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PubMed2004

High-performance liquid chromatographic analysis of a selective cyclooxygenase-1 inhibitor SC-560 in rat serum: application to pharmacokinetic studies.

A method of analysis of SC-560 (5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole) in biological fluids is necessary to study the kinetics of in vitro and in vivo metabolism. A simple high-performance liquid chromatographic method was developed for simultaneous determination of SC-560 and other products of metabolism in rat serum. Serum (0.1 ml) was precipitated with acetonitrile after addition of the internal standard, testosterone 17-propionate. Separation was achieved on a C(8) column with UV-detection at 240 nm. The calibration curve was linear ranging from 0.02 to 100 microg/ml. The mean recovery was >86.7%. Precision of the assay was <10% (R.S.D.%), and was within 15% at the limit of quantitation (20 ng/ml). Bias of the assay was lower than 15.5%. The limit of detection was 10 ng/ml for a 0.1 ml sample. The assay was applied successfully to the in vivo kinetic study of SC-560 in rats.

Administration, Oral↗
PubMed2006

Development of a mouse model of mammary gland versus uterus tissue selectivity using estrogen- and progesterone-regulated gene markers.

We have identified mRNA markers of estradiol and progesterone action in the mouse mammary gland and uterus to establish an in vivo model for the evaluation of novel and potentially tissue selective estrogens and progestins. Gene chip analysis of mRNA from ovariectomized (OVX) mice treated with vehicle (V), 17beta-estradiol (E2), progesterone (P) or E2+P for 7 days identified defensinbeta1 (Defbeta1) and indoleamine-pyrrole 2,3 dioxygenase (INDO) as markers of E2 and P action in the mammary gland, and serine protease inhibitor, Kazal type 3 (Spink3) and G protein-coupled receptor 105 (GPR105) as markers in the uterus. Defbeta1 and Spink3 are both upregulated by E2+P, whereas INDO and GPR105 have a complementary profile of upregulation by E2 alone and suppression of the E2 effect by P. Quantitative RT-PCR analysis of mammary gland markers was concordant with histological changes. Using this model, medroxyprogesterone acetate (MPA) and tanaproget (TNPR), a novel nonsteroidal progesterone receptor agonist, were evaluated and found to have no marked tissue selectivity relative to progesterone. In addition, the ERalpha selective ligand propyl pyrazole triol (PPT) and the ERbeta selective ligands ERB-041 and WAY-202196 were evaluated on the mammary gland endpoints of histology and Defbeta1 mRNA expression, and showed that ERalpha stimulation is necessary and sufficient for eliciting estradiol-mediated changes in the mammary gland.

Animals↗
PubMed2004

Estrogen receptor-alpha agonists promote angiogenesis in human myometrial microvascular endothelial cells.

OBJECTIVE: The relative role of the two estrogen receptors, ERalpha and ERbeta, in mediating angiogenic responses in adult human endothelium is unknown. The aim of this study was to determine whether novel ERalpha-selective agonists, propyl pyrazole triol (PPT) and the tetrahydrochrysene (R,R-THC), up-regulate the expression of vascular endothelial growth factor receptor-2 (VEGFR-2), and promote VEGF-stimulated endothelial cell proliferation in primary cultures of adult female microvascular endothelial cells co-expressing endogenous ERalpha and ERbeta. METHODS: Confluent primary cultures of microvascular endothelial cells isolated from human myometrium were incubated with 17beta-estradiol (1 and 10 nM), PPT (10 nM to 3 microM), or R,R-THC (10 nM to 3 microM) for 18 hours and VEGFR-2 expression measured by biotin-VEGF165 binding and flow cytometry. Endothelial cell proliferation was assessed in microvascular endothelial cells after incubation with 17beta-estradiol (10 nM), PPT (100 nM), and R,R-THC (100 nM) for 6 days using a tetrazolium-based bioassay. RESULTS: Both PPT and R,R-THC increased VEGFR-2 expression on myometrial microvascular endothelial cells in a dose-dependent manner, reaching a maximum at 1 microM. Approximately 40% of myometrial microvascular endothelial cell isolates only express ERbeta and do not express ERalpha, and in these neither PPT, R,R-THC, nor 17beta-estradiol increased VEGF binding. PPT- or R,R-THC-stimulated increase in VEGF binding was significantly different between ERalpha+ and ERalpha- microvascular endothelial cell samples (P < .001 and P < .05, respectively). PPT, R,R-THC, and 17beta-estradiol significantly augmented VEGF-stimulated microvascular endothelial cell proliferation in ERalpha+ (P < .05), but not in ERalpha- samples. CONCLUSIONS: This angiogenic effect of 17beta-estradiol on adult female microvascular endothelial cells is mediated by ERalpha, rather than ERbeta.

