It has been recognized that atopic dermatitis (AD) involves allergen-driven Th2 cell polarization. In patients with AD, cytokines induce allergic inflammatory responses and subsequently enhance IgE production. Recent reports revealed that a reduced barrier function as well as altered immunity are fundamental to the development of AD because barrier disruption due to aberrant filaggrin expression is a pathological factor. However, although recent studies have improved our understanding of the pathogenesis of AD, the overall pathophysiology remains elusive. I herein discuss it based on the natural history of AD.

View full abstract

Aspirin (acetylsalicylic acid) is a well-known nonsteroidal anti-inflammatory drug that can potentiate some acute allergies and causes adverse immunological reactions collectively referred to as aspirin intolerance, a disorder that induces urticaria, asthma, and anaphylaxis in response to oral administration of the drug. Aspirin also potentiates some acute allergies such as food-dependent exercise-induced anaphylaxis (FDEIA), a food allergy induced by physical exercise. The anti-inflammatory actions as well as the adverse immunological effects have been thought to be primarily due to inhibition of cyclooxygenase activity. However, a growing body of evidence suggests that mechanisms unrelated to inhibition of prostaglandin synthesis are involved. One key feature of aspirin intolerance is the overproductions of cysteinyl leukotrienes (LTs), in which mast cells have been implicated to play a role. In this review, we provide an overview of our current knowledge about the regulatory mechanisms of LTC₄ secretion in mast cells and its modulation by aspirin, with a special emphasis on the role of Ca²⁺ signals. We also introduced our recent findings that mast cells express dihydropyridine-sensitive L-type Ca²⁺ channels (LTCCs) and that Ca²⁺ channels of this kind mediate aspirin modulation of LTC₄ secretion in mast cells.

View full abstract

We established a novel allergic dermatitis model in mouse ear lobes in which antigen-nonspecific inflammation was induced by painting 12-O-tetradecanoylphorbol 13-acetate (TPA) between sensitization and challenge with picryl chloride (PiCl). This model has an advantage for analyzing atopic dermatitis-like inflammation within a short period. Analysis of the time course changes in the PiCl-induced swelling showed that the allergic inflammation was shifted from a delayed-type response to a biphasic response consisting of a weak immediate-phase response and a late-phase response by painting with TPA. The application of TPA increased the PiCl-induced infiltration of eosinophils and mast cells at the inflammatory site and shifted the cytokine milieu from Th1 to Th2. The expression of the Th2-inducing cytokine thymic stromal lymphopoietin (TSLP) mRNA was also increased by TPA. These findings suggested that the induction of antigen-nonspecific inflammation by TPA before the antigen challenge enhanced the Th2 response and modified the PiCl-induced delayed type-hypersensitivity. Using this model, we clarified that histamine plays significant roles in the early-phase swelling via H₁ receptors and the late-phase swelling via H₃/H₄ receptors. Thus, we suggested the usefulness of the combined treatment with an H₁ antagonist and an H₄ antagonist for the suppression of atopic dermatitis.

View full abstract

Animal models for human diseases are important for the elucidation of mechanisms involved in as well as for the establishment of effective treatment strategies for the diseases. Many mouse allergic dermatitis models have been established and applied for the development of remedies for human allergic dermatitis. One of the simplest allergic cutaneous reaction models is passive cutaneous anaphylaxis. Skin mast cells passively sensitized with antigen-specific IgE are activated upon antigen challenge to cause vascular permeability increase. The triphasic cutaneous reaction is another interesting model in which triphasic cutaneous swelling appears in mice passively sensitized with IgE upon challenge with specific antigen. Recently, many allergic dermatitis models have been established by repeated antigen exposure. Although the induced dermatitis seems to be complex, these models may possess the characteristic features observed in patients. Naturally occurring dermatitis model mice such as NC/Nga, NOA, and DS-Nh mice, and gene-knockout and transgenic mice exhibiting spontaneous dermatitis are also known. Establishment and characterization of the mouse dermatitis models seem to be important for understanding dermatitis and development of new strategies for the treatment of these diseases.

