Biomedical subjects

Jun Ren

Publications and source records attributed to Jun Ren.

At least 19 recordsLinked to original sources

PubMed2006

Biodegradable cationic polyester as an efficient carrier for gene delivery to neonatal cardiomyocytes.

Viral-mediated gene delivery has been explored for the treatment and protection of cardiomyocytes, but so far there is only one report using cationic polymer for gene delivery to cardiomyocytes in spite of many advantages of polymer-mediated gene delivery. In this study, a cationic poly(beta-amino ester) (PDMA) with a degradable backbone and cleavable side chains was synthesized by Michael addition reaction. The toxicity of PDMA to neonatal mouse cardiomyocytes (NMCMs) was significantly lower than that of polyethyleneimine (PEI). PDMA formed stable polyplexes with pEGFP. The dissociation of the polyplexes could be triggered by PDMA degradation, and the dissociation time was tunable via the polymer/pEGFP ratio. In vitro transfection showed that PDMA was an effective and low toxic gene delivery carrier for NMCMs. The PDMA/pEGFP polyplexes transfected EGFP gene to NMCMs with about 28% efficiency and caused little death. In contrast, a significant portion of cardiomyocytes cultured with PEI/pEGFP died.

Acrylamides↗

PubMed2006

Chinese white Rongchang pig does not have the dominant white allele of KIT but has the dominant black allele of MC1R.

The mast/stem cell growth factor receptor (KIT) and melanocortin receptor 1 (MC1R) mutations are responsible for coat color phenotypes in domestic pigs. Rongchang is a Chinese indigenous pig breed with a white coat color phenotype. To investigate the genetic variability of the KIT and MC1R genes and their possible association with the coat color phenotype in this breed, a gene duplication and splice mutation of KIT were diagnosed in a sample of 93 unrelated Rongchang animals. The results show that Rongchang pigs have a single copy of KIT without the splice mutation at the first nucleotide of intron 17, indicating that the dominant white I allele of KIT is not responsible for their white phenotype. The KIT mRNA and MC1R coding sequences were also determined in this breed. Three putative amino acid substitutions were found in the KIT gene between Rongchang and Western white pigs, their association with the Rongchang white phenotype remains unknown. For the MC1R gene, Rongchang pigs were demonstrated to have the same dominant black allele (E(D1)) as other Chinese breeds, supporting the previous conclusion that Chinese and Western pigs have independent domestication origin. We also clarified that the Rongchang white phenotype was recessive to nonwhite color phenotypes. Our results provide a good starting point for the identification of the mutations underlying the white coat color in Rongchang pigs.

Alleles↗

PubMed2006

Advanced glycation endproduct induces ROS accumulation, apoptosis, MAP kinase activation and nuclear O-GlcNAcylation in human cardiac myocytes.

Accumulation of advanced glycation endproduct (AGE) has been implicated in the pathogenesis of diabetic complications. However, the precise role and mechanism behind AGE-associated diabetic heart injury are not fully clear. This study was designed to evaluate the effect of AGE on accumulation of reactive oxygen species (ROS), apoptosis, mitogen-activated protein kinase (MAPK) activation and nuclear O-GlcNAcylation in fetal human cardiac myocytes. Myocytes were maintained for 24-72 h in a defined culture medium containing high glucose, the AGE carbon precursor methylglyoxal (MG), and MG-AGE derived from MG and bovine serum albumin (BSA). Generation of ROS was detected by 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by caspase-3 activity and quantitative DNA fragmentation. Both high glucose (25.5 mM) and MG (200 microM) significantly enhanced ROS and AGE formation with greater effects elicited by MG. Both high glucose and MG-AGE significantly facilitated apoptosis with a more predominant effect from MG-AGE. In addition, phosphorylation of MAPK cascade [extracellular signal-regulated kinase-1/2 (ERK1/2) and p38] and nuclear O-GlcNAcylation were enhanced in MG-AGE-treated myocytes, similar to those elicited by high glucose. MG-AGE-induced phosphorylation of ERK1/2 and p38 was nullified by neutralizing AGE with specific anti-AGE antibody but not nonspecific antiserum. Collectively, these results indicated that AGE or its precursor MG may trigger ROS generation, apoptosis, MAPK activation and nuclear O-GlcNAcylation in human cardiac myocytes, in a manner reminiscent of high extracellular glucose.

