Dichloroacetic acid improves in vitro myocardial function following in vivo endotoxin administration

1986 ◽  
Vol 1 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Alastair H. Burns ◽  
Mary E. Giaimo ◽  
Warren R. Summer
Keyword(s):  
Myocardial Function ◽  
Dichloroacetic Acid ◽  
Endotoxin Administration

Modulation of lymphatic pumping by lymph-borne factors after endotoxin administration in sheep

1990 ◽  
Vol 68 (1) ◽  
pp. 199-208 ◽  
Author(s):  
R. M. Elias ◽  
M. G. Johnston
Keyword(s):  
Potent Inhibitor ◽  
Lymphatic Vessels ◽  
Transmural Pressure ◽  
Test Animal ◽  
Indwelling Catheter ◽  
Endotoxin Administration ◽  
Lymphatic Pumping ◽  
Pumping Activity

The purpose of this study was to test the hypothesis that endotoxin administration to sheep results in host-derived lymph-borne factors that modulate lymphatic pumping activity. To achieve this, two sheep were used for each experiment. In the test animal, a segment of intestinal lymphatic was isolated from all lymph input and provided with lymph from a reservoir. Pumping activity was initiated with a fixed transmural pressure applied to the test vessel, and the only input to this duct was provided by lymph from an indwelling catheter in a second donor sheep. The intravenous administration of endotoxin to the donor animals (33 micrograms/kg) generally resulted in increased pumping in the test vessels over the 1st h, but this was followed by reductions in pumping until flow stopped in all preparations. In control experiments (no endotoxin administered) pumping was unaffected. Further investigation revealed that these activities were relatively unstable and, in the case of the inhibitory material, appeared to act by decreasing the sensitivity of the vessel to changes in transmural pressure, because flow could be reestablished in the test vessels by elevating transmural pressures above the level originally chosen for the experiment. Endotoxin itself had no direct effect on sheep lymphatics in vivo or on bovine lymphatic vessels in vitro. However, the appearance of erythrocyte hemolysate (erythrolysate) in lymph was regularly observed after endotoxin infusion, and we demonstrated that erythrolysate (diluted to contain 10(-5) M hemoglobin) was a potent inhibitor of lymphatic pumping in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of mouse intestinal microflora in the metabolism of trichloroethylene, an in vivo study

1997 ◽  
Vol 16 (11) ◽  
pp. 629-635 ◽  
Author(s):  
AP Moghaddam ◽  
R. Abbas ◽  
JW Fisher ◽  
JC Lipscomb
Keyword(s):  
Trichloroacetic Acid ◽  
Liver Tumors ◽  
Dichloroacetic Acid ◽  
Gut Microflora ◽  
Acid Produce ◽  
Different Content ◽  
The Impact

1 Both trichloroethylene and its metabolite, dichloroa cetic acid, produce liver tumors peroxisome prolifera tion and other adverse cellular alterations in rodents. 2 The hepatic mechanism by which dichloroacetic acid is formed is not conclusively demonstrated, but pharmacokinetic models have successfully associated its formation with trichloroacetic acid as immediate precursor. 3 Previous investigations have shown that dichloroace tic acid is formed from trichloroacetic acid by gut microflora isolated in vitro. 4 To determine the impact of gut microflora on dichlor oacetic acid formation from a trichloroethylene dose in vivo, we developed a procedure which reduced gut microflora some 3 orders of magnitude below pub lished levels. 5 The administration of trichloroethylene to control mice and to mice whose gut was practically sterile resulted in equivalent concentrations of dichloroace tic acid and other metabolites in blood and liver, but significantly different content of these metabolites in cecum contents. 6 These data indicate that gut microflora contribute minimally, if at all, to the formation of circulating dichloroacetic acid under these conditions.

