Biomedical subjects

L Mao

Publications and source records attributed to L Mao.

At least 37 records · Page 2Linked to original sources

PubMed2001

Loss of Fhit expression is a predictor of poor outcome in tongue cancer.

Abnormalities of FHIT, a candidate tumor suppressor gene located at 3pl4.2, have been found frequently in multiple tumor types, including head and neck squamous cell carcinoma. To determine the role of FHIT in tongue cancers, Fhit expression was determined by immunohistochemistry studies in tissue samples from 41 patients with stages II-IV squamous cell carcinomas of the tongue. All of the patients underwent curative surgical treatment with a median of 83 months of follow-up care. We found that 28 (68%) of the 41 tumor specimens demonstrated a lack of or significantly decreased staining for Fhit. Fhit expression tended to be stronger in well-differentiated tumor areas than it was in poorly differentiated areas, although this trend was not statistically significant. There was no significant correlation between Fhit expression and a patient's age or sex or the histological grade or clinical stage of disease. As expected, clinical stage and nodal involvement correlated with prognosis. Interestingly, patients whose tumors demonstrated low levels of or no Fhit expression had a significantly shorter time of disease-free survival than those whose tumors had high Fhit expression (P = 0.035, by log-rank test). This prognostic value of Fhit was independent of other clinical parameters, including stage of disease and nodal status. We conclude that Fhit plays an important role in the development of squamous cell carcinomas of the tongue and that loss of Fhit expression may be an independent prognostic indicator for clinical outcome in patients with this tumor type.

Acid Anhydride Hydrolases↗

PubMed2001

Upregulation of preprodynorphin and preproenkephalin mRNA expression by selective activation of group I metabotropic glutamate receptors in characterized primary cultures of rat striatal neurons.

Group I metabotropic glutamate receptors (mGluRs) are positively coupled to phosphoinositide hydrolysis, and are expressed in medium spiny neurons of rat striatum in vivo. By modifying intracellular activities, this group of mGluRs is involved in the regulation of gene expression important for neuroplasticity. To characterize the regulatory role of group I receptors in opioid peptide mRNA expression in vitro, primary cultures of striatal cells were prepared from neonatal day-1 rat pups. Cells were cultured in the presence of a mitotic inhibitor, cytosine arabinoside, which generated predominant neuronal cell cultures after 12-14 days in culture as demonstrated by dense immunostaining of more than 90% of cultured cells to a specific marker for neurons (microtubule-associated protein) but not for astroglial cells (glial fibrillary acidic protein). The vast majority of neurons (>90%) were also verified as GABAergic neurons according to their positive immunoreactivity to GABA and glutamic acid decarboxylase-65/67 antibodies. A few large neurons (<5%) showed high levels of choline acetyltransferase immunoreactivity, presumably cholinergic neurons. To confirm group I mGluR expression in cultured neurons, both in situ hybridization and immunocytochemistry were performed, which detected moderate levels of mGluR1 and mGluR5 mRNAs and protein products in most neurons (>70%), respectively. On this culture system, quantitative in situ hybridization was then performed to quantify changes in preprodynorphin (PPD) and preproenkephalin (PPE) mRNA levels in response to mGluR stimulation. Acute incubation of a non-subgroup selective agonist, 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), increased PPD and PPE mRNA levels in a concentration-dependent manner (176 and 189% over control for PPD and PPE after 100 microM ACPD incubation, respectively). Application of a selective group I agonist, 3,5-dihydroxyphenylglycine (DHPG), produced much greater induction of either mRNA (285 and 289% over control for PPD and PPE after 100 microM DHPG incubation, respectively). Co-incubation of a selective group I antagonist, n-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), blocked both ACPD- and DHPG-induced PPD/PPE expression. These data demonstrate the validity of a neuronal cell culture model for studying the molecular regulation of opioid gene expression in vitro. Selective activation of identified group I mGluRs facilitates constitutive expression of PPD and PPE mRNAs in cultured striatal neurons.

Animals↗

PubMed2001

Loss of PTEN expression as a prognostic marker for tongue cancer.

