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PubMed2003

[Inhibition of respiratory syncytial virus replication in cultured cells by RNA-cleaving DNAzyme].

OBJECTIVE: DNAzyme/Deoxyribozyme is another novel molecular biological tool following the ribozyme. DNAzyme consists of a 15-nucleotide (nt) internal loop as its catalytic domain and two flanking substrate-recognition domains of 7 to 8 nt each which is complementary to substrate. The RNA substrate is cleaved at a particular phosphodiester located between an unpaired purine and a paired pyrimidine residue. DNAzyme has been applied in fields such as viral infectious disease, tumor, cardiovascular disease and genetic disease. But there is no report about using DNAzyme for anti-respiratory syncytial virus purpose. To observe the inhibitory effects of RNA-cleaving DNAzymes on respiratory syncytial virus (RSV) replication in cultured cells. METHODS: Anti-RSV RNA-cleaving DNAzyme DZ604 was designed to target the RSV genome at the start of the NS2 gene in an effort to inhibit the RNA replication. Microscope and electron microscope were used to observe the effects of anti-RSV genomic RNA DNAzyme on cytopathogenic effect (CPE) and ultrastructural change of 9HTE cell induced by RSV infection. Viral plaque forming reduction assay and MTT assay were used to detect the anti-RSV activity and protective function for RSV infected 9HTE cells of DNAzyme. RESULTS: Anti-RSV genomic RNA DNAzyme (DZ604) significantly improved CPE of RSV-infected 9HTE cells. The time to appearance of CPE and of total CPE was delayed by using DZ604 in a dose-dependent manner. At a 5 micro mol/L concentration of DZ604, CPE of 9HTE cells induced by RSV infection at 10 and 1 multiplicity of infection (MOI) was not improved. At smaller MOI (0.1, 0.01, 0.001, 0.0001) of RSV infection, CPE of 9HTE cells was significantly lightened by DZ604 at the same concentration. DZ604 also significantly improved ultrastructural change of 9HTE cells at early stage of RSV infection. Reduction in RSV yield was 85.56% and 8.33% at concentrations of 5 micro mol/L and 0.25 micro mol/L of DZ604. DZ604 inhibited RSV yield in a dose-dependent manner (P < 0.05). Non-specific DNAzyme did not have anti-RSV activity (P > 0.05). CONCLUSION: Anti-RSV genomic RNA DNAzyme designed and synthesized in our laboratory was capable of inhibiting respiratory syncytial virus replication specifically in cultured cells. Our data indicated that DNAzymes could be useful for the prevention against respiratory syncytial virus infection.

Animals↗
PubMedDate not supplied

[Serological studies of the role of the respiratory syncytial virus in acute respiratory diseases in children].

The presence of the syncytial respiratory virus was determined by CF in 281 children admitted with acute respiratory diseases between 15 Sept. 1971 and 30 Dec. 1973, using the Long antigen prepared in the "St. Nicolau" Institute of Virology, Bucharest. In 38 children (13.5%) a serologic diagnosis of infection with the syncytial virus was established; in the other cases of respiratory infection of different etiology, antibodies to the syncytial virus were found in low but constant titers in both serum samples. The presence of these antibodies in a high proportion of the children points to the wide circulation of the syncytial virus in the infantile population, with all its clinico-epidemiologic implications.

Acute Disease↗
PubMed1988

Studies on the pathogenesis and interspecies transmission of respiratory syncytial virus isolated from sheep.

