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PubMed2004

Caspase inhibition after neonatal ischemia in the rat brain.

Caspase-3 has been identified as a key protease in the execution of apoptosis and appears to be an important downstream event after hypoxia-ischemia in the immature brain. The efficacy of a pan-caspase inhibitor, boc-aspartyl-(Ome)-fluoromethyl-ketone (BAF), was tested in a model of unilateral focal ischemia with reperfusion in 7-day-old rats. The BAF inhibitor was given intraperitoneally 5 minutes before reperfusion via the carotid artery. This procedure reduced the activity of caspase-3 by 79% but did not induce a significant reduction in infarct volume (23.8 +/- 7.5% versus 30.1 +/- 6.4%). Animals were distributed in two populations. One population exhibited an infarct, whereas the other appeared to be fully protected. BAF-treated animals exhibiting an infarct mostly displayed necrotic cell death, whereas apoptotic nuclei were observed in untreated or vehicle-treated animals. Repeated dose of BAF (5 minutes before and 9 hours after reperfusion) did not also provide benefit after neonatal ischemia, although a general trend to reduce lesion was observed (20.5 +/- 3.7% versus 34.4 +/- 5.9%). These findings raise critical questions about the use of peptide ketone apoptotic inhibitors in improving histopathologic outcomes after neonatal stroke.

Amino Acid Chloromethyl Ketones↗

PubMed2000

Effects of reduced vesicular filling on synaptic transmission in rat hippocampal neurones.

The consequence of reduced uptake of neurotransmitters into synaptic vesicles on synaptic transmission was examined in rat hippocampal slices and culture using bafilomycin A1 (Baf), a potent and specific blocker of the vacuolar-type (V-type) ATPase, which eliminates the driving force for the uptake of both glutamate and GABA into synaptic vesicles. After incubation with Baf, both the amplitude and frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were reduced in the slice preparation. Similar effects were seen with glutamatergic miniature excitatory postsynaptic currents (mEPSCs) and GABAergic mIPSCs from cultured neurons. This result indicates that vesicular content is reduced by Baf. The dramatic reduction in the frequency of mPSCs could result either from the exocytosis of empty vesicles or from a mechanism which prevents the exocytosis of depleted vesicles. Vesicle cycling was directly examined using confocal imaging with FM 1-43. In the presence of Baf, vesicles could still be endocytosed and they were released at the same probability as from control untreated synapses. Prolonged high-frequency electrical stimulation of synapses in culture failed to alter the amplitude of mEPSCs, suggesting that the filling of vesicles is rapid compared to the rate of vesicle recycling during repetitive synaptic stimulation. Profound release of glutamate with alpha-latrotoxin did cause a small, but reproducible, reduction in quantal size. These results indicate that decreasing the amount of glutamate and GABA in synaptic vesicles reduces quantal size. Furthermore, the probability of vesicle exocytosis appears to be entirely independent of the state of filling of the vesicle. However, even during high-frequency action potential-evoked release of glutamate, quantal size remained unchanged.

Animals↗

PubMed2000

A specificity and targeting subunit of a human SWI/SNF family-related chromatin-remodeling complex.

The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. This family includes BAF (also called hSWI/SNF-A) and PBAF (hSWI/SNF-B) from humans and SWI/SNF and Rsc from Saccharomyces cerevisiae. However, the relationship between the human and yeast complexes is unclear because all human subunits published to date are similar to those of both yeast SWI/SNF and Rsc. Also, the two human complexes have many identical subunits, making it difficult to distinguish their structures or functions. Here we describe the cloning and characterization of BAF250, a subunit present in human BAF but not PBAF. BAF250 contains structural motifs conserved in yeast SWI1 but not in any Rsc components, suggesting that BAF is related to SWI/SNF. BAF250 is also a homolog of the Drosophila melanogaster Osa protein, which has been shown to interact with a SWI/SNF-like complex in flies. BAF250 possesses at least two conserved domains that could be important for its function. First, it has an AT-rich DNA interaction-type DNA-binding domain, which can specifically bind a DNA sequence known to be recognized by a SWI/SNF family-related complex at the beta-globin locus. Second, BAF250 stimulates glucocorticoid receptor-dependent transcriptional activation, and the stimulation is sharply reduced when the C-terminal region of BAF250 is deleted. This region of BAF250 is capable of interacting directly with the glucocorticoid receptor in vitro. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.

