European Journal of Pharmacology (v.608, #1-3)
Editorial Board (ii).
Rapid component IKr of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by α1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways by Sen Wang; Dong-Jie Xu; Jing-bo Cai; Yuan-zhu Huang; Jian-Gang Zou; Ke-Jiang Cao (1-6).
Ventricular tachyarrhythmias are often precipitated by physical or emotional stress, indicating a link between increased adrenergic stimulation and cardiac ion channel activity. Human ether-a-go-go related gene (hERG) potassium channels conduct the rapid component of delayed rectifier potassium current, Ikr, a crucial component for action potential repolarization. To evaluate the correlation between increased α1-adrenergic activity and the rapid component of cardiac Ikr, whole-cell patch-clamp recording was performed in isolated guinea-pig ventricular myocytes. Stimulation of α1-adrenoceptors using phenylephrine (0.1 nM–100 μM) reduced Ikr current in a dose-dependent manner at 37 °C. Phenylephrine (0.1 μM) reduced Ikr current to 66.83 ± 3.16%. Chelerythrine (1 μM), a specific inhibitor of protein kinase C (PKC) completely inhibited the changes in Ikr trigged by 0.1 μM phenylephrine. KT5720 (2.5 μM), a specific inhibitor of protein kinase A (PKA) partially inhibited the current decrease induced by 0.1 μM phenylephrine. Both chelerythrine and KT5720 drastically reduced the phenylephrine-induced effects, indicating possible involvement of PKC and PKA in the α1-adrenergic inhibition of Ikr. Our data suggest a link between Ikr and the α1-adrenoceptor, involving activation of PKC and PKA in arrhythmogenesis.
Keywords: Adrenergic receptor; Phenylephrine; Arrhythmia; Potassium channel; PKA; PKC;
Gender-related differences in the effects of antidepressant imipramine on glucocorticoid receptor binding properties and association with heat shock proteins in the rat liver and kidney by Ivana Elaković; Jelena Brkljačić; Gordana Matić (7-13).
Gender-related differences in susceptibility to stress and stress-related disorders such as depression, and in response to treatment with antidepressants have been observed, but the underlying molecular mechanisms are still unknown. Considering the role of glucocorticoid hormones in the systemic reaction against stress and in pathogenesis of depression, the aim of the present work was to study gender-related differences in glucocorticoid signaling and in response of this system to a typical antidepressant drug, imipramine. Gender-related differences in glucocorticoid receptor functional properties were assessed using hepatic and renal whole cell extracts of female and male rats before and after long-term imipramine treatment. The receptor's hormone-binding parameters, B max and K D, were determined by radioligand binding assay, the glucocorticoid receptor and heat shock proteins (Hsp70 and Hsp90) levels by quantitative immunoblotting, and the interaction of these proteins within glucocorticoid receptor heterocomplex by co-immunoprecipitation. Glucocorticoid receptor binding potency (B max/K D ratio) was significantly higher in males than females both before and after treatment with imipramine. Gender-specific changes in the glucocorticoid receptor binding parameters in the examined tissues were observed in response to imipramine, and were found to be associated with alterations in the receptor interaction with Hsp70 and Hsp90. The results of the study point to sexual dimorphism in the glucocorticoid signaling and imply that glucocorticoid receptor functional alterations contribute to gender-related differences in vulnerability to stress and stress-related disorders, and in response to antidepressant drugs.
Keywords: Glucocorticoid receptor; Antidepressant; Imipramine; Gender difference; Liver; Kidney;
Muscarinic M1, M3 receptors function in the brainstem of streptozotocin induced diabetic rats: Their role in insulin secretion from the pancreatic islets as a function of age by Savitha Balakrishnan; Jobin Mathew; Sherin Antony; Cheramadathikudyil S. Paulose (14-22).