Inoculation of lambs with an ovine isolate of respiratory syncytial virus (RSV) by a combined intranasal and intratracheal route resulted in mild respiratory tract illness, with respiratory tract lesions. Lung lesions were characterized by bronchitis and bronchiolitis, hyperplasia of bronchial and bronchiolar epithelium, peribronchiolar and perivascular accumulations of lymphocytes, alveolar septal thickening, and collapse. Respiratory syncytial virus was recovered from the respiratory tract of inoculated lambs, and RSV antigen was demonstrated by immunoperoxidase staining of bronchiolar and alveolar epithelial cell in pneumonic lesions of lambs euthanatized on post-inoculation days 5 and 6. Other primary respiratory tract pathogens were not isolated. Clinical signs of respiratory tract illness or respiratory tract lesions did not develop in the in-contact control lamb. Inoculation of the ovine RSV isolate into calves and deer fawns resulted in infection in both species, and at necropsy, pneumonic lesions were present. A mild to moderate respiratory tract illness developed in the calves, but clinical disease was not seen in the fawns. Lung lesions in fawns were similar to those seen in lambs; lesions in calves were characterized by collapse, scattered areas of parenchymal necrosis, and bronchiolitis. Respiratory syncytial virus was reisolated from the lower respiratory tract of inoculated calves and fawns, and immunoperoxidase-positive epithelial cells were seen in pneumonic lesions. Other primary respiratory pathogens were not detected. Respiratory syncytial virus infection was not demonstrable in control animals that were in contact with inoculated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Application of a modified indirect fluorescent antibody test to the detection of antibodies to bovine respiratory syncytial virus in Ontario cattle.

A modified indirect fluorescent antibody test for the detection of serum antibodies to bovine respiratory syncytial virus was developed. The test made use of Terasaki plastic microtiter plates in which bovine respiratory syncytial virus (Saskatchewan strain) infected Georgia bovine kidney cells were grown and fixed in situ by a modified acetone fixation procedure. Evans blue dye was used as a counterstain to reduce nonspecific fluorescence. In a study of 986 field sera from a geographically broad cross-section of mature Ontario cattle, 95% of the samples were found to be positive at or above a 1:2 dilution. No seronegative regions, counties or herds were identified. When representative samples covering a range of indirect fluorescent antibody titers were further examined by a microtiter virus neutralization assay, a significant agreement was found between the two tests. Up to a fourfold decrease in titer was observed when antigen coated plates were stored at -70 degrees C for four months. The modified indirect fluorescent antibody test for bovine respiratory syncytial virus antibody detection proved to be a rapid, practical procedure for use in the diagnostic laboratory. This study confirms that bovine respiratory syncytial virus is widespread in the Ontario cattle population and that most mature cattle can be assumed to have been exposed to this virus.

Animals↗
PubMed1980

Bovine respiratory syncytial virus in Quebec: antibody prevalence and disease outbreak.

The prevalence of antibody to bovine respiratory syncytial virus in Quebec and the role of the virus in a respiratory disease outbreak was investigated. The indirect immunofluorescent, neutralization and haemagglutination inhibition techniques were used to carry out this study. Of the 1,444 adult animals examined 519 (35.9%) had antibody to bovine respiratory syncytial virus. These positive reactors were found in each agricultural region of Quebec. The highest (53.0%) and the lowest (21.8%) prevalence was observed in the sera collected by the laboratories of St. Hyacinthe and Sherbrooke. During a respiratory disease outbreak affecting 77 calves on a farm, bovine respiratory syncytial virus was shown to be associated with infectious bovine rhinotracheitis, bovine parainfluenza type 3, bovine viral diarrhea viruses and bovine adenovirus type 3 as detected by seroconversion. Of the 38 seroconverted animals 14 were seropositive to bovine respiratory syncytial virus.

Animals↗
PubMed1994

Respiratory syncytial virus infections in human beings and in cattle.