Amino Acid Sequence↗

PubMed1994

Luminal acidification in K-replete OMCDi: contributions of H-K-ATPase and bafilomycin-A1-sensitive H-ATPase.

We have previously demonstrated that basolateral addition of the gastric H-K-adenosinetriphosphatase (H-K-ATPase) inhibitor Sch-28080 (10 microM) profoundly reduced net total CO2 flux (JtCO2) in the inner stripe of the outer medullary collecting duct (OMCDi) of K-replete rabbits. In the present studies, we first addressed whether the inhibitory effect of Sch-28080 is dependent on the side of the membrane to which it is added. Second, we reassessed the relative magnitude of contribution of H-K-ATPase. Third, we formally tested whether a bafilomycin-A1 (BAF)-sensitive H-ATPase also contributes to luminal acidification in the OMCDi under K-replete dietary conditions. We found that luminal addition of the structurally and functionally dissimilar gastric H-K-ATPase inhibitor A80915A (10 microM) profoundly reduced JtCO2 while transepithelial voltage (VT) was unchanged. This degree of inhibition was statistically indistinguishable from our previous results when Sch-28080 was applied basolaterally. Inhibition of JtCO2 by the less membrane-permeable N-methyl cation of Sch-28080, H224/25, was significant when applied luminally but was not significant when applied basolaterally. VT was not significantly affected by either the luminal or basolateral addition of H224/25. To evaluate the possible contribution of an H-ATPase, the effect of both 5.0 nM and 10.0 nM luminal BAF on JtCO2 and VT was examined. At 5.0 nM, BAF significantly inhibited JtCO2). However, this observation was significantly less (P < 0.05) than the inhibition observed with 10 microM A80915A. No additional inhibition was observed by increasing the concentration of BAF to 10.0 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗

PubMed1995

Luminal acidification in K-replete OMCDi: inhibition of bicarbonate absorption by K removal and luminal Ba.

We have previously demonstrated that significant luminal acidification in the K-replete rabbit inner stripe of the outer medullary collecting duct (OMCDi) occurs via a renal H-K-adenosinetriphosphatase (H-K-ATPase) sensitive to several of the gastric H-K-ATPase inhibitors. To investigate further the mechanism of K-dependent luminal acidification in K-replete OMCDi, we examined the effects of luminal K removal, luminal addition of Ba in the presence and absence of luminal 5.0 nM bafilomycin A1 (BAF), and basolateral addition of Ba on net bicarbonate flux (JtCO2, pmol.mm-1.min-1) and transepithelial voltage (VT, mV). Removal of K from the perfusate inhibited JtCO2 by 74% (13.4 +/- 4.0 for control, 3.5 +/- 1.4 pmol.mm-1.min-1 for experimental, P < 0.05) and was statistically equivalent to the degree of inhibition previously observed under identical experimental conditions by either 10 microM Sch-28080 or 10 microM A-80915A. Approximately 50% inhibition of JtCO2 was observed following luminal application of 2.0 mM Ba2+, and the degree of inhibition was statistically equivalent regardless of whether BAF was present (12.2 +/- 2.7 for control, 6.0 +/- 1.4 pmol.mm-1.min-1 for 2.0 mM Ba2+, P < 0.05; 9.6 +/- 1.2 for control with 5 nM BAF, 5.7 +/- 1.3 pmol.mm-1.min-1 for 2.0 mM Ba2+ with 5 nM BAF, P < 0.05). Additionally, increasing the luminal concentration of Ba2+ from 2.0 to 4.0 mM resulted in no further inhibition of JtCO2 (8.5 +/- 1.7 for control, 3.9 +/- 1.3 pmol.mm-1.min-1 for 4.0 mM Ba2+, P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed2002

Interactions between GSK3beta and caspase signalling pathways during NGF deprivation induced cell death.