Acylation↗

PubMed2006

Thiophene adsorption and activation on MoP(001), gamma-Mo2N(100), and Ni2P(001): density functional theory studies.

The adsorption and dissociation of thiophene on the MoP(001), gamma-Mo(2)N(100), and Ni(2)P(001) surfaces have been computed by using the density functional theory method. It is found that thiophene adsorbs dissociatively on MoP(001), while nondissociatively on gamma-Mo(2)N(100) and Ni(2)P(001). On MoP(001), the dissociation of the C-S bonds is favored both thermodynamically and kinetically, while the break of the first C-S bond on gamma-Mo(2)N(100) has an energy barrier of 1.58 eV and is endothermic by 0.73 eV. On Ni(2)P(001) there are Ni(3)P(2)- and Ni(3)P-terminated surfaces. On the Ni(3)P(2)-terminated surface, the dissociation of the C-S bonds of adsorbed thiophene is endothermic, while it is exothermic on the Ni(3)P-terminated surface.

Journal Article↗

PubMed2006

Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage.

Aging is associated with hepatic growth hormone resistance resulting in a fall in serum insulin-like growth factor 1 (IGF-1) level. However, whether loss of IGF-1 contributes to cardiac aging is unclear. This study was designed to examine the effect of cardiac overexpression of IGF-1 on cardiomyocyte contractile function in young (3 mo) and old (26-28 mo) mice. Cardiomyocyte contractile function was evaluated, including peak shortening (PS), time to 90% PS, time to 90% relengthening (TR(90)), and maximal velocity of shortening/relengthening (+/-dL/dt). Levels of advanced glycation end product, protein carbonyl, sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban, and Na(+)/Ca(2+) exchanger were assessed by Western blot analysis. SERCA activity was measured by (45)Ca(2+) uptake. Aging induced a decline in plasma IGF-1 levels. Aged cells exhibited depressed +/-dL/dt, prolonged TR(90), and a steeper PS decline in response to increasing stimulus frequency compared with those in young myocytes. IGF-1 transgene alleviated aging-induced loss in plasma IGF-1 and aging-induced mechanical defects with little effect in young mice. The beneficial effect of IGF-1 transgene on aging-associated cardiomyocyte contractile dysfunction was somewhat mimicked by short-term in vitro treatment of recombinant IGF-1 (500 nM). Advanced glycation end product and protein carbonyl levels were higher in aged mice, which were not affected by IGF-1. Expression of SERCA2a (but not Na(+)/Ca(2+) exchanger and phospholamban) and SERCA activity were reduced with aging, which was ablated by the IGF-1 transgene. Collectively, our data suggest a beneficial role of IGF-1 in aging-induced cardiac contractile dysfunction, possibly related to improved Ca(2+) uptake.

Aging↗

PubMed2006

Cardiac overexpression of metallothionein rescues chronic alcohol intake-induced cardiomyocyte dysfunction: role of Akt, mammalian target of rapamycin and ribosomal p70s6 kinase.