Respiratory syncytial virus (RSV) causes yearly outbreaks of respiratory disease in human beings and cattle all over the world. Most severe human respiratory syncytial virus (HRSV)-associated disease is observed in children less than 1 year of age while most severe bovine respiratory syncytial virus (BRSV)-associated disease is observed in calves less than 6 months of age. Two subgroups of HRSV have been identified. The existence of two subgroups of BRSV has been repeatedly suggested but is not yet well established. BRSV and HRSV are closely related antigenically but antigenic differences have been observed. Seasonal periodicity of RSV infection is usual with highest incidences in autumn and winter. Stress such as caused by movement, crowding and temperature changes are considered to play a role in bovine outbreaks. Human beings and cattle are the natural hosts of HRSV and BRSV, respectively. Primarily infected individuals are the most important source of RSV during outbreaks. The role of other species in the spread of HRSV and BRSV is unknown. Protective efficacy of maternally derived antibodies is considered to be incomplete. Such antibodies do not reduce shedding of virus after HRSV and BRSV infection. RSV is often transmitted by contact with nasal secretions but may also be transmitted by aerosols. Seroprevalence of HRSV and BRSV among adult human beings and cattle is over 70% and is always higher than it is among younger individuals. Both human beings and cattle of all ages may be reinfected with RSV. During BRSV reinfections, signs of respiratory tract disease and shedding of virus are seldom observed whereas these are common during HRSV reinfections. Persistent HRSV and BRSV infections in human beings and cattle have been suggested but have not so far been reported.

Adult↗
PubMed2000

Evolution of bovine respiratory syncytial virus.

Until now, the analysis of the genetic diversity of bovine respiratory syncytial virus (BRSV) has been based on small numbers of field isolates. In this report, we determined the nucleotide and deduced amino acid sequences of regions of the nucleoprotein (N protein), fusion protein (F protein), and glycoprotein (G protein) of 54 European and North American isolates and compared them with the sequences of 33 isolates of BRSV obtained from the databases, together with those of 2 human respiratory syncytial viruses and 1 ovine respiratory syncytial virus. A clustering of BRSV sequences according to geographical origin was observed. We also set out to show that a continuous evolution of the sequences of the N, G, and F proteins of BRSV has been occurring in isolates since 1967 in countries where vaccination was widely used. The exertion of a strong positive selective pressure on the mucin-like region of the G protein and on particular sites of the N and F proteins is also demonstrated. Furthermore, mutations which are located in the conserved central hydrophobic part of the ectodomain of the G protein and which result in the loss of four Cys residues and in the suppression of two disulfide bridges and an alpha helix critical to the three-dimensional structure of the G protein have been detected in some recent French BRSV isolates. This conserved central region, which is immunodominant in BRSV G protein, thus has been modified in recent isolates. This work demonstrates that the evolution of BRSV should be taken into account in the rational development of future vaccines.

Amino Acid Sequence↗
PubMed2003

Vaccine-induced immunopathology during bovine respiratory syncytial virus infection: exploring the parameters of pathogenesis.

The bovine and human respiratory syncytial viruses cause severe lower respiratory tract infections. Effective vaccines against the respiratory syncytial viruses have been lacking since vaccine failures in the 1960s and 1970s. In this report, we describe a bovine respiratory syncytial virus (bRSV) challenge model in which both classical bRSV respiratory infection and vaccine-enhanced immune pathology were reproduced. The classical, formalin-inactivated (FI) bRSV vaccine that has been associated with vaccine failure was efficient in inducing high antibody titers and reducing viral loads but also primed calves for a far more serious enhanced respiratory disease after a bRSV challenge, thereby mimicking the enhanced clinical situation in FI human RSV (hRSV)-immunized and hRSV-infected infants in the 1960s. We show that immunization with FI-bRSV mainly primes a Th2-like inflammatory response that is characterized by a significant eosinophilic influx in the bronchial alveolar lung fluid and lung tissues and high levels of immunoglobulin E serum antibodies. The current model may be useful in the evaluation of new bRSV candidate vaccines for potency and safety.

Animals↗
PubMed2003

Immunoprotective activity and safety of a respiratory syncytial virus vaccine: mucosal delivery of fusion glycoprotein with a CpG oligodeoxynucleotide adjuvant.