Withdrawal of NGF (NGF-W) in PC12 cells leads to caspase and GSK3beta activation which results in cell death. Our recent findings suggest that inhibition of GSK3beta promotes PC12 cell survival after NGF-W. To determine whether these pathways interact from a signalling perspective, we compared the effects of BAF (a general caspase inhibitor), Li+ (a GSK3beta inhibitor) and insulin on NGF-W induced PC12 cell death. Maximal increase in DNA fragmentation was observed 3 h after NGF-W and was inhibited by BAF (7.5 microM), Li+ (IC(50) = 2 mM) and insulin (IC(50) = 100 nM). BAF inhibited caspase-3 activity and delayed cell death up to 6 h after NGF-W indicating that caspase inhibition is sufficient to prevent apoptosis. BAF had no major effect on GSK3betaactive site phosphorylation or activity suggesting the caspase pathway does not regulate GSK3beta activity. Conversely, Li+ inhibited caspase activity by only 20% but promoted cell survival for 24 h after NGF-W. Overexpression of dominant negative mutants of GSK3beta also inhibited apoptosis, but had only a minor effect on caspase activity after NGF-W. Taken together, these results suggest that GSK3beta is upstream of caspase signalling, and exerts a small effect on the caspase pathway.

Animals↗

PubMed2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma.

PURPOSE: SWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. EXPERIMENTAL DESIGN: We performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. RESULTS: Approximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A -mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. CONCLUSIONS: BAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

Journal Article↗

PubMed2001

Simultaneous nitrification and denitrification in biofilters with real time aeration control.

The aim of this article is to present a new biological aerated filter (BAF) for nitrogen removal based on simultaneous nitrification and denitrification. Contrary to the systems which integrate both an aerated and a non-aerated zone to allow complete nitrogen removal in one compact or two different units (pre-denitrification and nitrification), this upflow BAF system is based on the principle of simultaneous nitrification and denitrification since the filter is completely aerated. The denitrification process is possible due to the diffusion effect which dominates biofilm processes. The real time aeration control allows us to maintain a low dissolved oxygen value (0.5 to 3 mg O2/l). In this case, the biofilm will not be fully (or less) penetrated with oxygen and denitrification will be carried out in a large part of the biofilm. Therefore, nitrification and denitrification is running simultaneously in different depths of the biofilm. By using 50% less air this BAF gave the same results (less than 20 mg TN/l) on pilot plant as a classical nitrification and denitrification BAF (Toettrup et al., 1994). Less recirculation was necessary to achieve the same denitrification.

Biofilms↗

PubMed2003

Factors influencing the design of bioaccumulation factor and biota-sediment accumulation factor field studies.

A series of modeling simulations was performed to evaluate the underlying factors and principles that drive the uncertainty in measured bioaccumulation factors (BAFs) and biota-sediment accumulation factors (BSAFs) for fish, and to determine which sampling designs minimize those uncertainties. Temporal variability of chemical concentrations in the water column, and the metabolism rate and n-octanol-water partition coefficient (Kow) for the chemical were determined to be the dominant factors that influenced the field-sampling design. Spatial variability of the chemical concentrations, food web structure, and the sediment-water column concentration quotient had a lesser importance upon the overall design. The simulations also demonstrated that collection of composite water samples in comparison to grab water samples resulted in reductions in the uncertainties associated with measured BAFs. Some illustrative sampling design structures for BAF and BSAF measurements based upon the temporal variability of chemical concentrations in the water column and the metabolism rate and Kow for the chemical were developed. These illustrative designs provided a sense of how sampling design structures, that is, the number and spacing over time of sampling events, might be influenced by differences in temporal variabilities, metabolism rates, and Kow. Although the importance of spatial variability was discounted as a major factor in the design process, sampling of water and sediment across the immediate home range of the sampled organism is required for successful measurements because poor spatial coordination of organism, water, or sediment samples will yield BAFs and BSAFs with large and unknown biases.

