Linoleic acid salt with ultrapure soft water as an antibacterial combination against dermato-pathogenic Staphylococcus spp.

AIMS: Skin colonization of Staphylococcus spp. critically affects the severity of dermatitis in humans and animals. We examined different types of fatty acid salts for their antibacterial activity against Staphylococcus spp. when used in ultrapure soft water (UPSW). We also evaluated their therapeutic effect on a spontaneous canine model of dermatitis. METHODS AND RESULTS: UPSW, in which Ca(++) and Mg(++) were replaced with Na(+) , was generated using a water softener with cation-exchange resin. Staphylococcus aureus (Staph. aureus), Staphylococcus intermedius (Staph. intermedius), and Staphylococcus pseudintermedius (Staph. pseudintermedius) were incubated with various fatty acid salts in distilled water (DW) or UPSW and the number of bacteria was counted. Among the fatty acids, oleic acid salt and linoleic acid (LA) salt reduced the number of these bacteria. Also, UPSW enhanced the antibacterial effect of LA on Staph. spp. In spontaneously developed itchy dermatitis in companion dogs, shampoo treatment with liquid soap containing 10% LA in UPSW improved skin conditions. CONCLUSIONS: LA salt showed antibacterial activity against Staph. spp. Treatment with soap containing LA with UPSW reduced clinical conditions in dogs with dermatitis. SIGNIFICANCE AND IMPACT OF THE STUDY: Because colonization of Staph. spp. on the skin exacerbates dermatitis, the use of LA-containing soap in UPSW may reduce unpleasant clinical symptoms of the skin.

Induction of inner ear hair cell-like cells from Math1-transfected mouse ES cells.

Math1, a basic helix-loop-helix transcription factor homolog of the Drosophila atonal gene, is considered to be a key factor for induction of sensory hair cells (HCs) during development of the organ of Corti or cochlea. Although embryonic stem (ES) cells are able to produce HC-like cells, the role of Math1 in induction of those cells has not been thoroughly elucidated. In the present study, we introduced Math1 into ES cells in order to achieve efficient generation of HC-like cells. ES cells carrying Tet-inducible Math1, Math1-ES cells, were generated using a Tet-On gene expression system. Embryoid bodies (EBs) formed in the absence of doxycycline (Dox) for 4 days were allowed to grow for an additional 14 days in the dishes in the presence of 400 µg/ml of Dox. At the end of those 14-day cultures, approximately 10% of the cells in EB outgrowths expressed the HC-related markers myosin6, myosin7a, calretinin, α9AchR, and Brn3c (also known as Pou4f3) and showed formation of stereocilia-like structures, whereas few cells in EB outgrowths grown without Dox showed those markers. Reporter assays of Math1-ES cells using a Brn3c-promoter plasmid demonstrated positive regulation of Brn3c by Math1. Furthermore, such HC-related marker-positive cells derived from Math1-ES cells were found to be incorporated in the developing inner ear after transplantation into chick embryos. Math1-ES cells are considered to be an efficient source of ES-derived HC-like cells, and Math1 may be an important factor for induction of HC-like cells from differentiating ES cells.

Antifungal effects of palmitic acid salt and ultrapure soft water on Scedosporium apiospermum.

AIMS: Scedosporium apiospermum sometimes causes serious infectious diseases on the skin of immunodeficient subjects. Antifungal effects of fatty acid salts in soap against S. apiospermum were investigated under different water conditions. METHODS AND RESULTS: Ultrapure soft water (UPSW) was generated by the water softener with cation-exchange resin. The calcium and magnesium ions were replaced with sodium ions in UPSW. Scedosporium apiospermum was incubated with different fatty acid salts that constituted soap in distilled water (DW), tap water (TW) and UPSW. After incubation, the number of fungi was counted. Among the fatty acids, palmitic acid salt (C16) reduced the number of S. apiospermum. UPSW enhanced the antifungal effect of C16 on S. apiospermum. The absence of both calcium and magnesium ions and the existence of sodium chloride in UPSW were responsible for its antifungal effect. In addition, repeated short-term treatment with UPSW and C16 decreased the number of S. apiospermum. CONCLUSIONS: Antifungal effects of C16 on S. apiospermum were demonstrated. Moreover, the use of UPSW promoted the antifungal effect of C16. SIGNIFICANCE AND IMPACT OF STUDY: This study provides the preventive method for diseases associated with S. apiospermum infection using novel palmitic acid soap in UPSW.