View full abstract

Atopic dermatitis frequently accompanies bronchial asthma, allergic rhinitis, and allergic conjunctivitis, the pathogenesis of which has frequently focused on the immunological aspects; however, skin eruption in atopic dermatitis occurs mainly in the epidermis, whose barrier function and cytokine expression have been revealed to be abnormal. In addition, the epidermis contains Langerhans cells, antigen-presenting cells, which could be considered the sentinel of the immune system. Some atopic dermatitis patients have been revealed to have mutations or SNPs (single-nucleotide polymorphisms) in the filaggrin gene, which affect the epidermal barrier function. Proteinases in the epidermis are of importance in maintaining the epidermal barrier, abnormalities of which have been reported in atopic dermatitis. Abnormalities of various cytokines and chemokines produced by keratinocytes have also been reported. Thymic stromal lymphopoietin (TSLP) produced by keratinocytes has recently been a focus in atopic dermatitis. Adrenergic/cholinergic responses in the epidermis could also influence the pathogenesis of atopic dermatitis. Considering epidermal keratinocytes as a trigger of immune abnormalities, not only as a peripheral effector, would be important to further disclose the pathogenesis of this enigmatic disorder.

View full abstract

Although the identification of neural pathways for histamine-induced itch was a breakthrough in itch research, other pathways also seem to be involved in itch. In regard to itch of atopic dermatitis, neural sensitization complicates its mechanisms. Inflammatory mediators such as bradykinin that, normally, do not induce itch can function as pruritogens under neural sensitization, which also affects the treatment to a considerable extent. Complete inhibition of skin inflammation is, for now, the most effective way to suppress itching in atopic dermatitis, since there might be countless potential mediators inducing itch. Centrally acting anti-pruritic drugs as well as drugs against neural sensitization are prospective treatments for itch of atopic dermatitis.

View full abstract

The present study investigated whether the platelet-derived growth factor receptor (PDGFR)-β–mediated mechanisms are involved in the hypoxic ventilatory response through modulating the N-methyl-D-aspartate (NMDA) function. The ventilatory changes during hypoxic challenge (10% O₂, 30 min) were measured plethysmographically in mice selectively lacking the PDGFR-β in neurons (KO mice) and in control wild-type mice (WT mice) before and after blockade of NMDA receptors. In baseline breathing at rest, respiratory rate, tidal volume, and minute ventilation were similar between WT and KO mice. Hypoxia caused an increase of ventilation during the early period of exposure (an initial excitation), followed by a progressive decrease along with the exposure period (a late decline). The initial excitation occurred similarly in KO and WT mice, while the late decline was markedly attenuated in KO mice. Administration of an antagonist of NMDA receptors, dizocilpine (0.3 mg/kg, i.p.) decreased the initial excitation and hastened the late decline of hypoxic ventilatory response. Furthermore, the hypoxic ventilatory response in KO mice was indistinguishable from that in WT mice after blockade of NMDA receptors. The present study suggests that the PDGF-BB/PDGFR-β signal axis contributes to the hypoxic ventilatory response by its inhibitory effect on the NMDA receptor–mediated function.