Cell Division↗
PubMed2006

Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice.

Involvement of cannabinoid CB2 receptors in the IgE-mediated cutaneous reaction was investigated. Epicutaneous challenge with 2,4-dinitrofluorobenzene caused a triphasic swelling in the ear of BALB/c and C57BL/6 mice passively sensitized with anti-dinitrophenol IgE. Peak responses of the ear swelling appeared at 1 h, 24 h, and 8 days after the challenge in both strains of mice. In contrast, cannabinoid CB2 receptor-deficient mice failed to exhibit the obvious triphasic ear swelling observed in wild-type mice. Oral administration of cannabinoid CB2 receptor antagonist/inverse agonists [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide} (SR144528) at doses of 0.1-10 mg/kg significantly and dose-dependently suppressed all three phases of ear swelling in BALB/c mice. Interestingly, epicutaneous treatment with an ether-linked analogue of endogenous cannabinoids, 2-arachidonoylglycerol, caused an ear swelling that could be detected at 1 h, 24 h, and 8 days after treatment of both BALB/c and C57BL/6 mice. These results suggest that cannabinoid CB2 receptors are involved in induction of the triphasic cutaneous reaction mediated by IgE, and that cannabinoid CB2 receptor antagonist/inverse agonists may serve as anti-allergic agents in the treatment of allergic dermatitis.

Animals↗
PubMed2004

Antagonism of cannabinoid CB1 receptors in the paraventricular nucleus of male rats induces penile erection.

The effect of cannabinoid CB1 receptor agonists and antagonists on penile erection was studied in male rats when injected into the paraventricular nucleus of the hypothalamus. The CB1 receptor antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (0.5-5 microg) induced penile erection in a dose-dependent manner. The minimal effective dose was 1 microg, while the maximal response was found with 5 microg of the compound. In contrast, the CB1 receptor agonists WIN 55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-I,j]quinolin-6-one] (0.5-5 microg) and CP 55,940 [1alpha,2beta-(R)-5alpha]-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)cyclohexyl]phenol (0.5-5 microg) were ineffective at all the doses tested. Nevertheless, both compounds reduced the enhancing effect of SR 141716A on penile erection when given into the paraventricular nucleus at the above doses before SR 141716A. The pro-erectile effect of SR 141716A was also reduced by the non-competitive NMDA receptor antagonist dizolcipine (MK-801) (0.2 microg) and by the NO synthase inhibitor NG-nitro-l-arginine methylester (L-NAME) (20 microg) but not by the dopamine receptor antagonist cis-flupenthixol (10 microg) or the oxytocin receptor antagonist d(CH2)5Tyr(Me)2-Orn8-vasotocin (0.1 microg), when given into the paraventricular nucleus. In spite of its inability to prevent the pro-erectile effect of SR 141716A when given in the paraventricular nucleus, d(CH2)5Tyr(Me)2-Orn8-vasotocin) (1 microg) reduced almost completely SR 141716A-induced penile erection when given into the lateral ventricles. The present results show that cannabinoid CB1 receptors present in the paraventricular nucleus may influence erectile function and sexual activity by modulating paraventricular oxytocinergic neurons mediating erectile function.

Animals↗
PubMed2004

The mechanism of inhibition by xanthine of adenosine A1-receptor responses in rat hippocampus.