AIMS: Reduced insulin sensitivity following alcohol intake plays a role in alcohol-induced organ damage although its precise mechanism is undefined. This study was designed to examine the effect of cardiac overexpression of the antioxidant metallothionein on alcohol-induced cardiac contractile dysfunction and post-receptor insulin signaling. METHODS: FVB and metallothionein mice were fed a 4% alcohol diet for 16 weeks. Cardiomyocyte contractile function was evaluated including peak shortening (PS), time-to-PS (TPS), and time-to-relengthening (TR(90)). Post-insulin receptor signaling molecules Akt, mammalian target of rapamycin (mTOR), and ribosomal p70s6 kinase (p70s6k) were evaluated using western blot analysis. Akt1 kinase activity was assayed with a phosphotransferase kit. RESULTS: Alcohol intake dampened whole body glucose tolerance, depressed PS, shortened TPS, and prolonged TR(90), which were abrogated by metallothionein with the exception of glucose intolerance. Our results revealed reduced expression of total Akt, phosphorylated mTOR, and phosphorylated p70s6k-to-p70s6k ratio as well as Akt1 kinase activity in alcohol consuming FVB mice. Phosphorylated Akt, total mTOR, and phosphorylated p70s6k were unaffected by alcohol. Metallothionein ablated reduced Akt protein and kinase activity without affecting any other proteins or their phosphorylation. CONCLUSION: In summary, our data suggest that chronic alcohol intake interrupted cardiac contractile function and Akt/mTOR/p70s6k signaling. Akt but unlikely mTOR and p70s6k may contribute to metallothionein-elicited cardiac protective response.

Alcohol Drinking↗

PubMed2006

Cardiac nitric oxide synthases are elevated in dietary copper deficiency.

Dietary copper (Cu) deficiency leads to cardiac morphological and functional defects suggestive of heart failure. However, simultaneous cytoprotective events also appear to occur. The molecular mechanisms responsible for this complex alteration of cardiac function by Cu deficiency have not been elucidated. Because prior work has implicated altered nitric oxide (NO) metabolism in this altered function, we have examined this pathway in further detail. Male Sprague-Dawley rats were fed diets that were either Cu adequate (6 mg Cu/kg diet) or Cu deficient (<0.5 mg Cu/kg diet) for 5 weeks. Endothelial NO synthase (NOS) and inducible NOS (iNOS) protein expressions, as measured by Western blot analysis, were 58% and 40% higher, respectively, in Cu-deficient than in Cu-adequate rat hearts. Cardiac NOS activity, as measured by conversion of (3)H-arginine to (3)H-citrulline, was 130% higher in Cu-deficient than in Cu-adequate rats. NFkappaB is a known transcription factor for iNOS. Activation of NFkappaB, determined by an ELISA for the p65 subunit, was found to be 33% higher in Cu-deficient than in Cu-adequate rats. Coupled with prior evidence of elevated cardiac nitrate/nitrite production in Cu-deficient rats, these data suggest multiple pathways for enhanced NO production that may contribute to altered cardiac function under dietary Cu deficiency.

Animals↗

PubMed2006

Characterization of cardiomyocyte excitation-contraction coupling in the FVB/N-C57BL/6 intercrossed "chocolate" brown mice.

Mice are extensively used for gene modification research and isolated cardiomyocytes are essential for evaluation of cardiac function without interference from non-myocyte contribution. This study was designed to characterize cardiomyocyte excitation-contraction coupling in FVB/N-C57BL/6 intercrossed brown mice. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix softedge system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), maximal velocity of shortening and relengthening (+/- dL/dt), intracellular Ca(2+) rise and decay rate. Resting cell length was longer in age- and gender-matched C57BL/6 and brown mice compared to FVB strain. PS and +/- dL/dt were significantly lower in brown mice compared to FVB/N and C57BL/6 groups. TPS was shortened in C57BL/6 mice and TR(90) was prolonged in brown mice compared to other groups. Resting intracellular Ca(2+) level and single exponential intracellular Ca(2+) decay constant were comparable among all three mouse lines. Rise in intracellular Ca(2+) in response to electrical stimulus was higher in C57BL/6 mouse myocytes whereas bi-exponential intracellular Ca(2+) decay was faster in brown mice. Myocytes from all three groups exhibited similar fashion of reduction in PS in response to increased stimulus frequency. These data suggest that inherent differences in cardiomyocyte excitation-contraction coupling exist between strains, which may warrant caution when comparing data from these mouse lines.