BACKGROUND: Abnormalities of PTEN, a candidate tumor suppressor gene located at 10q23.3, play an important role in the tumorigenesis of multiple tumor types. OBJECTIVES: To investigate the expression of PTEN and its clinical implication in squamous cell carcinoma of the tongue. DESIGN: Retrospective analysis of PTEN protein expression in archived primary oral tongue tumor samples. SETTING: Academic center. PATIENTS AND METHODS: PTEN expression was determined by immunohistochemical analysis in tissue samples from 41 patients with stage II, III, and IV squamous cell carcinoma of the tongue. All the patients underwent curative surgical treatment with a median follow-up of 81 months. The Kaplan-Meier method was used for survival analysis. Multivariate analysis was performed according to the Cox proportional hazards model. RESULTS: Lack of staining for PTEN was demonstrated in 12 (29%) of the 41 tumors. Patients whose tumors lacked PTEN expression had a significantly shorter overall survival time (P = .03) and event-free survival time (P = .01) than those patients with positive PTEN expression. Multivariate regression analysis demonstrated that PTEN expression is an independent predictor of poor outcome when compared with tumor stage and nodal status. CONCLUSIONS: Although genetic alterations of the PTEN gene are rare in head and neck squamous cell carcinoma, loss of PTEN is not an uncommon event in squamous cell carcinoma of the tongue. Lack of PTEN expression may be an independent prognostic indicator for clinical outcome in patients with this tumor type.

Carcinoma, Squamous Cell↗

PubMed2001

Selective activation of group I metabotropic glutamate receptors upregulates preprodynorphin, substance P, and preproenkephalin mRNA expression in rat dorsal striatum.

Group I metabotropic glutamate receptors (mGluRs) are positively coupled to phosphoinositide hydrolysis through G-proteins and are densely expressed in the medium-sized spiny neurons of striatum. Activation of this group of mGluRs in the striatum produces long-lasting stimulation of behavioral activity. In this study, the role of group I mGluRs in the modulation of neuropeptide mRNA expression in striatal neurons was investigated using a Group I-selective agonist, 3,5-dihydroxyphenylglycine (DHPG) in chronically cannulated rats. Unilateral injections of DHPG into the dorsal striatum (caudoputamen) at behaviorally active doses of 20, 40, and 80 nmol elevated basal levels of preprodynorphin (PPD), substance P (SP), and preproenkephalin (PPE) mRNAs in the injected dorsal striatum as revealed by quantitative in situ hybridization. The elevation of all three mRNAs was dose-dependent and the responsiveness of opioid peptide mRNAs (PPD and PPE) to acute injection of DHPG at each dose surveyed was greater than that of SP mRNA. Induction of the mRNAs was delayed and prolonged as increases in hybridization signal became evident at 2 (SP and PPE) or 3 (PPD) h, reached a peak between 3 and 6 h, and returned to normal levels 24 h after DHPG injection. Coadministration of a Group I-selective antagonist, n-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carbo xamide (PHCCC, 10 nmol), with DHPG markedly attenuated DHPG-stimulated PPD, PPE, and, to a lesser extent, SP expression. Administration of PHCCC alone had no significant effect on basal levels of three mRNA expression in the striatum. This study provides a detailed description of the dose- and time-related alterations in striatonigral PPD/SP and striatopallidal PPE mRNA expression in response to a single injection of the Group I agonist DHPG. Data obtained demonstrate a facilitatory, dynamic regulation of constitutive expression of PPD, SP, and PPE mRNAs by local enhancement of glutamatergic tone on DHPG- and PHCCC-sensitive Group I mGluRs.

Animals↗

PubMed2001

Molecular abnormalities in lung carcinogenesis and their potential clinical implications.

Development of lung cancer is multistep and requires accumulation of multiple genetic and epigenetic alterations. Modern molecular technology has facilitated a rapid and effective identification of these genetic alterations as well as epigenetic alterations. The determination of molecular alterations in the early tumorigenic process of the lung will not only extend our understanding of the underlying biology but also provide molecular markers for cancer risk assessment, early detection, and molecular classification. In this article, I will discuss the common molecular abnormalities in lung cancer and how these abnormalities may be used as biomarkers in clinical practice.

Biomarkers, Tumor↗

PubMed2001

Augmented motor activity and reduced striatal preprodynorphin mRNA induction in response to acute amphetamine administration in metabotropic glutamate receptor 1 knockout mice.