In vitro differentiation of mouse embryonic stem cells into inner ear hair cell-like cells using stromal cell conditioned medium.

Hearing loss is mainly caused by loss of sensory hair cells (HCs) in the organ of Corti or cochlea. Although embryonic stem (ES) cells are a promising source for cell therapy, little is known about the efficient generation of HC-like cells from ES cells. In the present study, we developed a single-medium culture method for growing embryoid bodies (EBs), in which conditioned medium (CM) from cultures of ST2 stromal cells (ST2-CM) was used for 14-day cultures of 4-day EBs. At the end of the 14-day cultures, up to 20% of the cells in EB outgrowths expressed HC-related markers, including Math1 (also known as Atoh1), myosin6, myosin7a, calretinin, α9AchR and Brn3c (also known as Pou4f3), and also showed formation of stereocilia-like structures. Further, we found that these cells were incorporated into the developing inner ear after transplantation into chick embryos. The present inner ear HC induction method using ST2-CM (HIST2 method) is quite simple and highly efficient to obtain ES-derived HC-like cells with a relatively short cultivation time.

Activation of caspases in intestinal villus epithelial cells of normal and nematode infected rats.

BACKGROUND: Small intestinal epithelial cells (IEC) show apoptosis in physiological turnover of cells and in certain inflammatory diseases. AIMS: To investigate the role of caspases in the progression of IEC apoptosis in vivo. METHODS: IEC were separated along the villus-crypt axis from the jejunum of normal and Nippostrongylus brasiliensis infected rats at 4 degrees C. Caspases were examined by a fluorometric assay method, histochemistry, and immunoblotting. RESULTS: Villus cell rich IEC from normal rats exhibited a high level of caspase-3-like activity whereas activities of caspase-1, -8, and -9 were negligible. Immunoblotting analysis of villus cell rich IEC revealed partial cleavage of procaspase-3 into a 17 kDa molecule as well as cleavage of a caspase-3 substrate, poly(ADP-ribose) polymerase (PARP), whereas in crypt cell rich IEC, caspase-3 cleavage was less significant. Caspase-3 activity was also observed histochemically in villus epithelium on frozen sections of the normal small intestine. IEC prepared at 4 degrees C did not reveal nuclear degradation whereas subsequent incubation in a suspension at 37 degrees C induced intense nuclear degradation within one hour in accordance with increases in active caspase-3. This apoptosis was partially suppressed by the caspase inhibitor Z-VAD-fmk. Nematode infected animals showed villus atrophy together with significant increases in levels of caspase-3 in IEC but not of caspase-1, -8, or -9. CONCLUSION: Caspase-3 may have an important role in the physiological replacement of IEC as well as in progression of IEC apoptosis induced by nematode infection.

Octa(mu3-selenido)hexarhenium(III) complexes containing axial monodentate diphosphine or diphosphine-monoxide ligands.

A series of the octahedral hexarhenium(III) complexes containing a variable number of diphosphine (diphos) or diphosphine-monoxide (diphosO) ligands have been prepared by the substitution of the diphosphine Ph2P(CH2)nPPh2 (n = 1 to 5) for the iodide ions in the parent octahedral hexarhenium cluster compound [Re6Se8I6]3-. The diphosphine Ph2P-(CH2)nPPh2 ligands adopt an eta1-bonding mode with the Re6(mu3-Se)8 core, and the P donor atom in the pendant arm is noncoordinated and oxygenated in most cases. The series of new hexarhenium(III) complexes have been well-defined by 1H, 13C, and 31P NMR spectroscopic and FAB-MS data. Four compounds among the series were characterized by X-ray structural determination. Geometrical isomers were identified by NMR spectroscopy as well as by the structural determinations. The apical ligand substitution induces significant change in the redox potentials and the photophysical properties of the Re6(mu3-Se), core. The E1/2 value of the reversible process ReIII6/ReIII5ReIV becomes more positive with the increasing number of the coordinated P donors. The phosphine-substituted hexarhenium(III) derivatives are highly luminescent, with microsecond scale emissive lifetime at ambient temperature, and the fully substituted derivatives with the formula [Re6Se8-(eta1-diphosO)6]2+ display the strongest luminescence with the longest emission lifetimes.