In the present study, we have investigated acetylcholine esterase (AChE) activity and muscarinic M1, M3 receptors kinetics in the brainstem of both young and old streptozotocin induced and insulin treated diabetic rats (D + I). Also, the functional role of acetylcholine and muscarinic receptors in insulin secretion from the pancreatic islets was studied in vitro. 90 week old control rats showed decreased V max (P < 0.001) for AChE compared to 7 week old control rats. V max was decreased (P < 0.001) in 7 week diabetic groups whereas 90 week old diabetic groups showed increased (P < 0.001) V max when compared to their respective controls. Binding studies using [3H]QNB and [3H]DAMP of 90 week old control showed significant increase in the B max (P < 0.001) and K d (P < 0.01) of muscarinic M1 receptors whereas M3 receptor number was decreased significantly (P < 0.001) with no change in affinity when compared to 7 week old control respectively. M1 receptor number was decreased significantly (P < 0.001) whereas M3 receptor number was increased significantly (P < 0.001) in both 7 week and 90 week old diabetic rat groups compared to their respective controls. The competition curve for [3H]QNB fitted for two sited model in 7 week old groups whereas fitted for one sited model in 90 week old groups. [3H]DAMP was fitted for two sited model in both 7 week and 90 week old groups. Insulin treatment significantly reversed (P < 0.001) the binding parameters to near control level. In vitro studies showed that acetylcholine through muscarinic M1 and M3 receptors stimulated insulin secretion from the pancreatic islets. Thus our studies suggest that both brainstem and pancreatic muscarinic M1, M3 receptors differentially regulate the cholinergic activity and insulin secretion which will have clinical significance in the management of diabetes and insulin treatment as a function of age.
Keywords: Acetylcholine; Muscarinic M1; M3 receptor; Brainstem; Pancreatic islet; Insulin secretion; Ageing; (Diabetic rat);
Probable involvement of α2C-adrenoceptor subtype and endogenous opioid peptides in the peripheral antinociceptive effect induced by xylazine by Thiago Roberto Lima Romero; Andrea de Castro Perez; Janetti Nogueira de Francischi; Igor Dimitri Gama Duarte (23-27).
Xylazine is an α2-adrenoceptor agonist extensively used in veterinary and animal experimentation. Evidence exists that α2-adrenoceptor agonists can activate opioid receptors via endogenous opioid release. Considering this idea and the multiple α2 subtypes currently known (α2A, α2B, α2C and α2D), the aim of this study was to investigate which α2 receptor subtype mediates xylazine-induced peripheral antinociception and possible opioid receptor and endogenous opioid involvement. The rat pressure test was used; the hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 µg). Xylazine was administered locally (25, 50 and 100 µg) into the right hind paw of Wistar rat alone and after either α2-adrenoceptor antagonist yohimbine (5, 10 and 20 µg/paw), the α2 antagonists to α2A, α2B, α2C and α2D subtypes (BRL 44 480, imiloxan, rauwolscine and RX 821002; 20 µg/paw, respectively) the opioid receptor antagonist naloxone (12.5, 25 and 50 µg) and the enkephalinase inhibitor bestatin (400 µg/paw). Intraplantar injection of xylazine (50 and 100 µg) induced peripheral antinociception; however, a dose of 25 µg/paw did not significantly reduce the hyperalgesic effect. Yohimbine, rauwolscine and naloxone prevented action of xylazine 100 µg/paw. BRL 44 480, imiloxan and RX 821002 were ineffective in blocking xylazine antinociception. Bestatin (400 µg/paw) potentiated the antinociceptive effect of xylazine 25 µg/paw. The present results provide evidence that the peripheral antinociceptive effect of xylazine probably results from activation of α2C-adrenoceptors and also by the release of endogenous opioids that act on their receptors.
Keywords: Xylazine; α2-adrenoceptor; Opioid; Peripheral antinociception;
Prostaglandin D2 sustains the pyrogenic effect of prostaglandin E2 by Wei Gao; Achim Schmidtko; Ruirui Lu; Christian Brenneis; Carlo Angioni; Ronald Schmidt; Gerd Geisslinger (28-31).
Prostaglandin D2 (PGD2) is involved in a variety of physiological and pathophysiological processes, but its role in fever is poorly understood. Here we investigated the effects of central PGD2 administration on body temperature and prostaglandin levels in the cerebrospinal fluid (CSF) of rats. Administration of PGD2 into the cisterna magna (i.c.m) evoked a delayed fever response that was paralleled by increased levels of prostaglandin E2 (PGE2) in the CSF. The elevated PGE2 levels were not caused by an increased expression of cyclooxygenase 2 or microsomal prostaglandin E synthase-1 in the hypothalamus. Interestingly, i.c.m. pretreatment of animals with PGD2 considerably sustained the pyrogenic effects of i.c.m. administered PGE2. These data indicate that PGD2 might control the availability of PGE2 in the CSF and suggest that centrally produced PGD2 may play a role in the maintenance of fever.
