32 results on '"Pastor CM"'
Search Results
2. Safety and effectiveness of ustekinumab in psoriatic arthritis. A multicenter Study
- Author
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Azuaga-Pinango, A, Frade-Sosa, B, Laiz, A, Estrada, P, Polino, L, Beltran, E, Prior-Espanol, A, Soria, LM, Pastor, CM, Sellas-Fernandez, A, Urruticoechea-Arana, A, Moreno, M, Miguel, JG, Tandaipan, JL, Pujol, M, Segarra, VT, Vilamajo, IR, Ordonez, S, Reina-Sanz, D, Cuervo, A, Canete, J, and Ramirez, J
- Subjects
Psoriatic Arthritis ,Effectiveness ,Ustekinumab - Published
- 2019
3. Real-world effectiveness and safety of combined calcium 600 mg and cholecalciferol 2000 IU for treating vitamin d deficiency: Results from a nationwide study with focus in osteoporosis.
- Author
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Pinto-Bonilla R, Baeza-Noci J, Blanco CC, Gumbau GJV, Fernández RJ, Pascual-Pastor M, Magamón BG, Lamothe BP, Pastor CM, Aviñó RI, Aguilar EG, and Saz-Leal P
- Abstract
Introduction: Treatment of calcium (Ca) and vitamin D (VD) deficiency (VDD) is crucial for health, especially in bone conditions, such as low bone mineral density (BMD) and osteoporosis. Despite updates in clinical guideline recommendations, no studies have evaluated the efficacy and safety of administering 2000 IU of cholecalciferol combined with calcium. Thus, the main objective of this study was to evaluate VD levels following treatment with Ca 600 mg/ cholecalciferol 2000 IU in real-life clinical practice., Methods: This multicenter, retrospective, observational study included 302 adult patients receiving Ca 600 mg/D3 2000 IU orodispersible tablets, daily for ≥24 weeks. The primary outcome was 25-hydroxivitamin D [25(OH)D] serum levels following treatment. Key secondary outcomes included changes in serum 25(OH)D levels and other bone metabolism (BM) parameters, safety and tolerability. The protocol was approved by a Research Ethics Committee., Results: 285 patients were evaluated (mean age [SD]: 67.4 [12.6] years old; 88.4 % women; basal serum 25(OH)D: 20.0 [8.6] ng/mL); 80.7 % reported previous history of osteoporosis/low BMD (osteopenia) and 37.2 % had received other Ca/VD prior to start study treatment. Median treatment duration was 38.5 weeks [range 24.0-82.4]. Overall, 94.4 % of patients increased serum 25(OH)D following treatment to a mean of 36.3 [11.8] ng/mL ( p < 0.001 vs. baseline). Patients with basal VDD, significantly increased serum 25(OH)D to a mean over 30 ng/mL; no significant change found in repleted patients (basal 25(OH)D level ≥ 30 ng/mL). PTH was significantly reduced after treatment, with no clinically relevant effect on serum Ca or phosphate. Three non-serious treatment-emergent adverse events were reported. A post-hoc analysis on osteoporotic patients revealed virtually identical results in this population., Conclusion: Treatment with Ca 600 mg/cholecalciferol 2000 IU for at least 24 weeks is effective and safe, especially in osteoporosis. Patients with VDD significantly increase plasma 25(OH)D to optimal range for bone health, with no clinically relevant changes on other bone metabolism parameters other than reducing secondary hyperparathyroidism. The magnitude of 25(OH)D increase directly correlates with the severity of VDD, with no effect in basally repleted patients., Competing Interests: The following authors declare potential conflicts of interest in relation to the proposed research: Juan A. Olmo Fernandez-Delgado has conducted work or training for Theramex, Grunenthal, Stada laboratories. Abelardo Montero Sáez has conducted work or training for Amgen, Stada, Ferrer, Theramex. Jenaro Graña Gil has conducted work or training for Theramex, Italfarmaco, Faes, Rubió, Gebro. Eva García Aguilar and Paula Saz-Leal are employed by the medical department of ITF Research Pharma SLU. The remaining authors signing this manuscript have no conflicts of interest to declare. The laboratory funding this research (ITF Research Pharma SLU, Alcobendas. Spain) has participated in the study design and manuscript preparation but not in the data analysis or the results obtained., (© 2024 Published by Elsevier Inc.)
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- 2024
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4. Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats.
- Author
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Pastor CM and Vilgrain V
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- Animals, Biological Transport, Hepatocytes metabolism, Liver metabolism, Monocrotaline metabolism, Monocrotaline toxicity, Rats, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Organic Anion Transporters metabolism
- Abstract
Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes.
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- 2022
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5. Transcription Factor DOF4.1 Regulates Seed Longevity in Arabidopsis via Seed Permeability and Modulation of Seed Storage Protein Accumulation.
