 for atropine, 0.2 microm kg-1 for 8-OH-DPAT, 6.2 microm kg-1 for SCH-23390, 8.5 microm kg-1 for PM and 13.9 microm kg-1 for cimetidine. 4. These findings indicated that all these four neurotransmitters may be involved in the regulation of the cough reflex. Multiple changes of these neurotransmitters in disorders of the central nervous system might synergically affect the cough reflex.

Neurochemical regulation of swallowing reflex in guinea pigs

Background:Most peripheral afferent fibers involved in swallowing travel through the glossopharyngeal and vagus nerves and terminate in the nucleus of the tractus solitarius (NTS) and nodose ganglion (NG). Sensory neurons within the NTS and NG contain several neurotransmitters, including acetylcholine, histamine, serotonin and dopamine. The roles of these four neurotransmitters were investigated.Methods:The effects of atropine (muscarinic cholinergic receptor antagonist); pyrilamine maleate (PM, histamine H1 receptor antagonist); cimetidine (histamine H2 receptor antagonist); 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT, specific 5‐HT1A receptor agonist); and selective dopamine D1 receptor antagonist (Sch‐23390) on the number of swallows elicited by distilled water in anesthetized guinea pigs were investigated.Results:Atropine (0.2 mg/kg) inhibited swallowing by approximately 70%; PM (30 mg/kg) inhibited swallowing by approximately 60%; cimetidine (30 mg/kg) inhibited swallowing by approximately 52.9% and Sch‐23390 (chronic treatment) inhibited swallowing by approximately 40%. In contrast, 8‐OH‐DPAT did not alter the number of swallows. Chronic pretreatment of Sch‐23390 markedly decreased the substance P (SP) content in the pharyngeal mucosa and the esophagus.Conclusion:These findings indicate that acetylcholine, histamine and dopamine are involved in the regulation of the swallowing reflex, whereas it is unlikely that serotonin is involved.

Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H(2) receptors.

1. Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2. Incubation of the minced granulation tissue in the presence of histamine (1 and 10 microM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3. The increase in the content of VEGF protein in the conditioned medium by histamine (10 microM) was suppressed by the H(2) receptor antagonist cimetidine (IC(50) 0.37 microM), but not by the H(1) receptor antagonist pyrilamine maleate, the H(3) receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4. The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC(50) 6.8 microM), and the protein kinase A inhibitor H-89 (IC(50) 12.5 microM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5. Simultaneous injection of cimetidine (400 microg) and indomethacin (100 microg) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6. These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H(2) receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue.

Effects of antihistamines on fenfluramine-induced depletion of indoles in the brain of rats.

Various effects of chlorpheniramine (CPA), diphenhydramine (DIPH), tripelennamine (TRIP), and pyrilamine (PYRI) on fenfluramine (FEN)-induced depletion of serotonin in the brain of rats were observed to be dependent on body temperature. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, and striatum of rats treated with FEN (10 mg/kg, once or twice daily x 4 days) decreased to approximately 30% (P < 0.01) that of controls with no significant changes after CPA, DIPH, TRIP, and PYRI. Treatment with FEN plus CPA (5, 10, 20 mg/kg) and FEN plus DIPH (20 mg/kg), but not FEN plus TRIP (20 mg/kg) and FEN plus PYRI (20 mg/kg), increased brain serotonin levels 2- to 3-fold more than those treated with FEN plus saline. Treatment with FEN plus CPA and FEN plus DIPH, but not FEN plus TRIP and FEN plus PYRI, decreased rectal temperature with no significant change after FEN. The antihistamines alone decreased temperature at a 1-hour period and enhanced FEN-induced reduction in body weight. Possible mechanisms of the different effects of antihistamines on FEN-induced depletion of serotonin are discussed.

Histamine-induced gastric acid secretion in horses

Abstract Objective To determine gastric secretory responses in horses treated with histamine and to determine the dose of histamine needed to elicit maximal gastric secretion. Animals 6 adult horses with an indwelling gastric cannula. Procedure Gastric contents were collected in 15-minute periods, and volume, pH, hydrogen ion concentration, hydrogen ion output, sodium concentration, and sodium output were determined. Values were determined without any treatment (baseline), after administration of pyrilamine maleate (1 mg/kg of body weight, IV, given during a 15-minute period), and during 1-hour infusions of histamine at 3 rates (7.5, 15, and 30 μg/kg/h, IV). Results Volume and hydrogen ion concentration of gastric contents and hydrogen ion output were significantly increased, compared with baseline values, during histamine infusion. Mean hydrogen ion concentration and hydrogen ion output were significantly greater during infusion of histamine at a rate of 15 or 30 μg/kg/h than at a rate of 7.5 μg/kg/h. Sodium concentration was significantly decreased, compared with baseline value, during histamine infusion, but sodium output was unchanged. Conclusions Histamine at doses of 15 and 30 μg/kg/h, IV stimulated maximal gastric secretion in horses. Histamine appeared to induce only parietal secretion. Clinical Relevance This study provides additional information related to equine gastric physiology, which may benefit further understanding of the pathogenesis of peptic ulcer disease. (Am J Vet Res 1998;59:1303–1306)