Keywords: PGD2; PGE2; Fever; Cerebrospinal fluid; Rat;
1-(m-Chlorophenyl)piperazine induces depressogenic-like behaviour in rodents by stimulating the neuronal 5-HT2A receptors: Proposal of a modified rodent antidepressant assay by Ramamoorthy Rajkumar; Dilip Kumar Pandey; Radhakrishnan Mahesh; Raghuraman Radha (32-41).
1-(m-Chlorophenyl)piperazine (mCPP) has a fairly complex neuropsychopharmacological profile owing to its affinity to multiple serotonergic receptors. This investigation was designed to establish the effect of mCPP on rodent depression-like behaviour. mCPP was screened in a rodent behavioural test battery comprising of validated antidepressant assays and interaction studies with conventional antidepressants and ligands were carried out in forced swim and tail suspension test (in mice). mCPP (1 mg/kg, i.p.) exhibited depressant-like effects in forced swim and tail suspension test (in mice), without influencing the locomotor status. Potentiation of 5-hydroxytryptophan/pargyline induced head twitches (in mice) and hyperthermic effects (in rats) were observed at the same dose level. Further, the behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic mCPP (1–2 mg/kg) treatment as observed from the modified open field, elevated plus maze and social interaction paradigms. Interaction studies revealed that the mCPP induced depressant-like effects were reversed by ketanserin, escitalopram, amitriptyline, ziprasidone, venlafaxine pretreatments but not by bupropion, harmane, ondansetron, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and MK-801. In conclusion, this study provided ample evidence that the stimulation of 5-HT2A receptors underlies the depressogenic-like effect of mCPP. Finally, the mCPP induced depression-like behaviour in rodents is envisaged as a modified antidepressant assay to identify novel serotonergic antidepressants.
Keywords: mCPP; Depressogenic; 5-HT2A receptor; Olfactory bulbectomy; Behavioural test battery;
Ginsenoside Rg1 inhibits rat left ventricular hypertrophy induced by abdominal aorta coarctation: Involvement of calcineurin and mitogen-activated protein kinase signalings by Jiang Deng; Xin-Tong Lv; Qin Wu; Xie-Nan Huang (42-47).
Ginsenoside Rg1 (Rg1), one of the active components of Panax ginseng, has been reported to inhibit proliferation of vascular smooth muscle cells induced by tumor necrosis factor-α. This study aims to investigate whether Rg1 has protective effect on rat left ventricular hypertrophy and to probe its protective mechanisms. The rat left ventricular hypertrophy was induced by abdominal aorta coarctation and Rg1 (3.75, 7.5 and 15 mg/kg/day) was given the day after surgery for 21 consecutive days. The left ventricular hypertrophy induced by abdominal aorta coarctation was evidenced by histopathology, electromicroscopy, and by determining the elevated left ventricular weight and the expression of atrial natriuretic peptide. Rg1 significantly ameliorated left ventricular hypertrophy induced by abdominal aorta coarctation in a dose-dependent manner. To examine the mechanism of protection, the expressions of calcineurin, CnA (the catalytic subunit of calcineurin), extracellular signal-regulated kinase-1, and mitogen-activated protein (MAP) kinase phosphatase-1 were determined at the transcript and protein levels. The abdominal aorta coarctation induced increases in calcineurin, CnA, and extracellular signal-regulated kinase-1 expressions were suppressed, but the expression of MAP kinase phosphatase-1 was increased by Rg1. These results demonstrate that Rg1 alleviates left ventricular hypertrophy induced by abdominal aorta coarctation, and the protection appears to be due, at least in part, to its inhibitory effects on calcineurin and MAP kinase signaling pathways.
Keywords: Ginsenoside Rg1; Left ventricular hypertrophy; Calcineurin; MAP kinase signaling;
Epigallocatechin-3-gallate relaxes the isolated bovine ophthalmic artery: Involvement of phosphoinositide 3-kinase-Akt-nitric oxide/cGMP signalling pathway by Maria Rosaria Romano; Marcello Diego Lograno (48-53).