Animals↗

PubMed2006

Ampakines alleviate respiratory depression in rats.

RATIONALE: There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the pre-Bötzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. OBJECTIVE: We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid- and barbiturate-induced respiratory depression. METHODS: Respiratory frequency and amplitude were measured in the following rat models: (1) perinatal in vitro brainstem-spinal cord, (2) neonatal in vitro medullary slice, (3) juvenile in situ perfused, working heart-brainstem preparation, and (4) newborn and adult in vivo. RESULTS: Administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not in older animals (greater than Postnatal Day 0). Furthermore, pharmacologic depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ, and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus. CONCLUSIONS: CX546 effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify the potential of ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea.

Analgesics, Opioid↗

PubMed2006

Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells.

Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [(3)H]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation.

Acetaldehyde↗

PubMed2006

Dendritic cell generated from CD34+ hematopoietic progenitors can be transfected with adenovirus containing gene of HBsAg and induce antigen-specific cytotoxic T cell responses.

Dendritic cells (DCs) are professional antigen presenting cells that are being considered as potential immunotherapeutic agents to promote host immune responses against tumor antigens. The use of such modified antigen-presenting cells for research or therapeutic have been limited by several factors, including maintaining DCs in a highly activated state, efficient transduction and expression, stable expression, identification of appropriate tumor-associated antigens, and absence of unintended functional changes or cytotoxicity. In this study, the feasibility of using CD34-DCs for tumor immunotherapy after transduction with a recombinant adenovirus containing HBsAg gene (AdVHBsAg), an HCC-associated antigen, was investigated. The gene transfer with recombinant adenovirus vectors (AdV) can obtained high levels of stable expression of HBsAg and its efficiency was increased in a multiplicity of infection (MOI)-dependent manner. Moreover, the AdVHBsAg infection had no appreciable effect on apoptosis of DCs compared with that of mock-infected DCs. The T cell lines, primed by the recombinant AdVHBsAg-infected DCs in vitro, recognized HBsAg-expressing tumor cell lines in a human leukocyte antigen (HLA) class I-restricted manner, and evoked a higher CTL response, which indicated that high potent and specific antitumor immune response could be induced by AdVHBsAg DC vaccine. It may be a promising the therapeutic modality for the treatment of HBsAg-expressing tumors, and will be a foundation for further study on DC vaccines and gene therapy for HCC.

Adenoviridae↗

PubMed2006

Atomic structure and bonding of water overlayer on Cu(110): the borderline for intact and dissociative adsorption.

By carefully comparing the calculated and measured work function data, energetics, and vibrational spectroscopy, we determine explicitly the water structure in c(2 x 2) periodicity on Cu(110) to be an intact water overlayer with a majority component of H-down bilayer (95%) in low temperature experiments. Water dissociation is accessible by heating or ultraviolet illumination, resulting in a sensitive change in electron density at the surface and could therefore be monitored by work function measurement.

Journal Article↗

PubMed2006

Induction of alpha-fetoprotein-specific CD4- and CD8-mediated T-cell response using RNA-transfected dendritic cells.

alpha-Fetoprotein (AFP) may be a possible target for a hepatocellular carcinoma (HCC)-specific vaccination. But some studies have demonstrated that dendritic cells (DCs) treated with AFP become dysfunctional. So in this study, we try to transfect AFP mRNA into DCs and observe the ability of DCs to induce AFP-specific CD4(+) and CD8(+) T cells. We hope that AFP can be processed and presented by DCs directly, rather than released to the cultures. So there will be no AFP negative effect on the function of DCs. In the study, immature DCs generated from peripheral blood mononuclear cells (PBMCs) of HLA-A2(+) HCC patients were transfected with AFP mRNA. Then the transfected, matured DCs were used to stimulate autologous T cells. The results showed that the expressions of membrane molecules of DCs after transfection were increased dramatically, and interleukin-12 (IL-12) p70 release in the supernatant was elevated significantly. There was only a minority of AFP release in the supernatants of transfected DCs. CTLs induced by the transfected DCs recognized HLA-matched AFP positive HepG2 cell line specifically and the AFP-specific proliferative T-cell responses could also be induced. These findings indicate that this AFP mRNA transfection strategy could generate fully functional DCs, which could induce specific T cells to recognize AFP(+) HCC cells.