Metabotropic glutamate receptor 1 (mGluR1) is a G-protein-coupled receptor and is expressed in the medium spiny projection neurons of mouse striatum. To define the role of mGluR1 in actions of psychostimulant, we compared both motor behavior and striatal neuropeptide mRNA expression between mGluR1 mutant and wild-type control mice after a single injection of amphetamine. We found that acute amphetamine injection increased motor activity in both mutant and control mice in a dose-dependent manner (1, 4, and 12 mg/kg, i.p.). However, the overall motor responses of mGluR1 -/- mice to all three doses of amphetamine were significantly greater than those of wild-type +/+ mice. Amphetamine also induced a dose-dependent elevation of preprodynorphin mRNA in the dorsal and ventral striatum of mutant and wild-type mice as revealed by quantitative in situ hybridization. In contrast to behavioral responses, the induction of dynorphin mRNA in both the dorsal and ventral striatum of mutant mice was significantly less than that of wild-type mice in response to the two higher doses of amphetamine. In addition, amphetamine elevated basal levels of substance P mRNA in the dorsal and ventral striatum of mGluR1 mutant mice to a similar level as that of wild-type mice. There were no differences in basal levels and distribution patterns of the two mRNAs between the two genotypes of mice treated with saline. These results demonstrate a clear augmented behavioral response of mGluR1 knockout mice to acute amphetamine exposure that is closely correlated with reduced dynorphin mRNA induction in the same mice. It appears that an intact mGluR1 is specifically critical for full dynorphin induction, and impaired mobilization of inhibitory dynorphin system as a result of lacking mGluR1 may contribute to an augmentation of motor stimulation in response to acute administration of psychostimulant.

Amphetamine↗

PubMed2001

Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy.

OBJECTIVES: We sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways. BACKGROUND: Cardiac hypertrophy is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Although considerable evidence suggests that G-protein-coupled receptors are involved in the hypertrophic response, it remains controversial whether catecholamines are required for the development of in vivo cardiac hypertrophy. METHODS: We performed transverse aortic constriction (TAC) in dopamine beta-hydroxylase knockout mice (Dbh(-/-), genetically altered mice that are completely devoid of endogenous norepinephrine and epinephrine) and littermate control mice. After induction of cardiac hypertrophy, the mitogen-activated protein kinase (MAPK) signaling pathways were measured in pressure-overloaded/wild-type and Dbh(-/-) hearts. RESULTS: Compared with the control animals, cardiac hypertrophy was significantly blunted in Dbh(-/-) mice, which was not associated with altered cardiac function, as assessed by transthoracic echocardiography in conscious mice. The extracellularly regulated kinase (ERK 1/2), c-jun-NH(2)-terminal kinase (JNK) and p38 MAPK pathways were all activated by two- to threefold after TAC in the control animals. In contrast, induction of the three pathways (ERK 1/2, JNK and p38) was completely abolished in Dbh(-/-) mice. CONCLUSIONS: These data demonstrate a nearly complete requirement of endogenous norepinephrine and epinephrine for the induction of in vivo pressure-overload cardiac hypertrophy and for the activation of hypertrophic signaling pathways.

Animals↗

PubMed2001

Genetic heterogeneity in saliva from patients with oral squamous carcinomas: implications in molecular diagnosis and screening.

We performed microsatellite analysis at chromosomal regions frequently altered in head and neck squamous carcinoma on matched saliva and tumor samples from 37 patients who had oral squamous carcinoma. The results were correlated with the cytologic findings and traditional clinicopathologic factors to assess the diagnostic and biological potential of these markers. Our data showed that 18 (49%) of the saliva samples and 32 (86%) of the tumors had loss of heterozygosity (LOH) in at least one of the 25 markers studied. In saliva, the combination of markers D3S1234, D9S156, and D17S799 identified 13 (72.2%) of the 18 patients with LOH in saliva (P < 0.001). For tumors, markers D3S1234, D8S254, and D9S171 together identified 27 (84.3%) of the 32 tumors with LOH at any of the loci tested (P < 0.001). Eleven (55%) of the 20 saliva samples with cytologic atypia and seven (35%) of the 17 specimens without atypia had LOH. Significant correlation between LOH in tumor at certain markers and smoking and alcohol use was found. Our results indicate that: 1) epithelial cells in saliva from patients with head and neck squamous tumorigenesis provide suitable material for genetic analysis; 2) combined application of certain markers improves the detection of genetic alteration in these patients; 3) clonal heterogeneity between saliva and matching tumor supports genetic instability of the mucosal field in some of these patients; and 4) LOH at certain chromosomal loci appears to be associated with smoking and alcohol consumption.