The present study investigates the direct action and the underlying mechanism(s) of epigallocatechin-3-gallate (EGCG) vasomotor effects on the bovine isolated ophthalmic artery. Adjacent rings were cut from each artery and mounted in a wire miograph system for isometric recording. Concentration–response curves for EGCG were constructed by adding cumulative concentrations of the drug to arterial rings pre-contracted with 5-HT (1 µM). Effects of mechanical endothelial cell removal and of selective blockers of the nitric oxide (NO)/cGMP pathways were investigated on the EGCG relaxant responses. EGCG relaxed ophthalmic arteries and maximum relaxation was 78.4 ± 2.64%. Mechanical removal of endothelium, blockade of soluble guanylyl cyclase by 1H-1,2,4-oxadiazolo [4,3-a]quinoxalin-1-one (ODQ, 1 and 5 µM) or inhibition of nitric oxide (NO) synthase by N G-nitro-L-arginine (L-NAME, 50 and 100 µM) reduced significantly the relaxant response to catechin; moreover, the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 100 µM) significantly increased the vasorelaxant responses to EGCG. Relaxation to EGCG was inhibited by iberiotoxin (200 nM), a blocker of big-conductance Ca2+-activated K+ (BKCa) channel, whereas the blockade of KATP channel by glibenclamide (5 µM) and of small-conductance Ca2+-activated K+ (SKCa) channel by apamin (100 nM) elicited no effect. Interestingly, also inhibition of phosphoinositide-3-kinase (PI3K) by wortmannin (100 nM) and of Akt by SH6 (1 µM) markedly decreased the EGCG-evoked vasorelaxation. These data suggest that EGCG induced vasorelaxation in ophthalmic arteries with endothelium-intact via the activation of the NO/cGMP signalling pathway and defined an intriguing role for PI3K and Akt as upstream mediators for activation of NO-mediated relaxant responses.
Keywords: Epigallocatechin-3-gallate; Relaxation; Nitric oxide; Phosphoinositide-3-phosphate; Ophthalmic artery;
Effect of pilsicainide on dominant frequency in the right and left atria and pulmonary veins during atrial fibrillation: Association with its atrial fibrillation terminating effect by Daisuke Horiuchi; Atsushi Iwasa; Kenichi Sasaki; Shingen Owada; Masaomi Kimura; Shingo Sasaki; Ken Okumura (54-61).
Dominant frequency reflects the peak cycle length of atrial fibrillation. In 34 patients with atrial fibrillation, bipolar electrograms were recorded from multiple atrial sites and pulmonary veins and the effect of pilsicainide, class Ic antiarrhythmic drug, on dominant frequency was examined. At baseline, mean dominant frequencies (Hz) in the right and left atria, coronary sinus and right and left superior pulmonary veins were 5.87 ± 0.76, 6.08 ± 0.60, 5.65 ±0.95, 6.12 ± 0.88 and 6.59 ± 0.89, respectively (P < 0.05, left superior pulmonary vein vs right atrium and coronary sinus). After pilsicainide (1.0 mg/kg/5 min), dominant frequency decreased at all sites in all patients. Atrial fibrillation was terminated at 5.9 ± 2.2 min in 16 patients (Group A) with a decrease in the average of mean dominant frequencies at all sites from 5.80 ± 0.72 to 3.57 ± 0.63 Hz, was converted to atrial flutter at 7.3 ± 1.4 min in 5 (Group B) with a decrease in the average dominant frequency from 5.83 ± 0.48 to 3.08 ± 0.19 Hz, and was not terminated in the other 13 (Group C) despite the average dominant frequency decrease from 6.59 ± 0.76 to 4.42 ± 0.52 Hz. In 14 of the 21 Groups A and B patients (67%), mean dominant frequencies at all recording sites were < 4.0 after pilsicainide, while they were < 4.0 in 1 of the 13 Group C patients (8%, P < 0.01). In conclusion, the degree of dominant frequency decrease by pilsicainide is closely related to its atrial fibrillation terminating effect: When dominant frequency in the atria decreases to < 4.0 Hz, atrial fibrillation is terminated with 93% positive and 63% negative predictive values.
Keywords: Pilsicainide; Atrial fibrillation; Dominant frequency; Pulmonary vein;
α1-adrenoceptor modulation of spontaneous electrical waveforms in the guinea-pig prostate by Dan-Thanh T. Nguyen; Richard J. Lang; Betty Exintaris (62-70).