View full abstract

The nasal decongestant oxymetazoline (OMZ) exhibits anti-oxidative and anti-inflammatory properties (I. Beck-Speier et al., J Pharmacol Exp Ther. 2006;316:842–851). In a follow up study, we hypothesized that OMZ generates pro-resolving lipoxins being paralleled by production of immune-modulating prostaglandin E₂ (PGE₂) and anti-inflammatory 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] and depletion of pro-inflammatory leukotriene B₄ (LTB₄). Human neutrophils (PMN) were chosen as the cellular system. The effect of OMZ on these parameters as well as on respiratory burst activity and oxidative stress marker 8-isprostane was analyzed in unstimulated and co-stimulated PMN by ultrafine carbon particles (UCP) or opsonized zymosan (OZ), respectively. In unstimulated cells, OMZ induced formation of PGE₂, 15(S)-HETE, and LXA₄. The levels of LTB₄ and 8-isoprostane were not affected, whereas respiratory burst activity was drastically inhibited. In UCP- and OZ-stimulated control cells, all parameters were elevated. Here, OMZ maintained the increased levels of PGE₂, 15(S)-HETE, and LXA₄, but substantially suppressed levels of LTB₄ and 8-isoprostane and inhibited the respiratory burst activity. These findings suggest a switch from the pro-inflammatory eicosanoid class LTB₄ to the pro-resolving LXA₄. Since LXA₄ is most relevant in returning inflamed tissue to homeostasis, OMZ is postulated to terminate rhinitis-related inflammation, thus contributing to shortening of disease duration.

View full abstract

Heme oxygenase (HO)-1 is implicated in cytoprotection in various organs. We tested a possibility that polaprezinc (PZ), an anti-ulcer drug, could induce HO-1 in the gastric mucosa. Male 6-week-old Wistar rats were intragastrically administered PZ. Gastric expression of HO-1 was assessed by real time RT-PCR and western blotting, and localization of HO-1 was observed by in situ hybridization and immunohistochemistry. The levels of HO-1 mRNA were increased in a dose-dependent manner. The levels of HO-1 mRNA were increased 4-fold by PZ at the dose of 200 mg/kg at 3 h as compared with control levels. The levels of immunoreactive HO-1 were increased 3-fold at 6 h. Signals for HO-1 mRNA and immunoreactivity were detected strongly in the surface gastric mucosal cells and moderately in the gastric macrophages. Treatment with an HO-1 inhibitor, stannous mesoporphyrin (SnMP) significantly worsened the HCl-induced acute gastric mucosal lesions and increased the apoptosis of mucosal cells. Mucosal lesions were decreased by pretreatment with PZ, while they were increased by co-administration with SnMP. These data indicate for the first time that PZ is an effective inducer of HO-1 in the stomach. PZ-induced HO-1 functions as a part of the mucosal protective effects of PZ.

View full abstract

Ranolazine, a piperazine derivative, is currently approved for the treatment of chronic angina. However, its ionic mechanisms in other types of cells remain unclear, although it is thought to be a selective blocker of late Na⁺ current. This study was conducted to evaluate the possible effects of ranolazine on Na⁺ current (I_Na), L-type Ca²⁺ current (I_Ca,L), inwardly rectifying K⁺ current (I_K(IR)), delayed-rectifier K⁺ current (I_K(DR)), and Ca²⁺-activated K⁺ current (I_K(Ca)) in pituitary tumor (GH₃) cells. Ranolazine depressed the transient and late components of I_Na with different potencies. This drug exerted an inhibitory effect on I_K(IR) with an IC₅₀ value of 0.92 μM, while it slightly inhibited I_K(DR) and I_K(Ca). It shifted the steady-state activation curve of I_K(IR) to more positive potentials with no change in the gating charge of the channel. Ranolazine (30 μM) also reduced the activity of large-conductance Ca²⁺-activated K⁺ channels in HEK293T cells expressing α-hSlo. Under current-clamp conditions, low concentrations (e.g., 1 μM) of ranolazine increased the firing of action potentials, while at high concentrations (≥10 μM), it diminished the firing discharge. The exposure to ranolazine also suppressed I_Na and I_K(IR) effectively in NG108-15 neuronal cells. Our study provides evidence that ranolazine could block multiple ion currents such as I_Na and I_K(IR) and suggests that these actions may contribute to some of the functional activities of neurons and endocrine or neuroendocrine cells in vivo.