Alcohol Drinking↗

PubMed2001

Composite films based on biorelated agro-industrial waste and poly(vinyl alcohol). Preparation and mechanical properties characterization.

As a part of an ongoing project on the production of composite materials based on poly(vinyl alcohol) (PVA) and polymeric materials from renewable resources, the present paper reports on the incorporation of agricultural waste materials as organic fillers in a film matrix based on PVA as continuous phase. In this study lignocellulosic fibers byproducts, derived from sugar cane (SC) and apple (AP) and orange (OR) fruit juice extraction, were cast from PVA aqueous solutions. The effect of fiber type and composition on the relative properties of cast films was evaluated and compared. OR resulted to be suitable for blending in higher amounts by weight than SC and AP. Glycerol and urea were added as plasticizing agents and were observed to be effective in giving flexible films. Additionally, cornstarch was added to further increase the composition of polymers from renewable resources in cost-effective and ecoefficient composite film formulations. The prepared films resulted sensitive to moisture and water. To reduce water sensitivity, hexamethoxymethylmelamine (HMMM) was tested as a cross-linking agent for the present composite formulations. Cross-linked films exhibited significant improvement in water-resistance that can be taken as a tuneable structural feature for customized applications. The mechanical properties of the prepared composite films (elongation at break, tensile strength, Young modulus) were found to be dependent upon the nature and content of the filler and on environmental conditions.

Agriculture↗

PubMed2001

Sequence and analysis of the tomato JOINTLESS locus.

A 119-kb bacterial artificial chromosome from the JOINTLESS locus on the tomato (Lycopersicon esculentum) chromosome 11 contained 15 putative genes. Repetitive sequences in this region include one copia-like LTR retrotransposon, 13 simple sequence repeats, three copies of a novel type III foldback transposon, and four putative short DNA repeats. Database searches showed that the foldback transposon and the short DNA repeats seemed to be associated preferably with genes. The predicted tomato genes were compared with the complete Arabidopsis genome. Eleven out of 15 tomato open reading frames were found to be colinear with segments on five Arabidopsis bacterial artificial chromosome/P1-derived artificial chromosome clones. The synteny patterns, however, did not reveal duplicated segments in Arabidopsis, where over half of the genome is duplicated. Our analysis indicated that the microsynteny between the tomato and Arabidopsis genomes was still conserved at a very small scale but was complicated by the large number of gene families in the Arabidopsis genome.

Arabidopsis↗

PubMed2001

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice.

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.

Animals↗

PubMed2001

Effect of nitrogen on resistance of sweet potato to sweetpotato weevil (Coleoptera: Curculionidae) and on storage root chemistry.

The effects of nitrogen fertilizer on sweet potato, Ipomoea batatas (L.) Poir., resistance to the sweetpotato weevil, Cylas formicarius elegantulus (Summers), was studied. Adult weevil feeding and oviposition preference, larval survival, and pupal weight were used as measures of sweet potato resistance. Sweet potato resin glycosides and caffeic acid concentrations in the periderm tissue of storage roots also were measured. Sweet potato genotypes (Beauregard, Excel, W-244, W-250, and Sumor) with varying levels of resistance to sweetpotato weevil were grown in the field under three nitrogen regimes (0, 45, and 135 kg N/ha). Harvested storage roots were evaluated in the laboratory for feeding and oviposition activity of sweetpotato weevil female adults under no-choice and choice test conditions. Larval survival rate and pupal weight were determined by rearing the insects individually on storage root sections. Nitrogen level had a significant effect on the number of eggs deposited, but not on the number of feeding punctures. Sweetpotato weevils laid fewer eggs on plants with the highest level of nitrogen. Nitrogen levels did not significantly affect larval survival and pupal weight. Genotype had a significant effect on feeding, oviposition, and larval survival. Beauregard had higher levels of feeding, oviposition, and larval survival compared with the other genotypes. No interaction effects between nitrogen and genotype were significant. Resin glycosides and caffeic acid concentrations were significantly different among genotypes and between years. Nitrogen levels significantly affected the concentrations of caffeic acid in 1997.