We have recently observed that the free radical-generating mixture of xanthine and xanthine oxidase (X/XO) can suppress the inhibitory effects of adenosine on synaptic transmission in the hippocampus, but that this action can be mimicked by xanthine alone. We have now clarified the mechanism of these interactions by using the new, potent and highly selective inhibitor of xanthine oxidase, 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700). Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of rat hippocampal slices. X/XO induced a long-lasting increase of fEPSP slope and significantly reduced the presynaptic inhibitory effect of adenosine. Both these actions were prevented by Y-700 at a concentration of only 200nM. Similarly the superfusion of xanthine alone increased fEPSP slope and reduced sensitivity to adenosine but these effects were also prevented by Y-700. The results indicate that the antagonism of adenosine responses by X/XO or by xanthine alone are entirely attributable to the activity of the added or endogenous XO activity, probably generating free radicals, and are not likely to be caused by a direct antagonistic action at the xanthine-sensitive site on the adenosine receptor.

Adenosine A1 Receptor Antagonists↗
PubMed2004

Effect of estrogen receptor agonists treatment in MPTP mice: evidence of neuroprotection by an ER alpha agonist.

Beneficial effects of 17 beta-estradiol (17 beta-E(2)) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion are well documented but the mechanisms implicated are poorly understood. The present experiments investigated the effect of estrogen receptor (ER) agonists treatment in MPTP mice as compared to 17 beta-E(2). The agonists specific for each subtype were 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT) (ER alpha agonist), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and Delta 3-diol (5-androsten-3 beta, 17 beta-diol, also known as 5-androstenediol, androstenediol or hermaphrodiol) (ER beta agonists). Biogenic amines were assayed by HPLC with electrochemical detection. 8 mg/kg of MPTP was administered to give a moderate depletion of striatal DA and its metabolite dihydroxyphenylacetic acid (DOPAC). Protection against MPTP-induced striatal DA and DOPAC depletion was obtained with PPT and 17 beta-E(2) but not with DPN or Delta 3-diol. The striatal dopamine transporter (DAT) was assayed by autoradiography with [(125)I]RTI-121-specific binding. A positive and significant correlation was observed between striatal DA concentrations and [(125)I]RTI-121-specific binding, suggesting that estrogenic treatment that prevented the MPTP-induced DA depletion also prevented loss of DAT. The effect of PPT suggests the implication of an ER alpha in the estrogenic neuroprotection against MPTP. Pointing out which ER is implicated in neuroprotection becomes helpful in designing more specific estrogenic drugs for protection of the aging brain.

Animals↗
PubMed2006

Neurotensin selectively facilitates glutamatergic transmission in globus pallidus.

The tridecapeptide neurotensin has been demonstrated to modulate neurotransmission in a number of brain regions. There is evidence that neurotensin receptors exist in globus pallidus presynaptically and postsynaptically. Whole-cell patch-clamp recordings were used to investigate the modulatory effects of neurotensin on glutamate and GABA transmission in this basal ganglia nucleus in rats. Neurotensin at 1 microM significantly increased the frequency of glutamate receptor-mediated miniature excitatory postsynaptic currents. In contrast, neurotensin had no effect on GABA(A) receptor-mediated miniature inhibitory postsynaptic currents. The presynaptic facilitation of neurotensin on glutamatergic transmission could be mimicked by the C-terminal fragment, neurotensin (8-13), but not by the N-terminal fragment, neurotensin (1-8). The selective neurotensin type-1 receptor antagonist, SR48692 {2-[(1-(7-chloro-4-quinolinyl)-5-2(2,6-dimethoxyphenyl)pyrazol-3-yl)carbonylamino]-tricyclo(3.3.1.1.(3.7))-decan-2-carboxylic acid}, blocked this facilitatory effect of neurotensin, and which itself had no effect on miniature excitatory postsynaptic currents. The specific phospholipase C inhibitor, U73122 {1-[6-[[17beta-3-methoyyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione}, significantly inhibit neurotensin-induced facilitation on glutamate release. Taken together with the reported postsynaptic depolarization of neurotensin in globus pallidus, it is suggested that neurotensin excites the globus pallidus neurons by multiple mechanisms which may provide a rationale for further investigations into its involvement in motor disorders originating from the basal ganglia.

Anesthetics, Local↗
PubMed2005

ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks.

Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.

Animals↗
PubMed2006

Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression.