Time-resolved total internal reflection fluorometry study on polarity at a liquid/liquid interface.

The polarity of a water/oil (oil: cyclohexane, carbon tetrachloride, toluene, chlorobenzene, o-dichlorobenzene, or 1,2-dichloroethane) interface was investigated by means of time-resolved total-internal-reflection (TIR) fluorescence spectroscopy of a polarity-sensitive probe: sulforhodamine B (SRB). In bulk solutions, the nonradiative decay rate constant of SRB increased with an increase in a solvent polarity parameter [ET(30)], and this relationship was used to estimate the polarities of water/oil interfaces. For the oil having a relatively low solvent polarity [ET(30) < 35 kcal/mol], the polarity of the water/ oil interface agreed with that of the arithmetic average of the polarities of the two phases [ET(30)calc]. For water/odichlorobenzene and water/1,2-dichloroethane interfaces [ET(30) of the oil > 35 kcal/mol], on the other hand, the interfacial polarity determined by TIR spectroscopy was lower than the ET(30)calc. The results are discussed in terms of thickness/roughness of the water/oil interface.

Implantation of xenografts into the parkinsonian rat brain after portal venous administration of xenogeneic donor spleen cells.

OBJECT: The purpose of the present study was to examine the effect of pretransplantation portal venous immunization with ultraviolet B (UVB)-treated donor spleen cells on neural xenograft transplantation. METHODS: Cells from a murine catecholaminergic cell line derived from the B6/D2 F1 mouse, CATH.a, were used as a xenograft. Thirty hemiparkinsonian rats were divided into three different treatment groups. Group 1 received saline in the dopamine-denervated striatum; Group 2 received xenograft cells; and Group 3 received portal venous administration of UVB-irradiated B6/D2 F1 splenocytes 7 days before receiving xenograft cells. Xenograft function was determined by reviewing apomorphine-induced rotation at 2-week intervals, and xenograft survival was examined at 4 and 12 weeks after transplantation by immunohistochemical staining for murine tyrosine hydroxylase (THase). Rotational behavior was improved in both xenograft-transplanted groups (Groups 2 and 3); however, the animals in Group 3 displayed a significantly reduced rotational behavior compared with Group 2. In Group 2, many inflammatory cells and a few THase-positive cells were found at the graft sites 4 weeks after transplantation. In Group 3, however, a large number of THase-positive cells were found with few inflammatory cells. The THase-positive cells disappeared in the Group 2 rats at 12 weeks, but remained in Group 3 animals. In Group 3 rats proliferation of spleen cells in a mixed lymphocyte reaction was suppressed in a donor-specific fashion. CONCLUSIONS: This work demonstrates improved neural xenograft survival and function by pretransplantation portal venous immunization with UVB-irradiated xenogeneic donor splenocytes. On the basis of these findings, the authors suggest the possibility of creating donor-specific immunological tolerance in the brain by administration of xenogeneic donor lymphocytes via the portal vein.

Effect of tetra-peptide isolated from interleukin 1 (IL-1) on corneal epithelial wound healing in the rabbit.

To develop a new method for wound healing in case of injured corneal epithelium, the effects of the tetrapeptide (Val-Leu-Leu-Lys), showing the consensus sequence between human interleukin (IL)-1alpha and bovine parotid protein (parotin) on epithelial cell proliferation and elongation were analysed in vitro cell culture experiments on epithelial cells obtained from rabbit cornea. The peptide showed dose-dependent stimulatory effects on epithelial cell proliferation and elongation at 10-100 microg ml(-1)compared with the control experiments. Furthermore, the peptide also exhibited a significant wound healing activity for the epithelial cells in an in situ experiment using mechanically injured rabbit cornea, while the higher concentration of the peptide (100 microg ml(-1)) showed greater efficient results than a previously known agent, sodium hyaluronate (0.3%). In addition, no pyrogenic activity of this peptide was detected by the previously established pyrogenicity test using rabbits. These results suggest that the tetrapeptide (Val-Leu-Leu-Lys) is a promising agent for wound healing in the case of injured corneal epithelium.