Antigen Presentation↗

PubMed2006

Synergic antiproliferative effect of DNA methyltransferase inhibitor in combination with anticancer drugs in gastric carcinoma.

Epigenetic alterations of DNA methylation play an important role in the regulation of gene expression associated with chemosensitivity of gastric carcinomas. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of DNA methyltransferase inhibitor, 5-aza-CdR, on the chemosensitivity of five anticancer drugs was investigated. Human gastric cancer cell lines, OCUM-2M and MKN-74, and five anticancer drugs, 5-FU, PTX, OXA, SN38, and GEM, were used. In both gastric cancer cell lines, a synergistic antiproliferative effect by a combination of 5-aza-CdR at 5 microM was found in SN38 and GEM. 5-Aza-CdR at 5 microM increased apoptosis induced by SN38 and GEM in both cell lines. 5-Aza-CdR increases the expression of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes in both OCUM-2M and MKN-74 cells, but not that of hMLH1, p16, MGMT, E-cadherin, and p53 genes. These findings suggest that 5-aza-CdR is a promising chemotherapeutical agent for gastric carcinomas, in combination with the anticancer drugs SN38 and GEM, in apoptosis signaling. The upregulation of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes by 5-aza-CdR might be associated with the synergistic effect.

Antineoplastic Agents↗

PubMed2006

Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes.

Intermedin (IMD), also called adrenomedullin-2, is a 47-amino acid peptide from the calcitonin gene-related peptide (CGRP)/adrenomedullin family of peptides. Recent studies suggest that IMD may participate in the regulation of cardiovascular function and fluid and electrolyte homeostasis. To evaluate the role of IMD on cardiomyocyte contractile function, electrically paced murine ventricular myocytes were acutely exposed to IMD, and the following indexes were determined: peak shortening (PS), time to PS, time-to-90% relengthening, and maximal velocity of shortening and relengthening. Intracellular Ca(2+) was assessed using fura 2-AM fluorescent microscopy. Our results revealed that IMD (10 pM to 10 nM) significantly increased PS and maximal velocity of shortening and relengthening in ventricular myocytes, the maximal effect of which (approximately 46%) was somewhat comparable to those elicited by CGRP (1 nM) and adrenomedullin (100 nM). Exposure of IMD significantly shortened time-to-90% relengthening without affecting time to PS, similar to CGRP and adrenomedullin. IMD also enhanced intracellular Ca(2+) release, with a maximal increase of approximately 50%, and facilitated the intracellular Ca(2+) decay rate. The IMD-induced effects were abolished by the protein kinase C inhibitor chelerythrine (1 microM), downregulation of protein kinase C using phorbol 12-myristate 13-acetate (1 microM), and the protein kinase A inhibitor H89 (1 microM). Our data suggest that IMD acutely augments cardiomyocyte contractile function through, at least in part, a protein kinase C- and protein kinase A-dependent mechanism.

Animals↗

PubMed2006

Intracerebral hemorrhage elicits aberration in cardiomyocyte contractile function and intracellular Ca2+ transients.