UNLABELLED: Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a (125)I-labeled celecoxib analogue with a sulfonamide moiety ((125)I-IATP). METHODS: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of (125)I-IMTP and (125)I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured. RESULTS: The COX-2 inhibitory potency of IMTP (IC(50) = 5.16 microM) and IATP (IC(50) = 8.20 microM) was higher than that of meloxicam (IC(50) = 29.0 microM) and comparable to that of SC-58125 (IC(50) = 1.36 microM). The IC(50) ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of (125)I-IMTP and (125)I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of (125)I-IMTP was much faster than that of (125)I-IATP. Distribution of (125)I-IATP to blood cells (88.0%) was markedly higher than that of (125)I-IMTP (18.1%), which was decreased by CA inhibitors. CONCLUSIONS: Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in (125)I-IMTP. (123)I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.

Animals↗
PubMed2004

The effect of SR 141716 and apomorphine on sensorimotor gating in Swiss mice.

The aim of the present study was to investigate in Swiss mice the acute effects of the CB(1) receptor antagonist N-piperidino-5-(4-chlorphenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716) alone and in combination with apomorphine, a D(1)/D(2) receptor agonist, on prepulse inhibition (PPI) of the acoustic startle response, an operational measure of sensorimotor gating. SR 141716 (1 and 3 mg/kg i.p.) had no significant effect on PPI. Apomorphine (3 mg/kg i.p.) significantly disrupted PPI. The PPI of mice injected with SR 141716 (1 mg/kg i.p.) plus apomorphine (3 mg/kg i.p.) was not significantly different to that of vehicle plus apomorphine (3 mg/kg i.p.)-treated mice. However, the higher dose of SR 141716 used (3 mg/kg i.p.) significantly inhibited the disruption of PPI produced by apomorphine. These results suggest that antagonism of CB(1) receptors with SR 141716 has no significant effect on sensorimotor gating in Swiss mice. However, CB(1) receptors appear to be important in the effect of apomorphine on sensorimotor gating, as antagonism of CB(1) receptors with SR 141716 inhibits apomorphine-induced disruptions.

Animals↗
PubMed2005

3,4 Methylenedioxymethamphetamine-induced conditioned place preference (CPP) is mediated by endocannabinoid system.

The appetitive potential of i.c.v. injections of 3,4 methylenedioxymethamphetamine (MDMA), using a conditioned place preference (CPP) procedure, was investigated. In a range of doses (0.1-10 ng/rat), devoid of motor stimulation, a dose-dependent CPP was obtained. The effect of the most effective dose (10 ng/rat) was prevented by pre-treatment with the CB1 cannabinoid (SR 141716A) [N-piperidino-5-(4-chlorophenyl) 1-(2, 4-dichloro-phenyl)-4-methyl pyrazole-3-carboxamide hydrochloride] (0.5 mg kg(-1)), the opioid (naloxone) (2 mg kg(-1)), and the serotonin 5-HT3, tropisetron [endo-8-methyl-8-azabicyclo [3.2.1] oct-3-olindol-3-yl-carboxylate hydrochloride] (1 mg kg(-1)), receptor antagonists, which did not induce place conditioning on their own. SR 141716A was more efficient than naloxone and tropisetron in blocking the incentive learning supported by MDMA. These results demonstrate for the first time that i.c.v. MDMA, at very low doses, induces CPP and that endocannabinoid system may participate in this effect.

Animals↗
PubMed2005

Effects of selective estrogen receptor agonists on food intake and body weight gain in rats.

Ovariectomized (OVX) rats eat more and gain weight more rapidly than sham-operated (SO) rats and estradiol (E(2)) treatment attenuates food intake and body weight gain in OVX rats. Studies were designed to test the hypothesis that the alpha subtype of the estrogen receptor (ERalpha) mediates the attenuating effects of E(2) on food intake and body weight gain while the beta subtype (ERbeta) mediates opposing actions that lead to increased food intake and body weight gain. Female rats were SO or OVX and treated daily with vehicle (dimethylsulfoxide, DMSO) or E(2) (10 microg/day), or the ERalpha-selective agonist, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, 0.5 mg/day), or the ERbeta-selective agonist, 2,3-bis(4-hyroxyphenyl)-propionitrile (DPN, 0.5 mg/day) for 14 days. Total food intake was significantly reduced by E(2) and PPT, but not DPN. Total body weight gain was significantly increased in OVX rats compared to SO rats and treatment with E(2) or PPT, but not DPN, significantly decreased total body weight gain to levels that were not significantly different from SO rats. A dose-response study of PPT indicated that at 0.25 mg/day, PPT significantly reduced total 21-day food intake and body weight gain and, at 0.13 and 0.06 mg/day, PPT significantly reduced total body weight gain compared to OVX rats without significantly reducing total food intake. A dose-response study of DPN indicated that none of the three doses of DPN significantly altered total 21-day food intake or total body weight gain. These results suggest ERalpha mediates the attenuating effects of estrogens on food intake and body weight gain while ERbeta has no effect on these variables.