Animals↗

PubMed2003

A simulation study of methods for constructing confidence intervals for bioaccumulation factors.

Toxicokinetics describe the time course of xenobiotics in an exposed organism. The steady state concentration of the xenobiotic is a characteristic of frequent concern, often summarized in terms of bioaccumulation factors (BAFs). Two experimental protocols are commonly used when estimating BAFs: a continuous exposure experiment and a start-stop exposure experiment. Nonlinear regression is then used for estimating components of the BAF. A variety of methods are available for constructing confidence intervals (CI) for the BAF, including the delta method and Fieller's method. The properties of these CI methods are explored through a simulation study. In particular, the coverage properties of the two CI methods along with their interval widths are examined for a variety of time-course patterns, error distributions, experimental protocols, and sampling designs. Fieller's method is observed to exceed nominal coverage probabilities for all conditions considered (the coverage probability being the probability that a confidence interval contains a parameter it estimates over repeated experiments). The delta method exhibited observed coverage probabilities lower than nominally specified for a number of conditions. For sampling designs in which more of the sampling times are prior to steady state or the stop exposure time, the delta method is observed to provide nominal coverage probabilities with interval widths much narrower than observed with the Fieller's method. Thus, the delta method is preferable when the above sampling time condition is met; however, in all other cases, Fieller's method should be used.

Animals↗

PubMed1996

Inhibition of the vacuolar H(+)-ATPase with bafilomycin reduces delivery of internalized molecules from mature multivesicular endosomes to lysosomes in HEp-2 cells.

In the human carcinoma cell line HEp-2, endosomes are multivesicular bodies (MVBs) which gradually mature and eventually fuse with other mature endosomes and/or with preexisting lysosomes. Selective inhibition of the vacuolar H(+)-ATPase with bafilomycin A1 (Baf) did not influence endocytic uptake and recycling of the protein toxin ricin. Moreover, quantification of immunogold labeling on ultracryosections revealed that the frequency by which MVBs containing internalized cationized gold (Cat.Au) also labeled for the cation-independent mannose-phosphate receptor (MPR) was the same with and without Baf, suggesting that formation and maturation of MVBs were unchanged in the presence of Baf. However, degradation of ricin was strongly reduced by bafilomycin, and this reduction was not only due to increased pH in lysosomes. Thus, quantitative lmmunogold labeling showed that the Baf-induced alkalinization reduced the transfer of internalized Cat.Au to lysosomes, as defined by their content of human lysosome-associated membrane protein 1 (h-lamp-1) and cathepsin D. Accordingly, although low vacuolar pH does not seem to be required for transport to MPR-containing endosomes, it seems to be important for a late fusion step along the endocytic pathway.

Anti-Bacterial Agents↗

PubMed1997

The EBV IL-10 homologue is a selective agonist with impaired binding to the IL-10 receptor.

BCRF1 is an EBV homologue of human IL-10 (hIL-10) and is known as viral IL-10 (vIL-10). As found earlier for the effects of vIL-10 on mouse mast cells and CD4+ T cells, the efficiency of inhibition by vIL-10 of IL-2 production by human CD4+ T cell clones is approximately 1000-fold diminished compared with hIL-10. We studied the interaction of vIL-10 and an epitope-tagged homologue, vIL-10His6, with recombinant mouse and human IL-10 receptors (mIL-10R, hIL-10R). vIL-10His6 has approximately 1000-fold lower affinity for recombinant IL-10R than does hIL-10, yet stimulates proliferation of mouse Ba/F3 (BaF)-mIL-10R- and human TF1-hIL-10R-transfected cells with a sp. act. comparable to or greater than that of the cellular cytokine. In contrast, BaF-hIL-10R cells are approximately 1000-fold less sensitive to vIL-10His6 than are BaF-mIL-10R cells. An anti-hIL-10R mAb (3F9) blocks responses to both hIL-10 and vIL-10His6, while a soluble form of hIL-10R effectively neutralizes biologic responses only to hIL-10 by both BaF-IL-10R transfectants and normal human peripheral blood cells. The results indicate that biologic responses to both hIL-10 and vIL-10 require the known IL-10R, and suggest the existence of at least one additional IL-10R subunit. We suggest that vIL-10 is a selective agonist that is impaired in its ability to bind the defined IL-10R, which we now designate as IL-10R alpha.