The extra domain A of fibronectin activates Toll-like receptor 4.

Cellular fibronectin, which contains an alternatively spliced exon encoding type III repeat extra domain A (EDA), is produced in response to tissue injury. Fragments of fibronectin have been implicated in physiological and pathological processes, especially tissue remodeling associated with inflammation. Because EDA-containing fibronectin fragments produce cellular responses similar to those provoked by bacterial lipopolysaccharide (LPS), we examined the ability of recombinant EDA to activate Toll-like receptor 4 (TLR4), the signaling receptor stimulated by LPS. We found that recombinant EDA, but not other recombinant fibronectin domains, activates human TLR4 expressed in a cell type (HEK 293 cells) that normally lacks this Toll-like receptor. EDA stimulation of TLR4 was dependent upon co-expression of MD-2, a TLR4 accessory protein. Unlike LPS, the activity of EDA was heat-sensitive and persisted in the presence of the LPS-binding antibiotic polymyxin B and a potent LPS antagonist, E5564, which completely suppressed LPS activation of TLR4. These observations provided a mechanism by which EDA-containing fibronectin fragments promote expression of genes involved in the inflammatory response.

Reparability of lethal lesions produced by phosphorus photoabsorption in yeast cells.

The characteristics of DNA lesions produced by the photoabsorption of phosphorus in yeast cells were studied using monochromatized soft X-rays tuned to the absorption peak of the phosphorus K-edge (2153 eV) and below the peak energy (2147 eV). The repaired fractions of DNA double-strand breaks (dsb) were measured relatively by using both a mutant, rad 54-3, which shows the temperature-sensitive dsb repair-deficient phenotype, and a wild-type strain. The repaired fraction of lesion in rad 54-3, which corresponds to the relative yield of dsb reparable by the RAD 54 pathway, was not affected by the phosphorus photoabsorption. Repair of the produced lesions in the wild-type cells was also measured by comparing the surviving fraction of the immediately plated cells to that of those cells plated after holding in a non-nutrient medium for 80 hrs. The recovery of the surviving fraction after the holding treatment was dependent upon the irradiated X-ray energy. These results suggest that irreparable lesions are produced by the inner-shell photoabsorption of phosphorus in DNA, although its yield is small.

[Simple evaluation of CT findings in the paranasal sinuses for chronic sinusitis].

The CT scores and scoring for improvement based on them, which we proposed previously, is a simple and highly reproducible method of evaluation of sinus units before and after an operation for chronic sinusitis. We compared this evaluation method with the results of quantitative assay and showed its advantages and disadvantages. The subjects were 258 sinuses in patients who underwent endonasal sinus surgery (ESS) in the department of otolaryngology, Kyoto Prefectural University of Medicine Hospital from April 1996 to April 1997. The subjects were evaluated according to the following 4 grades negligible shadow in the paranasal sinus CT scored 0, less than 50% shadow scored 1, more than 50% of shadow scored 2, and mostly filled with shadow scored 3. Furthermore, the preoperative and postoperative CT scores were compared and the rate of improvement was rated in the following 3 grades: score 0 for unchanged or aggravated subjects, score 1 for subjects showing improved CT score by 1 grade, and score 2 for those showing improved CT score by 2 grades or a postoperative CT score of 0. Quantitative image analysis was input into a personal computer and the ratio occupied by the shadow was calculated, as the shadow ratio. While some discrepancies were seen in parts in the comparison of the quantitative image analysis and CT scores as the former captures minute shadows, a positive correlation was obtained overall. Attention is needed to accurately evaluate small paranasal sinuses such as the frontal sinus, and small amounts of shadow, which are areas where errors may occur. A satisfactory correlation was obtained between the score for the improvement rate and the difference in the shadow ratios before and after surgery. The CT scores and the scores for the improvement rate showed no difference from the results of other evaluation methods reported in the past, and evaluation of similar precision was possible. It was thought that this simple evaluation method of CT findings in the paranasal sinuses, which we examined in the present study, was quite useful as a simple stage-classification method that could be utilized in everyday practice considering its facility, reproducibility and satisfactory precision.