View full abstract

Intestinal myofibroblasts (IMFs) that exist adjacent to the basement membrane of intestines have contractility and contribute to physical barriers of the intestine. Nerve endings distribute adjacent to IMFs, suggesting neurotransmitters may influence IMFs motility; however, there is no direct evidence showing the interaction. Here, we isolated IMFs from rat colon and investigated the effect of acetylcholine on IMFs contractility. In the collagen gel contraction assay, carbachol (1 – 10 μM) and the muscarinic receptor agonist bethanechol (30 – 300 μM) dose-dependently induced IMFs contraction. Pretreatment with the muscarinic receptor antagonist atropine (1 – 10 nM) inhibited carbachol-induced contraction. In RT-PCR, mRNA expression of all muscarinic receptor subtypes (M₁ – M₅) was detected in IMFs. Subsequently we found pretreatment with the muscarinic M₂ receptor antagonist 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX116) (10 and 30 nM) or the muscarinic M₃ receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) (3 and 10 nM) dose-dependently inhibited carbachol-induced contraction. In Ca²⁺ measurement, 1 – 10 μM carbachol and 30 – 300 μM bethanechol elevated the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in IMFs. Atropine (10 nM) eliminated carbachol-induced [Ca²⁺]_i elevation. The Ca²⁺-channel blocker LaCl₃ (3 μM) abolished carbachol-induced [Ca²⁺]_i elevation and contraction. Furthermore, AF-DX116 and 4-DAMP dose-dependently inhibited the carbachol-induced [Ca²⁺]_i elevation. These observations suggest that acetylcholine elicits Ca²⁺-dependent IMF contraction through muscarinic M₂ and M₃ receptors.

View full abstract

The aim of this study was to clarify the relationship between receptor occupancy and in vivo pharmacological activity of mGluR1 antagonists. The tritiated mGluR1-selective allosteric antagonist [³H]FTIDC (4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide) was identified as a radioligand having high affinity for mGluR1-expressing CHO cells (K_D = 2.1 nM) and mouse cerebellum (K_D = 3.7 nM). [³H]FTIDC bound to mGluR1 was displaced by structurally unrelated allosteric antagonists, suggesting there is a mutual binding pocket shared with different allosteric antagonists. The binding specificity of [³H]FTIDC for mGluR1 in brain sections was demonstrated by the lack of significant binding to brain sections prepared from mGluR1-knockout mice. Ex vivo receptor occupancy with [³H]FTIDC revealed that the receptor occupancy level by FTIDC correlated well with FTIDC dosage and plasma concentration. Intracerebroventricular administration of (S)-3,5-dihydroxyphenylglycine is known to elicit face washing behavior that is mainly mediated by mGluR1. Inhibition of this behavioral change by FTIDC correlated with the receptor occupancy level of mGluR1 in the brain. A linear relationship between the receptor occupancy and in vivo activity was also demonstrated using structurally diverse mGluR1 antagonists. The receptor occupancy assays could help provide guidelines for selecting appropriate doses of allosteric mGluR1 antagonist for examining the function of mGluR1 in vivo.

View full abstract

It has been shown that enhancement of vasoconstrictor prostanoids plays an important role in the development of cardiovascular diseases. The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC), a low-molecular-weight thiol antioxidant and a potent inhibitor of nuclear factor-κB (NF-κB), on both the response to and production of prostanoids in arterial vessels isolated from rats at the chronic stage of type 2 diabetes. Using aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, control Long-Evans Tokushima Otsuka (LETO) rats, and LETO and OLETF rats treated with PDTC (30 mg/kg, s.c., daily, for 1 week), we measured the production of prostanoids and NF-κB activity. The arachidonic acid–induced contraction and the acetylcholine-induced endothelium-derived contracting factor (EDCF)-mediated contraction in mesenteric arteries were also compared among these groups. OLETF rats exhibited (vs. age-matched LETO rats) the following: increased responses to both arachidonic acid and EDCF and greater productions of PGE₂ and TXA₂. Treatment with PDTC resulted in the following: 1) reduced arachidonic acid– and EDCF-mediated contractions, 2) suppressed the production of prostanoids, and 3) normalized NF-κB activity. These results suggest that PDTC has beneficial effects against the abnormal vasoconstrictor prostanoid signaling present in rats at the chronic stage of type 2 diabetes.