Cocaine downregulates cardiac SERCA2a and depresses myocardial function in the murine model

2002 ◽  
Vol 80 (10) ◽  
pp. 1015-1021 ◽  
Author(s):  
Ju-Feng Wang ◽  
Xinhua Yan ◽  
Jiangyong Min ◽  
Matthew F Sullivan ◽  
Thomas G Hampton ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Statistical Difference ◽  
Myocardial Function ◽  
Saline Control ◽  
Myocardial Performance ◽  
Hemodynamic Parameters ◽  
Cocaine Exposure ◽  
Protein Levels

Cocaine has been shown to depress myocardial function, which may be linked to abnormal Ca2+ handling by the sarcoplasmic reticulum (SR). To examine whether cocaine affects Ca2+-handling proteins and myocardial performance, we injected BALB/c mice with cocaine daily (30 mg/kg, i.p.) for 14 d. Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) levels, phospholamban (PLB) protein levels, and hemodynamic parameters were measured. After cocaine exposure, myocardial function was significantly decreased both in vivo and in vitro. Also, SERCA2a protein levels were significantly decreased in all cocaine-treated hearts (p < 0.05 compared with saline control). Normalized SERCA2a levels were 1.2 ± 0.2 (densitometric units) in the cocaine groups (p < 0.05 compared with saline control). However, there was no statistical difference in PLB protein levels between the cocaine and the saline groups. In isolated papillary muscle studies, cocaine did not block the response to extracellular Ca2+ but it did prolong the relaxation time of the muscle. These results indicate that cocaine does not block extracellular Ca2+ entrance across the cell membrane, but that it decreases SERCA2a protein levels. In conclusion, our study demonstrates that cocaine decreases SERCA2a protein levels and depresses myocardial function.Key words: cocaine, SERCA2a, phospholamban, ventricular function, mouse.

An ultrasonic system for measurement of absolute myocardial thickness using a single transducer

1995 ◽  
Vol 268 (3) ◽  
pp. H1358-H1367 ◽  
Author(s):  
K. F. Pitsillides ◽  
J. C. Longhurst
Keyword(s):  
Wall Thickness ◽  
Piezoelectric Transducer ◽  
Animal Studies ◽  
Wall Motion ◽  
Myocardial Function ◽  
Error Signal ◽  
Myocardial Wall Motion ◽  
Myocardial Wall

We have developed an ultrasonic instrument that can measure absolute regional myocardial wall motion throughout the cardiac cycle using a single epicardial piezoelectric transducer. The methods in place currently that utilize ultrasound to measure myocardial wall thickness are the transit-time sonomicrometer (TTS) and, more recently, the Doppler echo displacement method. Both methods have inherent disadvantages. To address the need for an instrument that can measure absolute dimensions of myocardial wall at any depth, an ultrasonic single-crystal sonomicrometer (SCS) system was developed. This system can identify and track the boundary of the endocardial muscle-blood interface. With this instrument, it is possible to obtain, from a single epicardial transducer, measurement of myocardial wall motion that is calibrated in absolute dimensional units. The operating principles of the proposed myocardial dimension measurement system are as follows. A short duration ultrasonic burst having a frequency of 10 MHz is transmitted from the piezoelectric transducer. Reflected echoes are sampled at two distinct time intervals to generate reference and interface sample volumes. During steady state, the two sample volumes are adjusted so that the reference volume remains entirely within the myocardium, whereas half of the interface sampled volume is located within the myocardium. After amplification and filtering, the true root mean square values of both signals are compared and an error signal is generated. A closed-loop circuit uses the integrated error signal to continuously adjust the position of the two sample volumes. We have compared our system in vitro against a known signal and in vivo against the two-crystal TTS system during control, suppression (ischemia), and enhancement (isoproterenol) of myocardial function. Results were obtained in vitro for accuracy (> 99%), signal linearity (r = 0.99), and frequency response to heart rates > 450 beats/min, and in vivo data were acquired for end-systolic dimension (r = 0.99), end-diastolic dimension (r = 0.99), and percent wall thickness (r = 0.99). Both in vitro and in vivo tests indicate that the SCS functions identically to the two-crystal TTS. Use of the SCS allows measurement of absolute wall thickness and hence myocardial function, for both acute and chronically instrumented animal studies, with minimal or no trauma to myocardium.