Emission and metal- and ligand-centered-redox characteristics of the hexarhenium(III) clusters trans- and cis-[Re6(mu 3-S)8Cl4(L)2]2-, where L is a pyridine derivative or pyrazine.

Preparations of a series of face-capped octahedral hexarhenium(III) clusters having two N-heterocyclic ligands, [Bu4N]2[trans-[Re6(mu 3-S)8Cl4(L)2]] (Bu4N+ = tetra-n-butylammonium cation; L = pyrazine (1a), 4,4'-bipyridine (3a), 4-methylpyridine (5a), 4-(dimethylamino)pyridine (6a)) and their cis analogues (1b, 3b, 5b, and 6b, respectively), and their electrochemical and photophysical properties have been reported. An X-ray crystal structure determination has been carried out for 1a to confirm the trans configuration (C40H80N6S8Cl4Re6, orthorhombic, space group Cmca (No. 64), a = 19.560(5) A, b = 19.494(4) A, c = 18.592(4) A, beta = 115.76(2) degrees, Z = 4). The redox potential of the reversible ReIII6/ReIII5ReIV process of these complexes and previously reported [Bu4N]2[trans- and cis-[Re6(mu 3-S)8Cl4(4-cyanopyridine)2]] (2a and 2b, respectively) and [Bu4N]2[trans- and cis-[Re6(mu 3-S)8Cl4(pyridine)2]] (4a and 4b, respectively) in acetonitrile depends linearly on the pKa of the N-heterocyclic ligands, with the potentials being more negative with basic ligands. The ligand-centered-redox waves for 1a, 1b, 2a, and 2b were observed as split waves (delta E1/2 = 90-140 mV), the extent of the splitting being larger for the cis isomer and largest for the pyrazine complexes. Electronic interaction between the two ligands through the [Re6(mu 3-S)8]2+ core has been suggested. The second ligand-reduction wave was also observed for 3a and 3b, the potential being shifted positively to coalesce with the first reduction wave on addition of the weak proton donor imidazole. This is accounted for by the proton-coupled redox reaction at the free pyridyl site of the 4,4'-bipyridine ligands. All of the complexes show luminescence in acetonitrile at room temperature. While the complexes of pyridine and 4-methylpyridine show photophysical characteristics (lambda em 740-750 nm, phi em 0.031-0.057, tau em 4.2-6.2 microseconds) similar to those (770 nm, 0.039, and 6.3 microseconds, respectively) of [Re6(mu 3-S)8Cl6]4-, emissions of other complexes are significantly weak with lambda em, phi em, and tau em values in the ranges 763-785 nm, 0.0010-0.0017, and 0.013-0.029 microsecond, respectively. Suggestions are given for the excited states localized on the cluster core and the ligand pi* orbitals.

Glycyrrhizin inhibits TNF-induced, but not Fas-mediated, apoptosis in the human hepatoblastoma line HepG2.

To determine the transaminase-lowering action of glycyrrhizin (GL) immunologically, the effect of GL on tumor necrosis factor (TNF)-alpha- and Fas-mediated apoptosis was assessed using a human hepatoblastoma line, HepG2 cells. The HepG2 cells were resistant to TNF-alpha and anti-Fas antibody, but were rendered susceptible to TNF-alpha and anti-Fas antibody in the presence of actinomycin D (Act D), an inhibitor of RNA synthesis. The cytotoxicity induced by TNF-alpha/Act D or anti-Fas/Act D was accompanied by DNA fragmentation, indicating apoptotic death of HepG2 cells. GL partially prevented the apoptosis of HepG2 cells induced by TNF-alpha/Act D in a GL-dose dependent fashion. However, this protective effect of GL was not observed in the cytotoxicity of HepG2 caused by anti-Fas/Act D. Although the protection mechanism of GL, observed in a limited fashion against TNF-alpha-mediated apoptosis, is unclear, the present results provide an immunological explanation for the transaminase-lowering action of GL in the GL treatment of chronic liver diseases involving apoptotic hepatocyte death in their pathogenesis.