View full abstract

Propofol is a widely used intravenous general anesthetic. The negative inotropic effect of propofol has been best explained by inhibition of the L-type Ca²⁺ current (I_Ca). Using guinea-pig cardiac preparations, however, we found that the propofol concentration producing a 50% decrease in force of contraction was more than 10 times higher than that producing a 50% inhibition of I_Ca, implying that a compensatory mechanism may be present to counteract the negative inotropic effect associated with the I_Ca inhibition. Consistent with I_Ca inhibition, propofol produced a shortening of action potential duration (APD) in single cardiomyocytes. Yet, the concentrations necessary to shorten APD were greater than that for 50% inhibition of I_Ca. This was associated with the potent and effective inhibition of the slowly activating component of the delayed rectifier K⁺ current (I_Ks). Thus, the I_Ks blockade with propofol may counterbalance the APD shortening evoked by its I_Ca inhibition. Taken together, the negative inotropic effect of propofol is detectable only at supratherapeutic concentrations. At clinically relevant concentrations, the action potential prolongation mechanism due to I_Ks inhibition appears to alleviate the reduction in transsarcolemmal Ca²⁺ influx through L-type Ca²⁺ channels, which may help to counteract the net negative inotropism of propofol.

View full abstract

Myeloid cell leukemia-1 (Mcl-1), a member of the B-cell lymphoma-2 (Bcl-2) family, has been reported to be a critical survival factor in hematopoietic cells, yet little data exists for a role of Mcl-1 in human oral squamous cell carcinoma (SCC). A high level expression of Mcl-1 was observed in tumor cells of human primary SCC, lymph node metastasis tissues, and SCC cell lines. We manipulated expression of Mcl-1 protein in SCC cells by small interfering RNA (siRNA) for Mcl-1 and observed that Mcl-1 siRNA inhibited the growth of SCCs accompanied with apoptosis. Combination therapy of Mcl-1 siRNA and anti-tumor drug drastically inhibited the cell growth in comparison to that in each single treatment. In addition, phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with Mcl-1 siRNA, resulting in decreases in phosphorylation of MEK1/2 and MAPK. The cell growth inhibition caused by knockdown of Mcl-1 was suggested to be mainly a result of suppression of proliferation via the inhibition of intracellular FAK/MAPK signaling pathways. These results imply a potentially important and novel role of the inhibition of Mcl-1 function by the use of specific siRNA in the treatment of SCC.

View full abstract

Cigarette smoking is a major risk factor for cardiovascular disease. The induction of oxidative stress by smoking plays a key role in the progression of atherosclerosis. However, the underlying mechanisms are not fully understood. In the present study, we investigated whether long-term smoking can accelerate the progression of atherosclerosis and whether oxidative stress is implicated in its pathogenesis. Apolipoprotein E–deficient spontaneously hyperlipidemic mice, a model of atherosclerosis, were exposed to the gas-phase of smoke, from which tar and nicotine had been removed, for 15 min a day, 6 days a week, for 16 weeks. Exposure to cigarette smoke significantly increased the serum levels of oxidative stress markers such as thiobarbituric acid–reactive substances, oxidatively modified low-density lipoproteins, and 3-nitrotyrosine, but it did not affect serum cholesterol and triglyceride levels. Exposure to smoke also accelerated the accumulation of total cholesterol levels in the aorta that was accompanied by an increase in 3-nitrotyrosine levels of the atherosclerotic mice. These changes in the serum and aorta that progressed with exposure to smoke were prevented by vitamin E administration. Our data suggest that chronic cigarette smoking promotes and aggravates atherosclerosis and that the antioxidant vitamin E exerts an anti-atherogenic effect via reduction of oxidative stress.