CpG oligodeoxynucleotides (ODN) were identified that stimulated immunoglobulin production and cell proliferation in cotton rat cells in vitro. Three of these ODN were used as a mucosal adjuvant in the noses of cotton rats immunized via this route with respiratory syncytial virus fusion (F) protein. The CpG ODN markedly increased the cotton rat humoral neutralizing-antibody response to respiratory syncytial virus. Such immunized animals had a marked reduction in the production of infectious virus after a live-virus challenge. Animals immunized with the combination of F protein and CpG developed enhanced pulmonary pathology consisting of alveolitis and interstitial pneumonitis after a live-virus challenge. Similar enhanced disease has been seen in cotton rats and children immunized with formalin-inactivated respiratory syncytial virus.

Adjuvants, Immunologic↗
PubMed2006

Respiratory syncytial virus and innate immunity: a complex interplay of exploitation and subversion.

Respiratory syncytial virus causes significant disease in infants, the elderly and select groups of immunocompromised patients. Healthy individuals are also naturally infected with respiratory syncytial virus repeatedly throughout life. Therefore, safe and effective vaccines and therapies are needed. However, a number of factors have prevented development of such antiviral interventions to date. These include a failed vaccine trial, the very young age of the primary target population (neonates), the inability of natural infection to induce long-term protective immunity, and an incomplete understanding of virus-host interactions. The identification of pattern recognition receptors has led to significant increases in our understanding of induction and regulation of innate immune responses. This review will address the impact of these findings on respiratory syncytial virus research.

Adjuvants, Immunologic↗
PubMed2005

Pathogenic potentials of glycoprotein C-negative syncytial mutants from rabbit T cells infected persistently with herpes simplex virus type 1.

Human T cell lymphotropic virus type I (HTLV-I)-transformed T cells of rabbits were infected persistently with Herpes simplex virus type 1 (HSV-1) strain KOS. These infected cells yielded syncytial mutants, either glycoprotein C (gC)-negative or -positive, which predominated over and replaced the wild-type virus in a long-term culture for 2 years. An alignment of nucleotide sequences showed multiple mutations in glycoprotein B (gB) and gC genes of these mutants, which are or may be responsible for the mutant phenotypes. One of four mutants analyzed produced extensively large syncytia and possessed point mutations within the cytoplasmic domain of gB. All four mutants possessed multiple point mutations in gC and two possessed single insertions which resulted in a frame shift, leading to the premature termination of the gC polypeptide chain. The supernatant of the 2-year culture of cells infected persistently, containing only gC-negative syncytial mutants, induced encephalitic symptoms in B/Jas inbred rabbits, when injected intravenously. One gC-negative syncytial isolate from an encephalitic lesion, together with those from the culture supernatant, were examined for pathogenic potential in vitro and in vivo. All these mutants were more cytotoxic and more susceptible to complement inactivation than the parental virus, and could infect and replicate in adrenal glands when injected intravenously into rabbits. Invasion into the central nervous system appeared to be blocked at the portal of entry, the adrenal gland, i.e., none exhibited neuroinvasive potential by itself. Syncytial gC-negative mutants could thus be pathogenic in rabbits.

Adrenal Glands↗
PubMed1998

Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta.