Combined systemic and mucosal immunization with microsphere-encapsulated inactivated simian immunodeficiency virus elicits serum, vaginal, and tracheal antibody responses in female rhesus macaques.

We determined the efficacy of immunization with microsphere-encapsulated whole inactivated simian immunodeficiency virus (SIV) by combined systemic and mucosal administration to protect female rhesus macaques against vaginal challenge with homologous rhesus PBMC-grown SIVmac251. Animals in one group were primed and boosted intramuscularly. Two groups were primed intramuscularly and boosted either intratracheally or orally. A final group was primed by vaccinia/rgp140 scarification and subdivided for either intratracheal or oral boosting. Strong ELISA titers of circulating SIV-specific IgG and modest IgA responses were elicited in the animals primed intramuscularly. Intratracheal boosting in the intramuscularly primed macaques resulted in high bronchial alveolar wash (BAW) IgG and less pronounced IgA. SIV-specific vaginal wash (VW) IgG was also present in the intramuscular/intramuscular and intramuscular/intratracheal groups. Vaccinia/rgp140 priming gave low ELISA titers to whole SIV, and failed to elicit mucosal antibody regardless of the booster route. No animal in any group developed serum neutralizing antibody to homologous SIVmac251. On vaginal challenge none of the immunized groups was infected at a lesser frequency than the unimmunized controls. These data suggest that the use of microspheres in a combined parenteral and mucosal regimen is an effective method of eliciting IgG and IgA antibody at mucosal surfaces.

Induction of mucosal antibody responses by microsphere-encapsulated formalin-inactivated simian immunodeficiency virus in a male urethral challenge model.

Male rhesus macaques were immunized mucosally with microsphere-encapsulated formalin-inactivated simian immunodeficiency virus (SIV) particles in a test of immunogenicity and protection against mucosal SIV challenge. Tracheal boosting of animals that had been primed intramuscularly resulted in strong serum ELISA titers to SIV, and evidence of local IgA responses in broncho-alveolar washes. The bulk of the antibody response was against non-envelope epitopes. No neutralizing antibody was observed, and intraurethral challenge with cell-free rhesus-grown virus showed no evidence of protection against infection. Microsphere-based immunization efficiently raises local and system responses, but the resulting immunity to SIV is apparently not sufficient to protect against mucosal challenge.

Augmentation of natural killer cell activity in mice by oral administration of transforming growth factor-beta.

The latent form of transforming growth factor-beta (TGF-beta) in human milk and platelets was converted to the active form when conscious, pylorus-ligated mice were given human milk and platelets by intragastric intubation. Oral administration of TGF-beta exerted enhancing effects on the natural killer (NK)-cell activities in spleen and liver. Augmentation of NK-cell activities in spleen was observed for 7 days after oral administration of TGF-beta. TGF-beta at concentrations of 5 and 20 ng produced the greatest augmentation of NK-cell activities in spleen. However, NK-cell activities in spleen were unaffected when TGF-beta was given intravenously. Interleukin (IL)-12 production in spleen was enhanced by oral administration of TGF-beta, but not by intravenous administration of TGF-beta. These findings suggest that large amounts of TGF-beta in human milk are involved in early antiviral protection through the augmentation of NK-cell activities.

Intragastric administration of ursodeoxycholic acid suppresses immunoglobulin secretion by lymphocytes from liver, but not from peripheral blood, spleen or Peyer's patches in mice.