Evidence for hypernociception induction following histamine H 1 receptor activation in rodents

To characterize the mechanism of the analgesic action of H 1 antihistaminics the effects of a new, highly selective agonist, 2-(3-trifluoromethylphenyl)histamine dihydrogenmaleate (FMPH), and of the better known H 1 agonist, 2-thiazolylethylamine (2-TEA), were studied on pain threshold by means of three different kinds of tests for nociception (mouse hot plate and abdominal constriction, and rat paw pressure tests). Low doses of both substances (2.65 and 6.5 μg/animal i.c.v. for FMPH in the hot plate and paw pressure tests, and 0.3 μg/rat i.c.v. for 2-TEA in the paw pressure test) were slightly but significantly hypernociceptive. The selective H 1 receptor antagonist, pyrilamine maleate (10–30 mg/kg s.c.), induced a dose-dependent antinociception in all three tests, and both FMPH and 2-TEA prevented its effect, but not that of morphine, thus indicating action on H 1 receptors. The same low doses of FMPH were also able to enhance animals 1 spontaneous motility and curiosity. High doses of FMPH (13.23–132.3 μg/mouse i.c.v.) raised the pain threshold, but due to the severe motor impairment evidenced by the rota rod test, this cannot be considered as real antinociception. An increase in the pain threshold lacking any motor impairment was observed for tenfold higher doses of 2-TEA (3 and 10 μg/mouse i.c.v.). This may be due to action on H2 receptors, with the reported relative potency of 2-TEA for H 1 and H 2 receptors being about 12:1. It is therefore suggested that H 1 receptor activation increases sensitivity to noxious stimuli.

Histamine and prostaglandin interaction in the central regulation of ACTH secretion.

Since prostaglandins (PGs) and histamine (HA) seem to be involved in the activation of the hypothalamic-pituitary-adrenal axis following immunochallenges with lipopolysaccharide (LPS) endotoxin and cytokines, we investigated whether the histaminergic and eicosanoid systems in the male rat brain interact in their regulation of ACTH secretion. The PG synthesis inhibitor indomethacin (10 mg/kg i.p.) attenuated the ACTH response to LPS (10 micrograms/kg i.p.) and HA (30 micrograms i.c.v.). Infusion of PGE1, PGE2 or PGF2 alpha (1 and/or 5 micrograms infused intracerebroventricularly) stimulated ACTH secretion. The ACTH response to PGE1 was inhibited by the HA synthesis inhibitor alpha-fluoromethyl-histidine and the H1 receptor antagonist mepyramine (MEP) but not the H2 receptor antagonist cimetidine (CIM). Neither MEP nor CIM affected the ACTH response to PGE2. MEP and CIM attenuated the ACTH response induced by PGF2 alpha. The findings indicate that HA and some PGs in the brain interact in their stimulatory regulation of ACTH secretion. Such an interaction may also be involved in their mediation of the ACTH response to immunochallenges.

Effect of Antioxidants, Anti-inflammatory Drugs, and Histamine Antagonists on Sparfloxacin-Induced Phototoxicity in Mice

We examined the effects of antioxidants, anti-inflammatory drugs, and histamine antagonists on auricular inflammation and retinal degeneration induced by the phototoxicity of sparfloxacin (SPFX), a quinolone antibacterial agent. Catalase (CAT), dimethyl sulfoxide (DMSO), dexamethasone (DM), indomethacin (IM), phenidone (PD), AA-861 (AA), pyrilamine maleate (PY), or cimetidine (CM) was continuously administered to female Balb/c mice using microosmotic pumps for 72 hr and intraperitoneally once before SPFX administration. The mice were given a single oral administration of 50 or 100 mg/kg SPFX and irradiated with ultraviolet-A (UVA) light at 1.5 mW/cm2for 4 hr. SPFX administration plus UVA irradiation induced thickening and inflammation of the auricular skin and retinal degeneration in the eye. CAT and DMSO significantly inhibited the auricular thickening only 4 hr after SPFX administration. DM, IM, and PD also inhibited this toxicity from 4 to 48 or 72 hr. On the other hand, PY and CM showed no effect on this change. With regard to the eye, CAT and DMSO completely inhibited the occurrence of retinal degeneration and IM and PD tended to decrease its incidence, whereas DM, AA, PY, and CM showed no or an exacerbating effect. These results suggest that reactive oxygen species contribute to the initiation of auricular inflammation and retinal degeneration and that cyclooxygenase products are also involved in the initiation and later progression of auricular inflammation. They also show that histamine and 5-lipoxygenase products are not involved in either phototoxic lesion.