The aim of this study was to investigate the effects of phenylephrine on the spontaneous slow wave and pacemaker activity in the guinea-pig prostate. Membrane potential recordings were made using intracellular microelectrodes. Guinea-pig prostatic cells either displayed ‘slow wave’ activity or ‘pacemaker’ potentials. In the presence of nifedipine, none of the parameters measured were significantly different between both waveforms. Phenylephrine (1 µM) or histamine (5 µM) increased the frequency of slow waves and pacemaker potentials in the absence or presence of nifedipine (1 µM). In the presence of nifedipine (1 µM), the addition of either cyclopiazonic acid (CPA, 10 µM) or carbonyl cyanide 3-chlorophenylhydrazone (CCCP, 1–10 µM) caused an initial transient increase in frequency of the spontaneous electrical activity that was associated with a membrane depolarisation of 3–7 mV before abolishing activity. Following the cessation of electrical activity, phenylephrine (1 µM) was unable to restore the spontaneous electrical events. Although niflumic acid (10–100 µM) (in the presence of 1 µM nifedipine) similarly abolished all activity, electrical activity was promptly initiated upon the addition of phenylephrine (1 µM). These results demonstrate that in the presence of nifedipine, there are no differences between the slow waves and pacemaker potentials suggesting that both activities arise from cells that are well coupled. Both phenylephrine and histamine increased the frequency of pacemaker activity which is likely to; at least, partly explain the increase in slow wave discharge also evoked by these agents. In the presence of nifedipine, the effects observed upon α1-adrenoceptor activation were dependent on Ca2+ cycling by both the intracellular Ca2+ stores and mitochondria.
Keywords: Prostate; Slow wave activity; Pacemaker potential; Phenylephrine;
Role of histamine H4 receptor in allergic conjunctivitis in mice by Yoshiyuki Nakano; Yuji Takahashi; Rie Ono; Yasunori Kurata; Yoto Kagawa; Chiaki Kamei (71-75).
We investigated the character of histamine H1 receptor and H4 receptor in allergic conjunctivitis. Histamine is the most important mediator in allergic conjunctivitis. We measured eye scratching behavior and allergic-like symptoms score, that is, hyperemia and edema in ICR mice, and examined which receptors intimately involved in allergic conjunctivitis. Histamine caused a dose-dependent eye scratching behavior and allergic-like symptoms. Histamine H1 receptor antagonist (levocabastine) and H4 receptor antagonist (JNJ7777120) inhibited eye scratching behavior and histamine H1 receptor antagonist inhibited allergic-like symptoms induced by histamine. Additionally, combination of levocabastine and JNJ7777120 caused more potent inhibition in allergic conjunctivitis. On the other hand, both selective histamine H1 receptor agonist (HTMT) and selective H4 receptor agonist (4-methylhistamine) induced a dose-dependent eye scratching behavior and allergic-like symptoms. JNJ7777120 inhibited the effect of HTMT. However, levocabastine caused no inhibition on the response of 4-methylhistamine. H4 receptor was closely related with allergic conjunctivitis. H4 receptor antagonists may be effective in allergic conjunctivitis which showed no inhibition by histamine H1 receptor antagonists.
Keywords: Allergic conjunctivitis; Histamine; JNJ7777120; H4 receptor; ICR mice;
Chemotherapeutic potential of two gallic acid derivative compounds from leaves of Casearia sylvestris Sw (Flacourtiaceae) by Saulo L. Da Silva; Jamal da S. Chaar; Tomomasa Yano (76-83).
Casearia sylvestris is a plant used in the treatment of several diseases, including cancer. Studies have shown that C. sylvestris presents an interesting antitumoral potential, due to the presence of casearins and some sesquiterpens with antitumoral activity. In this work, we tested the potential chemotherapeutic of two gallic acid-derived compounds isolated from C. sylvestris leaves: isobutyl gallate-3,5-dimethyl ether (IGDE) and methyl gallate-3,5-dimethyl ether (MGDE). We utilized two tumoral models: Ehrlich ascites tumor cells (EAT)/BALB/c mice and Lewis lung cancer cells (LLC1)/C57bl/6 mice. MGDE and IGDE increased the survival of mice inoculated with EAT cells and decreased the tumor volume in the LLC1 model, compared to control groups. Both compounds presented similar and low in vitro cytotoxicity against Ehrlich ascites tumor cells and did not present any significant toxicity against Lewis lung cancer cells. Since the direct in vitro activity against Ehrlich tumor and Lewis lung cancer cells was low, we investigated the effects of MGDE or IGDE treatment on the activity of total natural killer cells from Ehrlich ascites tumor-bearing mice, as a possible explanation for the mechanisms of these compounds in vivo. MGDE and IGDE improved NK cell cytotoxicity against Ehrlich ascites cells. As expected, tumor growth in non-treated mice markedly suppressed NK cell cytolysis while, IGDE completely reversed this effect, when mice were treated with 0.5 mg/kg dosages of these compounds for 4 days. The pharmacokinetic studies showed that IGDE remains in the organism for a long period of time, possibly explaining the higher compound efficiency.