Animals↗

PubMed1993

Association of p56lck with IL-2 receptor beta chain is critical for the IL-2-induced activation of p56lck.

Previous studies demonstrate that p56lck, a member of the src-family of protein tyrosine kinases (PTKs), can physically associate with the interleukin-2 (IL-2) receptor beta chain (IL-2R beta) and that IL-2 receptor engagement stimulates p56lck activity. To examine the mechanisms underlying p56lck PTK activation by IL-2, we established a mouse pro-B cell line, BAF-B03, expressing both IL-2R beta (either the wild-type or mutant forms) and mouse p56lck at high levels. BAF-B03 cells expressing a mutant IL-2R beta chain lacking an 'acidic' region of the cytoplasmic domain, previously shown to be essential for association with p56lck, fail to induce p56lck PTK activation upon IL-2 stimulation. This suggests that the association of p56lck with the IL-2R beta chain, despite its low stoichiometry, is required for the activation of cellular p56lck PTK upon IL-2 stimulation. Intriguingly, BAF-B03 cells expressing an IL-2R beta chain which lacks a different cytoplasmic region, the 'serine-rich' region, also fail to activate p56lck in response to IL-2. Hence, physical association of p56lck with the IL-2R beta chain is not by itself sufficient to permit IL-2-mediated regulation of this PTK. Additional experiments suggest that one result of PTK activation is the accumulation of c-fos and c-jun transcripts.

Animals↗

PubMed2000

A novel protein MAJN binds to Jak3 and inhibits apoptosis induced by IL-2 deprival.

To find a possible signal interacting with the Jak3 N-terminal, we screened the human peripheral blood cDNA library through both a two-hybrid system and a tyrosine-phosphorylation-modified two-hybrid system using the N-terminal of Jak3 as bait. Results showed that one new homologue of myosin heavy chain, designated MAJN (molecule associated with Jak3 N-terminal), could bind to Jak3 in a tyrosine-phosphorylation-independent manner. The interaction between Jak3 and MAJN was further confirmed by immunoprecipitation in BAF-B03 beta cells. To investigate the function of MAJN, we have constructed the BAF-B03 beta/MAJN cell line that stably expresses MAJN and found that overexpression of MAJN can partially inhibit the apoptosis induced by interleukin-2 deprival. Further studies are needed to elucidate how MAJN executes its function to antagonize BAF-B03beta cell death in the absence of IL-2.

Apoptosis↗

PubMed2002

Bioavailability of sediment-associated benzo(a)pyrene within single- versus multiple-species systems.

A series of experiments were conducted with benzo(a)pyrene (B(a)P) spiked sediments to determine if bioavailability of sediment-associated contaminants is affected by multiple species interactions. Three benthic invertebrates, Hyalella azteca, Chironomus tentans, and Lumbriculus variegatus, were exposed to sediments spiked with radiolabeled B(a)P that was aged for 60 days. Organisms were introduced into the spiked sediments in single, binary, and ternary combinations. Changes in bioavailability were then determined for each species by estimating uptake clearance coefficients (ks) and bioaccumulation factors (BAFs) during 7-day exposures. In general, there was a trend toward lower ks values in binary and ternary exposures compared to the single-species systems. In contrast, BAF estimates were more variable with fewer significant differences noted among treatments. BAF estimates were highest for L. variegatus followed by C. tentans and H. azetca and appear to be dependent on specific feeding and habitat requirements as well as the relative biotransformation/elimination potential of each species. Overall, these results suggest that animal-animal interactions may be important to consider when estimating bioavailability of sediment-bound chemicals.