Effect of Antioxidants, Anti-inflammatory Drugs, and Histamine Antagonists on Sparfloxacin-Induced Phototoxicity in Mice

We examined the effects of antioxidants, anti-inflammatory drugs, and histamine antagonists on auricular inflammation and retinal degeneration induced by the phototoxicity of sparfloxacin (SPFX), a quinolone antibacterial agent. Catalase (CAT), dimethyl sulfoxide (DMSO), dexamethasone (DM), indomethacin (IM), phenidone (PD), AA-861 (AA), pyrilamine maleate (PY), or cimetidine (CM) was continuously administered to female Balb/c mice using microosmotic pumps for 72 hr and intraperitoneally once before SPFX administration. The mice were given a single oral administration of 50 or 100 mg/kg SPFX and irradiated with ultraviolet-A (UVA) light at 1.5 mW/cm2 for 4 hr. SPFX administration plus UVA irradiation induced thickening and inflammation of the auricular skin and retinal degeneration in the eye. CAT and DMSO significantly inhibited the auricular thickening only 4 hr after SPFX administration. DM, IM, and PD also inhibited this toxicity from 4 to 48 or 72 hr. On the other hand, PY and CM showed no effect on this change. With regard to the eye, CAT and DMSO completely inhibited the occurrence of retinal degeneration and IM and PD tended to decrease its incidence, whereas DM, AA, PY, and CM showed no or an exacerbating effect. These results suggest that reactive oxygen species contribute to the initiation of auricular inflammation and retinal degeneration and that cyclooxygenase products are also involved in the initiation and later progression of auricular inflammation. They also show that histamine and 5-lipoxygenase products are not involved in either phototoxic lesion.

Endogenous histamine contributes to drinking initiated without postprandial challenges to fluid homeostasis in rats

A role for endogenous histamine and its receptor subtypes for mediating drinking elicited by eating was examined in adult male Sprague-Dawley rats in two experimental paradigms in which drinking was initiated without accompanying change in systemic fluid balance: (a) nondeprived rats eating a small (0.57 g) salted cracker; (b) nondeprived rats receiving IG infusion (through a chronic gastric catheter) of 2 ml 900 mOsm/kg NaCl. The ability of IP, SC, or ICV (through a surgically implanted chronic cannula in a lateral ventricle) injections of antagonists to H 1, H 2, or H 3 receptors for histamine to inhibit drinking was examined. For rats ingesting a small cracker: systemic injection of H 1 antagonists dexbrompheniramine (DXB) or pyrilamine (PYR) delayed the latency to initiate drinking. Systemic injection of H 1 antagonists DXB, PYR, or terfenadine (TER; which fails to penetrate the blood-brain barrier) and ICV injection of DXB or PYR inhibited water intake. The H 2 antagonist cimetidine (C) given IP or ICV failed to affect drinking. The H 3 antagonist thioperamide (Th) given SC or ICV delayed the latency to drink and inhibited water intake. For rats receiving IG NaCl: systemic injection of H 1 antagonists DXB or PYR or the H 3 antagonist Th inhibited water intake, but the H 2 antagonist C failed to inhibit drinking. Our findings extend the evidence for the involvement of endogenous histamine in drinking elicited by eating in rats by suggesting roles for peripheral and brain H 1 and H 3 receptors for drinking initiated by postprandial gastrointestinal osmotic consequences that are subthreshold for changes in systemic fluid balance.

Chronic Toxicity/Carcinogenicity Study of Pyrilamine in B6C3F1 Mice

The chronic toxicity and carcinogenicity of pyrilamine maleate were evaluated in B6C3F1 mice by feeding for up to 2 years to groups of 60 male or female mice at dietary levels of 0,150, 750, or 1,500 ppm (as the free base). Up to 12 mice per sex and dose group were killed after 65 weeks for clinical chemistry, hematology, and histopathologic evaluation of control and high-dose animals. Histopathology was performed on all animals that were dead or moribund or lived until the study was terminated at 2 years. Daily exposures to pyrilamine ranged from ∼16 to 176 mg/kg, compared with maximum human exposure of 3 mg/kg. Regarding longevity, pyrilamine-treated male mice tended to survive longer than controls, whereas no differences among treated and control female mice were noted. Body weights did not differ among treated and control male groups, but final body weight average of treated female mice was 6–10% lower than that for controls. Although no dose-response trends were noted in male mice for histopathologic end points, liver /body and liver/ brain weight ratios were significantly greater in high-dose male mice than in controls. Chronic liver inflammation exhibited a positive dose-response trend in female mice, but there was no evidence for a carcinogenic response to pyrilamine by either sex.