Keywords: Casearia sylvestris; MTT; Ehrlich ascites tumor; Lewis lung carcinoma; Gallic acid;
MK-886, an inhibitor of the 5-lipoxygenase-activating protein, inhibits cyclooxygenase-1 activity and suppresses platelet aggregation by Andreas Koeberle; Ulf Siemoneit; Hinnak Northoff; Bettina Hofmann; Gisbert Schneider; Oliver Werz (84-90).
MK-886, an inhibitor of the 5-lipoxygenase-activating protein (FLAP), potently suppresses leukotriene biosynthesis in intact cells and is frequently used to define a role of the 5-lipoxygenase (EC 184.108.40.206) pathway in cellular or animal models of inflammation, allergy, cancer, and cardiovascular disease. Here we show that MK-886 also interferes with the activities of cyclooxygenases (COX, EC 220.127.116.11). MK-886 inhibited isolated COX-1 (IC50 = 8 µM) and blocked the formation of the COX-1-derived products 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid (12-HHT) and thromboxane B2 in washed human platelets in response to collagen as well as from exogenous arachidonic acid (IC50 = 13–15 µM). Isolated COX-2 was less affected (IC50 = 58 µM), and in A549 cells, MK-886 (33 µM) failed to suppress COX-2-dependent 6-keto-prostaglandin (PG)F1α formation. The distinct susceptibility of MK-886 towards COX-1 and -2 is apparent in automated molecular docking studies that indicate a preferred binding of MK-886 to COX-1 into the active site. MK-886 (10 µM) inhibited COX-1-mediated platelet aggregation induced by collagen or arachidonic acid whereas thrombin- or U-46619-induced (COX-independent) aggregation was not affected. Since leukotrienes and prostaglandins share (patho)physiological properties in the development and regulation of carcinogenesis, inflammation, and vascular functions, caution should be used when interpreting data where MK-886 is used as tool to determine the involvement of FLAP and/or the 5-lipoxygenase pathway in respective experimental models.
Keywords: 5-Lipoxygenase; Cyclooxygenase; Leukotriene; Prostaglandin; Platelet aggregation; MK-886;
Tacrolimus hydrate ointment inhibits skin plasma extravasation in rats induced by topical m-xylene but not capsaicin by Shiho Goto; Fumio Kondo; Yoshitomo Ikai; Mio Miyake; Masaki Futamura; Komei Ito; Tatsuo Sakamoto (91-96).
Tacrolimus ointment is used to treat various chronic inflammatory skin diseases. However, the effect of this ointment on acute neurogenic inflammation in the skin remains to be fully elucidated. Topical capsaicin and m-xylene produce tachykinin release from sensory nerves in the skin, resulting in skin plasma leakage. We investigated the effect of tacrolimus ointment (0.1%) on skin microvascular leakage induced by topical capsaicin (10 mM) and m-xylene (neat), and intracutaneous compound 48/80 (c48/80) (10 μg/ml, 50 μl/site) in two groups of rats pretreated with excessive capsaicin or its vehicle. The amount of leaked Evans blue dye reflected skin plasma leakage. Capsaicin, m-xylene or c48/80 was applied to the shaved abdomens of rats 8 h after topical application of tacrolimus ointment or its base. Desensitization with capsaicin reduced the skin response to capsaicin and m-xylene by 100% and 65%, respectively, but not to c48/80. Tacrolimus ointment significantly inhibited the skin response induced by m-xylene and c48/80, regardless of pretreatment with capsaicin. However, topical tacrolimus did not influence the skin response induced by capsaicin. We also evaluated whether topical capsaicin and m-xylene, and intracutaneous c48/80 cause mast cell degranulation in skin treated with tacrolimus. Mast cell degranulation was microscopically assessed. Topical tacrolimus only significantly suppressed degranulation induced by m-xylene and c48/80. Our data shows that tacrolimus ointment partially inhibits plasma leakage and mast cell degranulation in rat skin induced by m-xylene and c48/80 but not capsaicin, suggesting that the inhibitory effect is not associated with a reduction in neurogenic-mediated mechanisms.