Animals↗
PubMed2006

Feasibility of central cannabinoid CB1 receptor imaging with [124I]AM281 PET demonstrated in a schizophrenic patient.

We studied central cannabinoid CB1 receptors in a schizophrenic patient using the pyrazole derivative AM281 labelled with the positron-emitting nuclide iodine-124. A dynamic positron emission tomography (PET) acquisition with simultaneous blood sampling was performed up to 1.5 h post-injection. The classical Logan plot analysis was applied to generate a three-dimensional map of distribution volume (DV). The map was spatially normalised into the Montreal Neurological Institute stereotactic space. Using a volume of interest (VOI) template, mean values of DV were extracted from multiple grey matter regions and white matter (as a reference). As a measure of regional receptor availability, ratios of DV in grey matter to DV in white matter minus one (DVR-1) were calculated. The highest receptor binding was observed in the striatum and the pallidum (DVR-1: 0.35-0.37). Binding in basal ganglia regions was lower on the left than the right side. Moderately high binding was seen in the frontal cortex (0.22), the temporal cortex (0.18) and the cerebellum (0.15). In conclusion, 124I-AM281 PET can be used to reveal areas with prominent CB1 receptor binding. Nevertheless, limited image contrast and relatively high radiation exposure (physical half-life of 124I: 4 days) have to be taken into account. Asymmetric receptor binding may possibly reflect pathologic changes in schizophrenia.

Brain↗
PubMed2005

Chronic estrogenic drug treatment increases preproenkephalin mRNA levels in the rat striatum and nucleus accumbens.

Estrogens modulate the expression of preproenkephalin (PPE) in the hypothalamus but little is known for other brain regions. The present study investigated the effect of hormonal withdrawal and replacement therapy on PPE expression in the striatum, nucleus accumbens and cortex. Ovariectomized Sprague-Dawley rats were treated for 2 weeks with estradiol, a specific ligand for estrogen receptor alpha (ERalpha), 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and estrogen receptor beta (ERbeta) 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), or the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. Brain PPE mRNA levels, measured by in situ hybridization, were high in the striatum and nucleus accumbens compared to the low expression in the cortex. Ovariectomy decreased uterine weights compared to intact uterus, which was corrected by estradiol and PPT. Tamoxifen and raloxifene partially stimulated uterine weights while DPN left it unchanged. In the anterior, median and posterior striatum and in the core and shell of the nucleus accumbens, ovariectomy decreased PPE mRNA levels compared to intact rats, this was corrected by estradiol treatment except for the posterior striatum. PPT, DPN, tamoxifen and raloxifene reproduced the estradiol effect. In the prefrontal and cingulate cortices, neither ovariectomy nor treatments changed PPE mRNA levels. These results show for the first time that estradiol increases PPE mRNA in the striatum and nucleus accumbens. This effect is observed also with estrogen receptor agonists for the ERalpha and ERbeta as well as with SERMs.

Analysis of Variance↗
PubMed2006

17 beta-estradiol administration following trauma-hemorrhage prevents the increase in Kupffer cell cytokine production and MAPK activation predominately via estrogen receptor-alpha.