scholarly journals Glutathione transferase Zeta catalyses the oxygenation of the carcinogen dichloroacetic acid to glyoxylic acid

1998 ◽  
Vol 331 (2) ◽  
pp. 371-374 ◽  
Author(s):  
Zeen TONG ◽  
Philip G. BOARD ◽  
M. W. ANDERS
Keyword(s):  
Liver Enzyme ◽  
Rat Liver ◽  
Glutathione Transferase ◽  
Gel Filtration ◽  
Rabbit Antiserum ◽  
Glyoxylic Acid ◽  
Dichloroacetic Acid ◽  
Amino Acid Residues

Dichloroacetic acid (DCA), a common drinking-water contaminant, is hepatocarcinogenic in rats and mice, and is a therapeutic agent used clinically in the management of lactic acidosis. DCA is biotransformed to glyoxylic acid by glutathione-dependent cytosolic enzymes in vitro and is metabolized to glyoxylic acid in vivo. The enzymes that catalyse the oxygenation of DCA to glyoxylic acid have not, however, been identified or characterized. In the present investigation, an enzyme that catalyses the glutathione-dependent oxygenation of DCA was purified to homogeneity (587-fold) from rat liver cytosol. SDS/PAGE and HPLC gel-filtration chromatography showed that the purified enzyme had a molecular mass of 27–28 kDa. Sequence analysis showed that the N-terminus of the purified protein was blocked. An internal sequence of 30 amino acid residues was obtained that matched the recently discovered human glutathione transferase Zeta well [Board, Baker, Chelvanayagam and Jermiin (1997) Biochem. J. 328, 929–935]. Western-blot analysis showed that the purified rat-liver enzyme cross-reacted with rabbit antiserum raised against recombinant human glutathione transferase Zeta. The apparent Km and Vmax values of the purified enzyme with DCA as the variable substrate were 71.4 µM and 1334 nmol/min per mg of protein, respectively; the Km for glutathione was 59 µM. Both the purified rat-liver enzyme and the recombinant human enzyme showed high activity with DCA as the substrate. These results demonstrate that the glutathione-dependent oxygenation of DCA to glyoxylic acid is catalysed by a Zeta-class glutathione transferase.

Magnesium orotate elicits acute cardioprotection at reperfusion in isolated and in vivo rat hearts

2013 ◽  
Vol 91 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Silvia N. Mirica ◽  
Oana M. Duicu ◽  
Simona L. Trancota ◽  
Ovidiu Fira-Mladinescu ◽  
Denis Angoulvant ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Orotic Acid ◽  
Myocardial Function ◽  
Ex Vivo ◽  
Control Group ◽  
Mptp Opening ◽  
Rat Hearts ◽  
Magnesium Orotate

Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia–reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and MgCl2 treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R.

Partial recovery of neutrophil functions during prolonged hypothermia in pigs

1986 ◽  
Vol 60 (4) ◽  
pp. 1186-1189 ◽  
Author(s):  
W. D. Biggar ◽  
C. Barker ◽  
D. Bohn ◽  
G. Kent
Keyword(s):  
Bone Marrow ◽  
Gradual Increase ◽  
Neutrophil Migration ◽  
Neutrophil Function ◽  
Partial Recovery ◽  
Endotoxin Administration ◽  
Inflammatory Site ◽  
And Migration