View full abstract

Atherosclerosis is a complex inflammatory arterial disease. Oxidized low-density lipoprotein (ox-LDL) is directly associated with chronic vascular inflammation. In the current study, we tested the hypothesis that ginkgolide B, a component of traditional Chinese herbal medicine for heart disorder, may affect ox-LDL–induced inflammatory responses in human umbilical vein endothelial cells (HUVECs). The results showed that the ox-LDL treatment caused a significantly increase in the expression of intercellular adhesion molecule-1 (ICAM-1) in HUVECs, which was associated with a dramatic augmentation in phosphorylation of IκB and relocation of nuclear factor-κB (NF-κB) into the nuclei. Interestingly, the ox-LDL–induced ICAM-1 expression and NF-κB relocation could be attenuated by addition of ginkgolide B. Moreover, ginkgolide B significantly reduces ox-LDL–induced generation of reactive oxygen species (ROS). In conclusion, ginkgolide B may decrease inflammatory responses induced by ox-LDL via blocking NF-κB signaling and inhibiting ROS generation in HUVECs.

View full abstract

In the present study, we examined whether lipid infusion–induced insulin resistance in skeletal muscle could be reversed by the antioxidants tempol, glutathione (GSH), or tempol with GSH in male C57BL/6J mice via hyperinsulinemic-euglycemic clamp. Lipid infusion increased the mRNA level of mitochondrial type superoxide dismutase (Mn-SOD), glutathione peroxidase 1, tumor necrosis factor-α, and interleukin-6. Lipid infusion decreased GSH and GSH/glutathione disulfide (GSSG) ratio and increased the activities of JNK and p38 in skeletal muscle. Lipid infusion induced insulin resistance in whole body and skeletal muscle. Treatment with the SOD mimetic tempol did not prevent oxidative stress, the inflammatory response, and insulin resistance induced by lipid infusion. Tempol alone increased oxidative stress and aggravated the lipid-induced inflammatory response. GSH at 100 and 200 μmol · kg⁻¹ · h⁻¹ did not prevent insulin resistance and the inflammatory response by lipid infusion. On the contrary, GSH at 100 μmol · kg⁻¹ · h⁻¹ with tempol prevented insulin resistance in the whole body and skeletal muscle, and it completely reversed oxidative stress and the inflammatory response. These results suggest that lipid infusion–induced insulin resistance in skeletal muscle is produced by oxidative stress and cotreatment with tempol and GSH inhibits lipid-induced insulin resistance.

View full abstract

Tanshinone IIA, one of the main active components from the Chinese herb Danshen, is widely used to treat cardiovascular diseases in Asian countries, especially in China. To further elucidate its heart rate–reducing and anti-ischemic mechanisms, here we investigated the effects of tanshinone IIA on hyperpolarization-activated cyclic nucleotide–modulated (HCN) channels expressed in Xenopus oocytes using two-electrode voltage clamp techniques. When applied to the extracellular solution, 100 μM tanshinone IIA caused a slowing of activation and deactivation and an increase of minimum open probabilities (from 0.06 ± 0.01 to 0.29 ± 0.03, P<0.05) in HCN2 channels without shifting the voltage dependence of channel activation. Tanshinone IIA potently enhanced the amplitude of voltage-independent current (instantaneous current) of HCN2 at −90 mV in a concentration-dependent manner with an EC₅₀ of 107 μM. Similar but 2.3-fold less sensitivity to tanshinone IIA was observed in the HCN1 subtype. More significant effect on HCN2 and MiRP1 co-expression was observed. In conclusion, tanshinone IIA changed HCN channel gating by selectively enhancing the instantaneous current (one population of HCN channels), which resulted in the corresponding increment of minimum open probabilities, slowing channel activation and deactivation processes with little effect on the voltage-dependent current (another population of HCN channels).