Animals↗

PubMed2002

Synthetic musks in the environment. Part 1: Species-dependent bioaccumulation of polycyclic and nitro musk fragrances in freshwater fish and mussels.

Bioaccumulation of polycyclic musks (HHCB, AHTN) and nitro musks (musk xylene, musk ketone, and their amino metabolites) in aquatic biota was investigated by analyzing 18 fish samples (rudd, tench, crucian carp, eel) and 1 pooled zebra mussel sample from the pond of a municipal sewage treatment plant. Furthermore, water samples taken at the effluent of the sewage plant as well as water samples and two series of semipermeable membrane devices (SPMDs) from the pond were included. This comprehensive data set allowed the determination of species-dependent bioaccumulation factors on a lipid basis (BAF(L)), e.g., for HHCB the BAF(L) in tench were more than 20 times higher than in eel. The BAF(L) for HHCB and AHTN in biota were lower than the partition coefficients K(SPMD/W) obtained from SPMD samples, which are assumed to represent model bioconcentration values. This stresses that metabolism of these compounds in fish must not be neglected.

Animals↗

PubMed1998

Influence of Dispersants on the Bioavailability of Naphthalene from the Water-Accommodated Fraction Crude Oil to the Golden-Brown Algae, Isochrysis galbana

The golden-brown algae Isochrysis galbana, a primary producer, was used to determine the influence of the chemical dispersing agent, Corexit 9527((R)), on the bioavailability of naphthalene. Cells were exposed to laboratory preparations of either the water-accommodated fraction (WAF) of Prudhoe Bay crude oil (PBCO) or a dispersed oil (DO) mixture of PBCO and Corexit 9527 spiked with [U-14C]naphthalene. Uptake was determined by the amount of algae-associated [14C]. High-pressure liquid chromatography (HPLC) co-chromatography was used to fractionate and identify metabolic products. A 24-h bioaccumulation factor (BAF) was calculated in the absence of steady state. The presence of Corexit 9527, had significant influence (p = 0.001) on the uptake of naphthalene, but no significant effect on the 24-h BAF (BAF: 168 and 180 from WAF and DO, respectively), or metabolic fate of naphthalene in I. galbana. Results of this research indicate that dispersants have the potential to increase organismal exposure to certain petroleum hydrocarbons without increasing their aqueous concentration.

Journal Article↗

PubMed2006

Mechanisms of atrial tachyarrhythmia induction in a canine model of autonomic tone fluctuation.

BACKGROUND: The purpose of this study was to investigate the effect of cholinergic modulation in the presence of increased adrenergic tone (i. e., autonomic fluctuation) on atrial tachyarrhythmia (AT) induction. METHODS AND RESULTS: High-resolution optical mapping was used to measure action potentials from the left atrium in isolated arterially perfused canine atrial preparations. Optical recordings were made in the presence of isoproterenol during electrical stimulation of a fat pad at the right pulmonary veinatrial junction (Group I, n = 6), during electrical stimulation of a fat pad locating the superior vena cava contacted by the right pulmonary artery (Group II, n = 4), and during acetylcholine (ACh; Group III, n = 4) infusion. In the presence of isoproterenol,each of the three different transitory cholinergic interventions induced spontaneous AT in all preparations. In Group I, AT induced from the right atrium was sustained. However, AT induced from the left atrium was not sustained (RRB) in Group I. In Groups II and III, AT induced from the left atrium as well as the right atrium were also sustained (BAF-AT). The A1A2 coupling interval was shorter when BAF-AT was induced than it was when RRB was induced. Mean cycle length of repetitive focal excitation was shorter during the initiation of BAF-AT compared to RRB. Isochrone maps during the initiation of AT demonstrated a macroreentry with lines of conduction block following a single extrasystole (27 %) and focal repetitive excitation (73 %). CONCLUSIONS: These results suggest that transitory cholinergic activation in the presence of increased adrenergic drive in the left atrium causes a single premature extrasystole with a short coupling interval and a focal repetitive excitation with a short cycle length, which favors the generation of AT originating from the left atrium.

Adrenergic Fibers↗