BACKGROUND AND PURPOSE: The sequelae of intracerebral hemorrhage involve multiple organ damage including electrocardiographic alteration, although the mechanism(s) behind myocardial dysfunction is unknown. The aim of this study was to examine the impact of intracerebral hemorrhage on cardiomyocyte contractile function, intracellular Ca2+ handling, Ca2+ cycling proteins, I kappa B beta protein (IkappaB) phosphorylation, hypoxia-inducible factor 1alpha (HIF-1alpha), and nitrosative damage within 48 hours of injury. METHODS: Mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), and intracellular Ca2+ decay. RESULTS: Myocytes from intracerebral hemorrhage rats exhibited depressed PS, +/-dL/dt, prolonged TPS and TR90, as well as declined baseline FFI and slowed intracellular Ca2+ decay between 12 and 24 hours after injury. Most of these aberrations returned to normal levels 48 hours after hemorrhage with the exception of -dL/dt and TR90. Myocytes from 24-hour posthemorrhage rats exhibited a stepper negative staircase in PS with increased stimulus frequency. Cardiac expression of sarco(endo)plasmic reticulum Ca2+-ATPase 2a and phospholamban was enhanced, whereas that of Na+-Ca2+ exchanger and voltage-dependent K+ channel was decreased. IkappaB phosphorylation, HIF-1alpha, inducible NO synthase, and 3-nitrotyrosine were enhanced 12 hours after injury. CONCLUSIONS: These data demonstrated that intracerebral hemorrhage initiates cardiomyocyte contractile and intracellular Ca2+ dysregulation possibly related to altered expression of Ca2+ cycling proteins, nitrosative damage, and myocardial phosphorylation of IkappaB.

Animals↗

PubMed2006

Neurosteroid modulation of respiratory rhythm in rats during the perinatal period.

Neurosteroids regulate neuronal excitability and are expressed at particularly high levels in the CNS during the perinatal period. Further, neurosteroid levels are increased by a variety of stressors including hypoxia, asphyxia, parturition, ethanol exposure and infection. One mechanism by which neurosteroids regulate neuronal activity is by negative or positive modulation of GABA(A) receptor function. Perinatal respiration is strongly modulated by GABAergic synaptic drive, and GABA release is increased during hypoxia to contribute to hypoxia-induced depression of neonatal ventilation. Here, we use in vitro and in vivo rat models to test the hypothesis that GABA(A) receptor-mediated modulation of perinatal respiration is markedly influenced by the presence of neurosteroids. The principal finding of this study was that the efficacy of GABA(A) receptor-mediated modulation of respiratory membrane potential and rhythmogenesis is markedly enhanced by allopregnanolone and depressed by dehydroepiandrosterone sulphate. These data demonstrate that the modulation of breathing via GABA(A) receptor activation will be determined by the overall balance of negative and positive neurosteroid modulators within respiratory nuclei. This adds a level of complexity that must be considered when examining the depression of breathing in mammals associated with various behavioural states and pathogenic conditions such as apnoea and sudden death suspected to be associated with central respiratory dysfunction.

Action Potentials↗

PubMed2006

Modulation of respiratory rhythmogenesis by chloride-mediated conductances during the perinatal period.

Respiratory rhythmogenesis is modulated by chloride-mediated conductances via GABAA and glycine receptors. In this study, we determine the actions of chloride-mediated conductances on respiratory rhythmogenesis in perinatal rats from the time of inception of fetal inspiratory drive through to the newborn period. Data were obtained from perinatal rat models, including (1) recordings of nerve roots and neuronal population discharge from medullary slice and brainstem-spinal cord in vitro preparations, (2) gramicidin perforated-patch recordings of respiratory neurons in medullary slices, and (3) plethysmographic recordings from unanesthetized pups. The transition from excitatory to inhibitory effects on respiratory rhythmogenesis occurs at approximately embryonic day 19. By birth, GABA, glycine, and taurine all induce a hyperpolarization of the membrane potential in respiratory medullary neurons and a suppression of respiratory frequency. The age-dependant change in the actions of chloride-mediated conductances is regulated by the development of chloride cotransporters (KCC2 and NKCC1). The function of KCC2 chloride cotransporter is strongly modulated by [K+]o, which must be considered when evaluating responses observed using in vitro perinatal preparations.

Animals↗