View full abstract

[³H]-CGP12177 biphasically bound to β-adrenoceptors with high and low affinities in the segments and crude membranes of rabbit left ventricle. The low-affinity sites for [³H]-CGP12177 in the segments was double in density, compared to the density of high-affinity sites. Total abundance of the β-adrenoceptors decreased to approximately 10% upon tissue homogenization, and the proportion of low-affinity sites was the same as that of the high-affinity sites in the membranes. The majority of the high-affinity binding sites of [³H]-CGP12177 in the segments and the membranes were β_1H-adrenoceptor, being highly sensitive to propranolol and β₁-antagonists (atenolol and ICI-89,406), whereas the low-affinity binding sites showed a β_1L-profile (less sensitive to propranolol and β₁-, β₂-, and β₃-antagonists). Furthermore, a part of the β_1L-adrenoceptors was insensitive to atenolol, ICI-89,406, and/or isoproterenol. The present binding study clearly shows that β_1L-adrenoceptors occur as a distinct phenotype from β_1H-adrenoceptors in rabbit ventricle. However, quantitative imbalance between β_1H- and β_1L-adrenoceptors and divergent ligand–β_1L-adrenoceptor interactions suggest a possibility that the β_1L-adrenoceptor may not reflect a simple conformational change or allosteric state in the β₁-adrenoceptor molecule.

View full abstract

The present study was conducted to determine whether zinc ions are involved in the modulation of substance P release from cultured rat dorsal root ganglion (DRG) neurons. We show here that that lower concentrations (10⁻⁸ – 10⁻⁷ M) of zinc ions may evoke an extracellular Ca²⁺ influx through L-, N-, and T-type voltage-dependent Ca²⁺ channels, thereby increasing the substance P release from cultured DRG neurons, but higher concentrations (10⁻⁶ – 10⁻⁴ M) of zinc ions attenuate or even completely mask these responses. Zinc ions therefore seem to be an important modulator of substance P release from primary afferent neurons.

View full abstract

Genetically epilepsy-prone rats (GEPR-9s) were derived from Sprague–Dawley rats (SD). The number of kainate-induced wet dog shake behavior (WDS) responses was found to decrease significantly in GEPR-9s compared to SD. WDS responses were potentiated by 5-hydroxytryptophan or 2,5-dimethoxy-4-iodoamphetamine and antagonized by ritanserin. The antagonizing effect of ritanserin on WDS latency was more evident in GEPR-9s than in SD, and hippocampal expression of activity-regulated cytoskeleton-associated protein paralleled the severity of WDS. The results suggest that downstream serotonergic synaptic activation is less pronounced in GEPR-9s than in SD and that the serotonergic agent may directly activate postsynaptic 5-HT2A receptors in both strains.

View full abstract

In this study, we examined the effect of Cd on the expression of vascular cell adhesion molecule-1 (VCAM-1) and its mechanisms in bEnd.3 cells. The treatment with Cd increased protein and mRNA expressions of VCAM-1 and increased the phosphorylations of p38, JNK, and ERK. The Cd-induced VCAM-1 expression was significantly suppressed by either a specific p38 mitogen-activated protein kinase (MAPK) inhibitor (SB202190) or a JNK inhibitor (SP600125), but not by an ERK inhibitor (U0126). These results suggest that Cd induces the expression of VCAM-1, at least in part, via p38 and JNK pathways in bEnd.3 cells.

View full abstract

Pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects were simultaneously assessed using chronic atrioventricular block dogs. After application of the patch (9.8 mg/kg), pilsicainide was continuously absorbed through the skin with a C_max of 0.49 ± 0.13 μg/ml, while its plasma concentration was kept above the clinically reported minimum effective plasma concentration for 2 – 8 h. Inter-atrial conduction time was significantly prolonged, whereas statistically significant prolongation was not detected in the atrial effective refractory period. Prolongation of the cycle length of atrial fibrillation and anti-fibrillatory action were confirmed. Thus, pilsicainide can be absorbed transdermally to exert long-lasting electropharmacological effects leading to anti–atrial fibrillatory action.

View full abstract