BACKGROUND: 17 beta-estradiol (E2) administration following trauma-hemorrhage (T-H) attenuates the elevation in plasma cytokines and Kupffer cell (KC) cytokine production; however, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta. We hypothesized that E2 mediates its salutary effects via ER-alpha and normalization of MAPK under those conditions. METHODS: Male rats underwent T-H (mean blood pressure [BP] 40 mmHg for 90 min) and fluid resuscitation. ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), E2 (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, KCs were isolated and their cytokine production (IL-6, TNF-alpha, IL-10) and MAPK activation were measured. RESULTS: Cytokine production increased after T-H, however, PPT or E2 administration after T-H normalized KC cytokine production. Although DPN attenuated increased production of these cytokines, KC capacity to produce the cytokines remained significantly higher than sham. PPT or E2 also prevented T-H-mediated activation of MAPK in KC. However, DPN did not prevent MAPK activation. CONCLUSIONS: Since PPT administration after T-H was more effective in decreasing KC cytokine production and MAPK activation than DPN, the salutary effects of E2 on KC functions are mediated predominantly via ER-alpha and normalization of MAPK following T-H.

Animals↗
PubMed2006

Acrolein induces vasodilatation of rodent mesenteric bed via an EDHF-dependent mechanism.

Acrolein is generated endogenously during lipid peroxidation and inflammation and is an environmental pollutant. Protein adducts of acrolein are detected in atherosclerotic plaques and neurons of patients with Alzheimer's disease. To understand vascular effects of acrolein exposure, we studied acrolein vasoreactivity in perfused rodent mesenteric bed. Acrolein induced endothelium-dependent vasodilatation that was more robust and more sensitive than dilation induced by 4-hydroxy-trans-2-nonenal, trans-2-hexenal, or propionaldehyde. Acrolein-induced vasodilatation was mediated by K(+)-sensitive components, e.g., it was abolished in 0 [K(+)](o) buffer or in 3 mM tetrabutylammonium, inhibited 75% in 50 microM ouabain, and inhibited 64% in 20 mM K(+) buffer. Moreover, combined treatment with the Ca(2+)-activated K(+) channel inhibitors 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34, 100 nM) and apamin (5 microM) significantly reduced vasodilatation without altering sensitivity to acrolein. However, acrolein-induced % dilation was unaffected by l-NAME or indomethacin pretreatment indicating mechanistic independence of NO and prostaglandins. Moreover, acrolein induced vasodilatation in cirazoline-precontracted mesenteric bed of eNOS-null mice confirming eNOS independence. Pretreatment with 6-(2-propargyloxyphenyl) hexanoic acid (PPOH 50 microM), an epoxygenase inhibitor, or the superoxide dismutase mimetic Tempol (100 microM) significantly attenuated acrolein-induced vasodilatation. Collectively, these data indicate that acrolein stimulates mesenteric bed vasodilatation due to endothelium-derived signal(s) that is K(+)-, ouabain-, PPOH-, and Tempol-sensitive, and thus, a likely endothelium-derived hyperpolarizing factor (EDHF). These data indicate that low level acrolein exposure associated with vascular oxidative stress or inflammation stimulates vasodilatation via EDHF release in medium-sized arteries--a novel function.

Acrolein↗
PubMed2006

The expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats.

The objective of this study was to investigate the effects of estrogen receptor (ER) agonists and an ER antagonist on the expression of Hedgehog genes (Indian hedgehog: Ihh; Desert hedgehog: Dhh) and Hedgehog target genes (Patched 1: Ptc1; glioma-associated oncogene homolog 1: Gli1; chicken ovalbumin upstream promoter transcription factor II: Coup-TfII) in the rat uterus. Immature female rats were administered once with 17alpha-ethynyl estradiol (EE, an ER agonist), propyl pyrazole triole (PPT, an ERalpha-selective agonist), diarylpropionitrile (DPN, an ERbeta-selective agonist), or ICI 182,780 (an ER antagonist). Expression of mRNA for Ihh, Dhh, and Ptc1 was dose-dependently downregulated by EE in the uterus of immature rats, mediated by ER as confirmed by coadministration of ICI 182,780. The mRNA expression levels of Ptc1, Gli1, and Coup-TfII were simultaneously downregulated during the period in which the mRNA expression levels of Ihh and Dhh were downregulated in the uterus after administration of EE. PPT downregulated the transcription of Ihh, Dhh, Ptc1, Gli1, and Coup-TfII, indicating that expression of these genes was regulated by the ERalpha-dependent pathway. DPN also downregulated the transcription of Ihh and Dhh, although the effect was weaker than that of PPT, indicating that the regulation of uterine Ihh and Dhh transcription was also affected by the ERbeta-dependent pathway. These results suggest that the expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats.

Animals↗