Villous trophoblast in the human placenta consists of a population of proliferating stem cells which differentiate and individually fuse into the syncytiotrophoblast. We studied the apoptotic cascade in this complex epithelial layer by immunohistochemical localization of Fas, FasL, Bcl-2, Mcl-1, pro-caspase-3 and caspase-3, T-cell-restricted intracellular antigen-related protein (TIAR), poly(ADP-ribose) polymerase (PARP), lamin B, topoisomerase IIalpha, and transglutaminase II in cryostat and paraffin-fixed tissue sections from normal human first-trimester and term placental villi. The relationship between the apoptotic cascade and syncytial fusion was studied by coincubation of intact villi with FITC-coupled annexin-V, to detect the phosphatidylserine flip, and propidium iodide, to detect plasma membrane permeability. The final events of the apoptotic cascade were studied by the TUNEL reaction and ultrastructural appearance of the trophoblast. The phosphatidylserine flip was identified in some of the villous cytotrophoblastic cells, but the presence of both Bcl-2 and Mcl-1 proteins presumably prevented continuation of the apoptotic cascade. The syncytiotrophoblast demonstrated heterogeneous findings, suggesting variable progression along the apoptotic cascade. In some areas Bcl-2 and Mcl-1 predominated, with preservation of the nuclear proteins PARP, lamin B, and topoisomerase IIalpha; in other areas, especially in and around syncytial sprouts, Bcl-2 and Mcl-1 were absent, accompanied by loss of nuclear proteins, presence of phosphatidylserine flip, and TUNEL positivity. These data suggest that the apoptotic cascade is initiated in the villous cytotrophoblast, which in turn promotes syncytial fusion. Donation of anti-apoptotic proteins into the syncytium, such as Bcl-2 and Mcl-1, focally inhibits further progression along this cascade. Completion of the apoptotic cascade takes place in and around syncytial sprouts, providing further evidence that these are the sites of trophoblast shedding into the maternal circulation.

Apoptosis↗
PubMed2006

Proteomic analysis of hypoxia-induced responses in the syncytialization of human placental cell line BeWo.

Syncytiotrophoblast formation is affected by a number of pathological conditions and suppressed syncytiotrophoblast formation due to hypoxia may play a role in the pathogenesis of preeclampsia. However, the molecular basis of hypoxia-inhibited trophoblast syncytialization is poorly understood. To determine the effect of hypoxia on trophoblast syncytialization, a proteomic analysis was performed in the human cytotrophoblast cell line BeWo using two-dimensional electrophoresis and MALDI-TOF-TOF-MS. Hypoxia induced marked inhibition of BeWo cell fusion and differentiation. The proteomic profiling was established under hypoxia in BeWo cell syncytialization. The results showed that twenty proteins were significantly up-or down-regulated under hypoxia, compared with cells under normoxia. In response to hypoxia, three antioxidants, peroxiredoxin 1, peroxiredoxin 2 and 1-Cys peroxiredoxin, were down-regulated, two proteins involved in glycolysis pathway (malate dehydrogenase and enolase) were up-regulated. The expression of two members of the annexin family (annexin A2 and annexin A5) increased. We also found a decreased expression of 14-3-3 tau protein in hypoxia treated cells. Proteins implied in protein degradation and folding were also identified. The expression of two cytoskeleton components (keratin 1 and beta-actin) was found to be down-regulated. In addition, galectin-3 was up-regulated. These proteins have been implicated in regulating cellular oxidative stress, glycolysis, signal transduction, protein folding and degradation, cell mobility and cytoskeletal structure formation. Western blot analysis revealed that the levels of peroxiredoxin 1 and 14-3-3 tau decreased, whereas the levels of annexin A5 and annexin A2 increased in BeWo cells under hypoxia. These findings provided new insights into the molecular mechanisms in mediating cellular response to hypoxia in trophoblast syncytialization.

Cell Fusion↗
PubMed2004

Syncytial fusion of human trophoblast depends on caspase 8.

Differentiation of human placental villous trophoblast includes syncytial fusion of cytotrophoblast forming syncytiotrophoblast. Early stages of the apoptosis cascade were described to be involved in this differentiation process. We investigated the role of the initiator caspase 8 in syncytial fusion in vitro, cultivating placental villous explants with or without caspase 8 antisense oligonucleotides or peptide inhibitors for up to 120 h. Trophoblast fusion and differentiation were assessed by confocal microscopy, immunohistochemistry and Western blot analysis. Culture with caspase 8 antisense oligonucleotides or peptide inhibitors reduced the fusion of cytotrophoblast with the syncytiotrophoblast, and resulted in multilayered cytotrophoblast. Caspase 8 expression was suppressed by antisense oligonucleotides and caspase 8 activities were reduced by peptide inhibitors. The organic anion-transporter hOAT-4 normally expressed in the cytotrophoblast and transferred into the syncytiotrophoblast by syncytial fusion was retained in the cytotrophoblast due to lack of fusion. We conclude that expression and activity of caspase 8 is a prerequisite for differentiation and syncytial fusion of cytotrophoblast cells.