Animals↗

PubMed2001

[Biomarkers of carcinogenesis of the upper and lower airway epithelium and the role of chemoprevention].

Lung as well as head and neck cancer represent an important public health problem worldwide, with lung cancer being the leading cause of cancer death in western countries. Although early stage disease is often curable with surgery or radiotherapy, the majority of patients present with advanced disease in which despite advances in combined modality therapy the outcomes have not dramatically improved. Furthermore, patients cured of their initial early stage lung or head and neck carcinoma are at high risk for development of second primary tumors, which pose the main threat to their survival. An alternative approach in reducing the incidence and thus mortality of these cancers is chemoprevention, the use of agents to reverse, halt or delay carcinogenesis. The carcinogenesis process in lung and head and neck cancer results from a dysregulation of cellular proliferation, differentiation and cell death resulting from field-wide exposure of the upper and lower airway track to tobacco smoking. This review article presents main data regarding the actual understanding of lung and head and neck carcinogenesis, as well as results of major chemoprevention trials in this field.

Anticarcinogenic Agents↗

PubMed2001

Clinical significance of cyclin B1 protein expression in squamous cell carcinoma of the tongue.

PURPOSE: Cyclin B1 plays an important role in control of the G(2)-M transition of the cell cycle. We have shown recently that overexpression of cyclin B1 is associated with poor outcome in patients with early stage squamous cell carcinoma (SCC) of the lung. EXPERIMENTAL DESIGN: To determine the role of cyclin B1 in SCC of the tongue, we analyzed tumor specimens from 41 patients with stage II-IV SCC of the tongue who underwent curative surgery using immunohistochemistry. RESULTS: The median follow-up of all patients was 83 months. Overexpression of cyclin B1 was observed in 15 (37%) of the 41 tumors, a similar frequency to that found in SCC of the lung. Patients whose tumors showed overexpression of cyclin B1 had a poor event-free survival compared with those lacking this feature (P = 0.04 by Log-rank test). Multivariate analysis of traditional clinical/pathological factors showed that cyclin B1 overexpression was an independent prognostic indicator. CONCLUSIONS: Our study indicates that cyclin B1 is overexpressed in a subset of SCC of the tongue and is associated with a more aggressive biological behavior of the disease.

Carcinoma, Squamous Cell↗

PubMed2001

Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development.

PURPOSE: To better understand the role of G(1)-S transition regulator abnormalities in the pathogenesis of advanced premalignant lesions of the upper aerodigestive tract and the biological effects of chemoprevention, we studied biopsies obtained sequentially from participants in a prospective trial using 13-cis retinoic acid, IFN-alpha, and alpha-tocopherol for 12 months. EXPERIMENTAL DESIGN: Cyclin D1 and p16 expression were analyzed by immunohistochemistry, loss of heterozygosity by polymerase chain reacting amplification, and then electrophoretic separation of the products, methylation of the p16 promoter by methylation-specific polymerase chain reacting, and cyclin D1 gene amplification by fluorescence in situ hybridization. RESULTS: Baseline dysregulation of cyclin D1 expression was found in 50% (14 of 28) and was reversed in 6 of 14 cases, whereas p16 expression was lost in 46% (13 of 28) and regained in 2 of 13 cases. Loss of heterozygosity at 9p21 occurred in 68% and p16(INK4a) promoter methylation occurred in 75% of cases, with increasing frequency from mild to severe dysplasia. Cyclin D1 gene amplification was identified in two cases. Cyclin D1 protein dysregulation at last follow-up alone and in combination with p16 loss was associated with histological progression and cancer development (P < 0.01). CONCLUSIONS: Additional study of these alterations in a larger sample and exploration of the upstream signaling partners of these cell cycle regulators in vivo is warranted to identify cancer risk profiles that would be meaningful targets for chemopreventive intervention.

Adult↗

PubMed2001

[An experimental study of matrix metalloproteinase inhibitor BB-94 inhibits the invasion and metastasis of the human salivary adenoid cystic carcinoma in vitro and in vivo].