Keywords: Capsaicin; m-Xylene; Mast cell degranulation; Neurogenic plasma extravasation; Tacrolimus ointment;
Cyclooxygenase-2 inhibition reverts the decrease in adiponectin levels and attenuates the loss of white adipose tissue during chronic inflammation by Miriam Granado; Ana Isabel Martín; Estíbaliz Castillero; Asunción López-Calderón; Ma. Ángeles Villanúa (97-103).
Chronic arthritis leads to a decrease in body weight that is associated with a decrease in skeletal muscle and white adipose tissue mass. We have observed that overactivation of cyclooxygenase-2 (COX-2) is responsible for muscle wasting in arthritic rats. The aim of this work was to study the role of COX-2 in arthritis-induced white adipose tissue mass loss. Arthritis was induced in rats by Freund′s adjuvant injection, and the effect of the COX-2 inhibitor meloxicam on serum concentrations of leptin, adiponectin, insulin and glycerol, as well as on gene expression of leptin, adiponectin, hormone-sensitive lipase (HSL), fatty acid synthase (FAS), tumour necrosis factor alpha (TNF) and insulin-like growth factor I (IGF-I) in white adipose tissue were determined. Arthritis decreased adipose tissue weight, serum leptin and adiponectin as well as their mRNAs in adipose tissue. Meloxicam administration to arthritic rats increased adipose tissue weight, serum concentrations of adiponectin and its mRNA in adipose tissue, but it did not modify leptin. Arthritis decreased serum insulin and FAS and IGF-I gene expression in adipose tissue. Meloxicam administration did not modify these effects. Serum concentrations of glycerol were decreased in arthritic rats. In control rats, meloxicam administration did not modify serum glycerol or adipose tissue gene expression of HSL. However, in arthritic rats HSL gene expression in adipose tissue was decreased by meloxicam. All these data indicate that COX-2 activation plays a role in the decrease in adiponectin secreted by adipocytes and in the loss in white adipose tissue mass in arthritic rats.
Keywords: Adiponectin; Arthritis; Cyclooxygenase-2; Leptin; Meloxicam; White adipose tissue;
S26948, a new specific peroxisome proliferator activated receptor gamma modulator improved in vivo hepatic insulin sensitivity in 48 h lipid infused rats by Kyung-Ah Kim Sohn; Céline Cruciani-Guglielmacci; Nadim Kassis; Laurence Clément; Fetta Ouali; Michèle Caüzac; Nicolas Lebègue; Pascal Berthelot; Daniel-Henri Caignard; Jean-Paul Pégorier; Pierre Renard; Catherine Dacquet; Alain Ktorza; Christophe Magnan (104-111).
We examined whether S26948, a new specific peroxisome proliferator activated receptor γ modulator prevented insulin-resistance induced by a 48 h intralipid-infusion in normal rat (IL rats). The effect of S26948 (30 mg/kg) was compared to rosiglitazone (10 mg/kg). Rats were catheterized in the right jugular vein 4 days before the beginning of the 48 h lipid or saline infusions. Animals were intraperitoneally injected once daily with vehicle, S26948 or rosiglitazone. At the end of the infusion the rats underwent either a glucose tolerance test or a euglycemic–hyperinsulinemic clamp. Finally isolation and incubation of hepatocytes in another series of rats were performed. Intralipid infusion leads to a 4-fold increase in plasma free fatty acid concentration compared to controls (C). Both S26948 and rosiglitazone decreased plasma free fatty acid concentration in IL rats compared to vehicle treated IL rats. Glucose-induced insulin secretion was significantly increased in IL compared to C and was associated with insulin resistance. Both S26948 and rosiglitazone treatments normalized glucose-induced insulin secretion and improved insulin action in IL rats. However, S26948 specifically improved hepatic insulin sensitivity whereas rosiglitazone improved both hepatic insulin sensitivity and insulin-stimulated glucose utilization. Finally, studies on isolated hepatocytes showed differential effect of both compounds on gene expression of key enzymes of glucose metabolism. Our data show that non thiazolidinedione S26948 may represent an alternative way for the management of dysregulated hepatic insulin sensitivity.
Keywords: SPPARMγ agonist; Liver; Glucose hepatic production; Fatty acid; Glucose homeostasis;