Ursodeoxycholic acid (UDCA) has been recognized as a therapeutic drug for primary biliary cirrhosis (PBC) and chronic viral hepatitis. As one of the mechanisms by which UDCA improves liver function tests in those patients, its immunomodulatory effect is currently considered important. Although the suppressive effects of UDCA on some cytokine productions, T-cell mediated cytotoxicity and immunoglobulin production were observed from in vitro studies, the immunomodulation in vivo by UDCA remains unclear. In the present study, we investigated the effect of UDCA administration on the number of immunoglobulin secreting cells in liver, peripheral blood, spleen and Peyer's patches in mice using the enzyme linked immunospot assay and assessed whether the UDCA-mediated immunomodulation is liver-specific. It was demonstrated that intragastric administration of UDCA reduced immunoglobulin secretion by lymphocytes from liver, but not from peripheral blood, spleen, or Peyer's patches. However, immunoglobulin production of those lymphocytes cultured in the presence of UDCA was suppressed, irrespective of their distribution sites, in a UDCA dose-dependent manner. When the concentrations of UDCA in portal and peripheral blood were measured using high performance liquid chromatography, UDCA was detectable in the portal blood in UDCA-treated mice, but not in peripheral blood, suggesting that the concentrations of UDCA in the environment surrounding lymphocytes may be an important factor for the modulation of lymphocyte functions.

Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure.

To elucidate the time course of sympathovagal balance and its relationship to left ventricular function in heart failure, we serially evaluated left ventricular contractility and relaxation and autonomic tone in 11 conscious dogs with tachycardia-induced heart failure. We determined a dynamic map of sympathetic and parasympathetic modulation by power spectral analysis of heart rate variability. The left ventricular peak +dP/dt substantially fell from 3,364 +/- 338 to 1,959 +/- 318 mmHg/s (P < 0.05) on the third day and declined gradually to 1,783 +/- 312 mmHg/s at 2 wk of rapid ventricular pacing. In contrast, the time constant of left ventricular pressure decay and end-diastolic pressure increased gradually from 25 +/- 4 to 47 +/- 5 ms (P < 0.05) and from 10 +/- 2 to 21 +/- 3 mmHg (P < 0.05), respectively, at 2 wk of pacing. The high-frequency component (0.15-1.0 Hz), a marker of parasympathetic modulation, decreased from 1,928 +/- 1,914 to 62 +/- 68 x 10(3) ms2 (P < 0.05) on the third day and further to 9 +/- 12 x 10(3) ms2 (P < 0.05) at 2 wk. Similar to the time course of left ventricular diastolic dysfunction, plasma norepinephrine levels and the ratio of low (0.05- to 0.15-Hz)- to high-frequency component increased progressively from 135 +/- 50 to 532 +/- 186 pg/ml (P < 0.05) and from 0.06 +/- 0.06 to 1.12 +/- 1.01 (P < 0.05), respectively, at 2 wk of pacing. These cardiac and autonomic dysfunctions recovered gradually toward the normal values at 2 wk after cessation of pacing. Thus a parallel decline in left ventricular contractility with parasympathetic influence and a parallel progression in left ventricular diastolic dysfunction with sympathoexcitation suggest a close relationship between cardiac dysfunction and autonomic dysregulation during development of heart failure.

Effect of assisted circulation on left ventricular performance in a canine model.

BACKGROUND: Little is known about left ventricular performance during venoarterial bypass and left heart bypass (LHB) after cross-clamping the descending thoracic aorta. We evaluated the effects of venoarterial bypass and LHB on ventricular load optimization and left ventricular work efficiency. METHODS: We used the left ventricular conductance catheter and a micromanometer in 7 anesthetized mongrel dogs. We assessed preload by the end-diastolic volume, afterload by the effective arterial elastance, and left ventricular contractile properties by the slope of the end-systolic pressure-volume relationship. In addition, optimal ventricular arterial coupling (ratio of effective arterial elastance to slope of end-systolic pressure-volume relationship) and left ventricular work efficiency (ratio of external work to pressure-volume area) were calculated. RESULTS: The decrease in preload was much greater with LHB than venoarterial bypass. There were no significant differences in afterload and left ventricular contractility between venoarterial bypass and LHB. The ventricular arterial coupling during LHB was near 0.50 (0.69 +/- 0.16) in the "best heart" condition (effective arterial elastance = slope of end-systolic pressure-volume relationship/2), whereas the work efficiency during LHB was at maximum (0.73 +/- 0.12). CONCLUSIONS: We conclude that LHB has a more beneficial effect on left ventricular performance after cross-clamping of the descending thoracic aorta.