OBJECTIVE: To study the inhibitory effect of matrix metalloproteinase inhibitor BB-94 on the invasion and metastasis of salivary adenoid cystic carcinoma in vitro and in vivo. METHODS: Reconstituted basement membrane invasion assay was used to evaluate invasive ability of cancer cells. Type IV collagenase was assessed by PAGE substrate zymography. In addition, the antimetastasis effect of the compound was studied in in vivo experiments using nude mice model of pulmonary metastasis with ACC-M line of human salivary adenoid cystic carcinoma. RESULTS: BB-94, at the concentrations of 10 mumol/L and 100 mumol/L, suppressed the reconstituted basement invasion of ACC-M human salivary adenoid cystic carcinoma by 32.9%, 53.2% and reduced Type IV collagenase activities in the serum-free supernatant of the same cells. The pulmonary metastasis rate of the control and treated groups was 90.0% and 20.0%, respectively (P < 0.01). The lung weight of the control and treated groups was (0.2090 +/- 0.0667) g and (0.1532 +/- 0.0378) g, respectively (P < 0.05). CONCLUSIONS: These results suggest that the matrix metalloproteinase inhibitor BB-94 has a strong inhibitory effect on invasion and metastasis of salivary adenoid cystic carcinoma.

Animals↗

PubMed2000

Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy.

BACKGROUND: Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the ss-adrenergic receptor kinase (ssARKct) have increased in vivo cardiac function and enhanced ss-adrenergic receptor (ssAR) responsiveness. METHODS AND RESULTS: In the present study, we created transgenic mice with myocardium-targeted ssARKct transgene expression under control of the CARP (cardiac ankyrin repeat protein) promoter, which is active during cardiac development and inactive in the normal adult mouse heart. Consistent with this, adult CARP-ssARKct transgenic mice have normal in vivo cardiac contractility and ssAR responsiveness indistinguishable from their nontransgenic littermates (NLCs). However, because CARP is in a group of fetal genes activated in the adult ventricle during hypertrophy, we subjected animals to transverse aortic constriction (TAC) to induce pressure overload. Seven days after TAC, CARP-ssARKct hearts had elevations in left ventricular mass similar to those in NLCs; however, TAC did induce demonstrable ssARKct expression in the transgenic hearts. TAC in NLC mice resulted in an upregulation of myocardial ssARK1 and a loss of ssAR-mediated inotropic reserve. Importantly, although ssARK1 was increased in the hypertrophic CARP-ssARKct mice, the in vivo loss of ssAR responsiveness was not seen after induced ssARKct expression. CONCLUSIONS: These results demonstrate that acute ssARK1 inhibition can restore lost myocardial ssAR responsiveness and inotropic reserve in vivo. Furthermore, these mice demonstrate the novel utility of the CARP promoter as an inducible element responsive to pathophysiological conditions in the adult heart.

Animals↗

PubMed2000

Activation of group III metabotropic glutamate receptors inhibits basal and amphetamine-stimulated dopamine release in rat dorsal striatum: an in vivo microdialysis study.

Group III metabotropic glutamate (mGlu) receptors are negatively coupled to adenylate cyclase and are distributed pre-synaptically in the striatum. A behavioral study previously conducted in this laboratory shows that activation of this group of mGlu receptors attenuates acute amphetamine-stimulated motor activity. By administering a group III selective agonist or antagonist via the dialysis probe, the present study employed in vivo microdialysis to evaluate the capacity of the group III selective agents to alter extracellular levels of dopamine in the dorsal striatum of normal and amphetamine-treated rats. It was found that the group III agonist L-2-amino-4-phosphonobutyrate (L-AP4) dose-dependently (1, 10 and 100 microM) reduced basal levels of extracellular dopamine. In contrast, the group III antagonist alpha-methyl-4-phosphonophenylglycine (MPPG) dose-dependently (10, 50 and 250 microM) elevated the basal release of extracellular dopamine. This elevation was antagonized by co-perfusion of L-AP4. Perfusion of 5-microM amphetamine through the dialysis probe increased extracellular dopamine in the dorsal striatum. Co-perfusion of L-AP4 (100 microM) significantly reduced amphetamine-stimulated dopamine levels, whereas co-perfusion of L-AP4 (100 microM) and MPPG (100 microM) did not alter the capacity of amphetamine to elicit dopamine release. The data obtained from this study demonstrate the presence of a tonically active glutamatergic tone on group III mGlu receptors in the dorsal striatum to pre-synaptically regulate basal dopamine release in an inhibitory fashion. Moreover, activation of L-AP4-sensitive group III mGlu receptors can suppress the phasic release of dopamine induced by a dopamine stimulant amphetamine.

Alanine↗