Apoptosis↗
PubMed1993

Endometrial papillary syncytial change. A nonspecific alteration associated with active breakdown.

Papillary syncytial change (PSC) of endometrial epithelium, often regarded as a metaplastic change, shows syncytial to papillary aggregates of eosinophilic cells along the surface epithelium. To determine the cause and significance of PSC, 250 consecutive endometrial biopsy and curettage specimens and curettings in patients with suspected endometrial abnormalities were reviewed. Papillary syncytial change was found in 43 (17%) of the cases. Often PSC was focal, but in 12 cases it was multifocal and in 7 cases it was extensive. Patients with PSC ranged from 22 to 86 years of age. The primary pathologic findings in endometria with PSC included a variety of benign organic lesions and hyperplasia, as well as proliferative and secretory changes that suggested dysfunctional bleeding. One consistent finding in all cases was associated active endometrial bleeding with glandular and stromal breakdown, cell necrosis, and neutrophils in close proximity to PSC. Immunohistochemical study of 6 cases with extensive PSC showed no difference in reactivity to high and low molecular weight keratin, vimentin, and carcinoembryonic antigen compared with surrounding unaffected epithelium. The association of PSC with endometrial breakdown in a variety of conditions suggests that PSC is a benign retrogressive alteration rather than a metaplastic transformation to another cell type. Papillary syncytial change appears to be a useful histologic marker of acute endometrial breakdown and bleeding, and recognition of this phenomenon will prevent misclassification of this relatively common finding.

Adult↗
PubMed1998

Spatiotemporal effects of syncytial heterogeneities on cardiac far-field excitations during monophasic and biphasic shocks.

INTRODUCTION: It has recently been postulated that syncytial (anatomic) heterogeneities inherent within cardiac tissue might represent a significant mechanism underlying field-induced polarization of the bulk myocardium. This simulation study examines and characterizes the spatiotemporal excitatory dynamics associated with this newly hypothesized mechanism. METHODS AND RESULTS: Two-dimensional regions of syncytially heterogeneous cardiac tissue were simulated with active membrane kinetics. Heterogeneities were manifested via random spatial variations of intracellular volume fractions over multiple length scales. Excitation thresholds were determined for uniform rectangular monophasic (M) and symmetric biphasic (B) far-field stimuli, from which strength-duration and strength-interval relationships were constructed. For regions measuring 5.4 x 5.4 mm, baseline diastolic thresholds for longitudinal (L) and transverse (T) shocks of 5-msec total duration averaged (in V/cm, n = 10) M-L = 2.87+/-0.26, M-T = 6.71+/-0.83, B-L = 3.22+/-0.25, and B-T = 7.93+/-0.51. These thresholds decreased by 15% to 25% when the region sizes were increased to 10.8 x 10.8 mm. Strength-duration relationships correlated strongly with the Weiss-Lapicque hyperbolic relationship, with rheobases and chronaxies of 2.33 V/cm and 1.15 msec for M-L stimuli, and 2.28 V/cm and 2.04 msec for B-L stimuli. Strength-interval relationships for M-L and B-L stimuli decreased monotonically with increasing coupling intervals, with similar minimum coupling intervals at absolute refractoriness. However, the B-L thresholds were substantially less sensitive to changes in coupling intervals than their M-L counterparts. CONCLUSION: This study provides strong additional support for and understanding of the syncytial heterogeneity hypothesis and its manifested properties. Furthermore, these results predict that syncytial heterogeneities of even modest proportions could represent a significant mechanism contributing to the far-field excitation process.

Cell Membrane↗
PubMed1991

Altered pathogenesis in herpes simplex virus type 1 infection due to a syncytial mutation mapping to the carboxy terminus of glycoprotein B.