The changes in circulation and migration of mature and immature neutrophils during 12 h of hypothermia have been studied using an experimental pig model. At 29 degrees C the number of circulating neutrophils fell from 5 +/- 1.1 at 37 degrees C to 3.5 +/- 0.6 X 10(9)/l and then remained unchanged while hypothermia was maintained. The number of circulating immature neutrophils did not fall during hypothermia. During hypothermia, hydrocortisone failed to stimulate the release of mature and immature neutrophils from the bone marrow. In contrast, endotoxin caused a profound neutropenia followed by a gradual increase in the number of circulating mature neutrophils, which by 6 h, was similar to the number circulating before endotoxin administration. At 29 degrees C the number of circulating immature neutrophils also fell following endotoxin but then increased over the number circulating before endotoxin administration by approximately 10-fold. Compared with neutrophil migration at 37 degrees C, very few mature or immature neutrophils migrated to an inflammatory site during the 12 h of hypothermia (29 degrees C). Unlike hypothermia in vitro, where neutrophil function may improve with time in vivo, neutrophil function remains compromised.

Decrease in adenylate cyclase activity in dog livers during endotoxic shock

1983 ◽  
Vol 245 (5) ◽  
pp. R737-R742
Author(s):  
S. Ghosh ◽  
M. S. Liu
Keyword(s):  
Adenylate Cyclase ◽  
Plasma Membranes ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Guanine Nucleotide ◽  
Endotoxin Administration ◽  
Liver Plasma Membranes ◽  
Dog Liver

The effects of endotoxin administration on adenylate cyclase in dog liver plasma membranes were studied. The basal, fluoride-, guanine nucleotide-, isoproterenol-, and glucagon-stimulated adenylate cyclase activities were decreased by 61, 62, 69, 83, and 63%, respectively, 2 h after in vivo administration of endotoxin. Endotoxin (100 micrograms/ml) in vitro decreased the guanine nucleotide-, isoproterenol-, and glucagon-stimulated adenylate cyclase activities by 24, 25, and 21%, respectively. These data demonstrate that endotoxin administered in vivo or in vitro had an inhibitory effect on the adenylate cyclase enzyme system in dog liver plasma membranes. Because of the involvement of the adenylate cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) system in the regulation of hepatic carbohydrate metabolism, the finding that endotoxin administration decreased adenylate cyclase activity in the liver should contribute to the understanding of the pathophysiology of altered hepatic glucose homeostasis during shock.

The dimeric platelet collagen receptor GPVI-Fc reduces platelet adhesion to activated endothelium and preserves myocardial function after transient ischemia in mice

2012 ◽  
Vol 303 (7) ◽  
pp. C757-C766 ◽  
Author(s):  
Tanja Schönberger ◽  
Melanie Ziegler ◽  
Oliver Borst ◽  
Ildiko Konrad ◽  
Bernhard Nieswandt ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Proinflammatory Cytokines ◽  
Platelet Adhesion ◽  
Myocardial Function ◽  
Critical Role ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Collagen Receptor

Platelets play a critical role in the pathophysiology of reperfusion, sepsis, and cardiovascular diseases. In a multiple step process, they adhere to activated endothelium and release proinflammatory cytokines thereby promoting the inflammatory process. Glycoprotein VI (GPVI) is the major collagen receptor on the platelet surface and triggers platelet activation and primary hemostasis. Activation of GPVI leads to stable platelet adhesion and degranulation of platelet granules. However, GPVI is critically involved in platelet adhesion to activated endothelium without exposure of subendothelial matrix. Earlier studies show that the soluble GPVI-Fc binds to collagen and protects mice from atherosclerosis and decreases neointima proliferation after arterial injury. Here, we show for the first time that recombinant GPVI-Fc binds to activated endothelium mainly via vitronectin and prevents platelet/endothelial interaction. Administration of GPVI-Fc reduced infarct size and preserved cardiac function in a mouse model of myocardial infarction. This process was associated with reduced GPVI-induced platelet degranulation and release of proinflammatory cytokines in vitro and in vivo. Taken together, administration of GPVI-Fc offers a novel strategy to control platelet-mediated inflammation and to preserve myocardial function following myocardial infarction.

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