A syncytial (syn) variant of herpes simplex virus type 1 strain 17 syn+ was selected by serial passage in heparin, a glycosaminoglycan which potently inhibits herpes simplex virus infectivity. This virus, 17 hep syn, is sixfold more heparin resistant than its parent. By using marker transfer techniques, its syn phenotype, but not heparin resistance, was mapped first to the BamHI G fragment (0.343 to 0.415 map units) and then to a 670-bp KpnI-PstI subclone (0.345 to 0.351 map units) encoding the carboxy terminus of glycoprotein B (gB). Three cloned syncytial recombinants were generated from cotransfections of 17 syn+ with either 17 hep syn BamHI-G or the 670-bp subclone. After footpad inoculation of mice, 17 hep syn was as virulent as its parent, despite reaching lower titers in feet, sciatic nerves, dorsal root ganglia, spinal cords, and brains. Animals infected with 17 hep syn or the gB recombinant viruses developed a unique pattern of disease that was strikingly different than that seen with wild-type virus: severe inflammation and edema of the inoculated limb and death without antecedent paralysis. Histopathologic examination revealed limitation of spinal involvement by 17 hep syn to the dorsal aspect of the cord and decreased virus-induced damage in the central nervous system. The genetically unrelated syn variant MP, in contrast, was avirulent and did not cause severe local inflammation. After intracerebral inoculation, 17 hep syn was highly virulent and replicated to high titers in the brain. Yet, unlike the parental virus, it resulted in an altered distribution of herpes simplex virus antigens, which were limited to the ependymal and subependymal regions surrounding the lateral ventricles. Despite their syncytial phenotype and pathogenic properties, the recombinant viruses, unlike 17 hep syn, were not heparin resistant. We conclude that a transferable alteration in the 670-bp carboxy-terminal portion of the glycoprotein gB gene of 17 hep syn results in both its syncytial phenotype and the unique pattern of disease that it causes but does not result in heparin resistance. These observations provide direct biological evidence for an important role for herpes simplex virus gB in pathogenic events both at the peripheral site of infection and within the nervous system.

Animals↗
PubMed1992

Beta-adrenergic modulation of fast inward sodium current in canine myocardium. Syncytial preparations versus isolated myocytes.

Reports have suggested that the fast inward sodium current (INa) in cardiac tissues may be modulated by beta-adrenergic stimulation and that such modulation may affect conduction in the setting of myocardial ischemia and infarction. However, many of these studies have used dissociated myocytes or broken cell preparations, whose responses need not necessarily reflect those of syncytial preparations. To investigate further the possibility that beta-adrenergic stimulation of INa may differ in various preparations, we compared the effects of the beta-agonist isoproterenol (ISO) on syncytial canine Purkinje fibers and ventricular muscle preparations, as well as isolated ventricular myocytes. Alterations of the maximum rate of rise of the action potential upstroke (Vmax) were used as an index of changes of INa. ISO (1 microM) had no effect on Vmax of upstrokes of normally polarized (fast responses) or partially depolarized (elevated [K+]o, depressed fast responses) syncytial ventricular muscle preparations or Purkinje fibers. In contrast, lower concentrations of ISO (0.5-1.0 microM) modulated Vmax of isolated ventricular myocytes, depending on the technique used to monitor transmembrane potential. When 2.7 M KCl-filled microelectrodes were used, ISO reduced Vmax of partially depolarized myocytes without affecting Vmax of normally polarized myocytes. However, when myocytes were dialyzed using patch pipettes, ISO reduced Vmax of partially depolarized myocytes and increased Vmax of normally polarized myocytes, effecting a hyperpolarized shift of the normalized inactivation curve relating Vmax to resting membrane potential. The different beta-adrenergic responses of syncytial preparations and nondialyzed and dialyzed myocytes suggest that differences in the ionic or metabolic condition of the preparations likely alter cAMP-dependent responses and channel phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