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Niñoles R, Ruiz-Pastor CM, Arjona-Mudarra P, Casañ J, Renard J, Bueso E, Mateos R, Serrano R, and Gadea J
- Abstract
Seed longevity is modulated by multiple genetic factors in Arabidopsis thaliana . A previous genome-wide association study using the Elevated Partial Pressure of Oxygen (EPPO) aging assay pinpointed a genetic locus associated with this trait. Reverse genetics identified the transcription factor DOF4.1 as a novel seed longevity factor. dof4.1 loss-of-function plants generate seeds exhibiting higher germination after accelerated aging assays. DOF4.1 is expressed during seed development and RNAseq data show several putative factors that could contribute to the dof4.1 seed longevity phenotype. dof4.1 has reduced seed permeability and a higher levels of seed storage proteins mRNAs (cruciferins and napins) in developing seeds, as compared to wild-type seeds. It has been reported that mutant lines defective in cruciferins or napins present reduced seed longevity. The improved longevity of dof4.1 is totally lost in the quadruple mutant dof4.1 cra crb crc , but not in a dof4.1 line depleted of napins, suggesting a prominent role for cruciferins in this process. Moreover, a negative regulation of DOF4.1 expression by the transcription factor DOF1.8 is suggested by co-inoculation assays in Nicotiana benthamiana . Indeed, DOF1.8 expression anticorrelates with that of DOF4.1 during seed development. In summary, modulation of DOF4.1 levels during seed development contributes to regulate seed longevity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Niñoles, Ruiz-Pastor, Arjona-Mudarra, Casañ, Renard, Bueso, Mateos, Serrano and Gadea.)
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- 2022
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6. Usefulness of ultrasound in the diagnosis of crystal deposition diseases.
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Pastor CM, Perez EA, and Casares EG
- Abstract
Gout and calcium pyrophosphate crystal deposition disease (CPPD) are common forms of inflammatory arthritis whose prevalence has increased in recent years. Although the identification of monosodium urate crystals (MSU) and calcium pyrophosphate crystals (CPP) in synovial fluid (SF) by polarized light microscopy are the gold standard for diagnosing these diseases, SF analysis is not always available. An early diagnosis and specific treatment, especially in gout, allows avoiding irreversible structural damage, comorbidities, and a severe impact on the quality of life of patients. Musculoskeletal ultrasound (US) is a noninvasive tool that allows detecting aggregates of microcrystals at multiple anatomical sites and helps to establish a specific diagnosis. The objective of this review is to evaluate the applications of US in the diagnosis and clinical management of the main microcrystalline arthropathies. The US has helped improve our understanding of the natural history of the disease, due to its ability to visualize not only soft tissue inflammation and structural damage, but also the characteristics of MSU and CPP crystal deposition. The anatomical sites of crystal deposition are also a key factor for differential diagnosis in different microcrystalline diseases. The US allows establishing an early diagnosis, especially in asymptomatic hyperuricemia, to discriminate with other inflammatory diseases, to assess the extent of microcrystalline deposition and their sensitivity to change after treatment. Given its increasing availability in clinical practice and strong evidence, US is a bedside imaging technique helping clinicians to improve diagnosis and therapy monitoring in their daily practice.
- Published
- 2022
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7. New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments.
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Pastor CM and Brouwer KLR
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- Aniline Compounds pharmacokinetics, Animals, Bile Canaliculi metabolism, Biliary Tract diagnostic imaging, Diagnostic Imaging, Extracellular Space metabolism, Genes, erbB-2 genetics, Glycine pharmacokinetics, Hepatocytes metabolism, In Vitro Techniques, Male, Models, Biological, Nonlinear Dynamics, Rats, Rats, Sprague-Dawley, Contrast Media pharmacokinetics, Liver diagnostic imaging, Liver metabolism
- Abstract
Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2022
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8. Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats.
- Author
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Pastor CM and Vilgrain V
- Subjects
- Animals, Bile Acids and Salts metabolism, Bile Canaliculi drug effects, Bile Canaliculi metabolism, Hepatocytes drug effects, Liver drug effects, Liver metabolism, Meglumine analogs & derivatives, Meglumine pharmacokinetics, Meglumine pharmacology, Organometallic Compounds pharmacokinetics, Organometallic Compounds pharmacology, Perfusion, Rats, Rats, Zucker, Rheology drug effects, Fatty Liver metabolism, Fatty Liver pathology, Hepatocytes metabolism, Hepatocytes pathology, Membrane Transport Proteins metabolism, Obesity metabolism, Obesity pathology
- Abstract
Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty ( fa/fa ) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.
- Published
- 2021
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9. Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments.
- Author
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Pastor CM, Joly F, Vilgrain V, and Millet P
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- Aniline Compounds, Animals, Biological Transport, Glycine, Rats, Tomography, Emission-Computed, Single-Photon, Liver diagnostic imaging, Magnetic Resonance Imaging
- Abstract
Background: In hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it., Methods: We perfused labelled gadobenate dimeglumine (Bopta, 200 μM, 7% liver extraction ratio) and mebrofenin (Meb, 64 μM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used., Results: Hepatocyte concentrations were 2,043 ± 333 μM (Meb) versus 360 ± 69 μM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers., Conclusion: Hepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images., (© 2021. The Author(s).)
- Published
- 2021
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10. Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers.
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Bonnaventure P, Cusin F, and Pastor CM
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- ATP-Binding Cassette Transporters metabolism, Animals, Biliary Tract drug effects, Biliary Tract metabolism, Biological Transport drug effects, Contrast Media metabolism, Drug Interactions physiology, Hepatocytes drug effects, Liver drug effects, Male, Meglumine analogs & derivatives, Meglumine metabolism, Membrane Transport Proteins drug effects, Membrane Transport Proteins metabolism, Organic Anion Transporters metabolism, Organometallic Compounds metabolism, Rats, Rats, Sprague-Dawley, Rifampin pharmacology, Biological Transport physiology, Hepatocytes metabolism, Liver metabolism
- Abstract
In the liver, several approaches are used to investigate and predict the complex issue of drug-induced transporter inhibition. These approaches include in vitro assays and pharmacokinetic models that predict how inhibitors modify the systemic and liver concentrations of the victim drugs. Imaging is another approach that shows how inhibitors might alter liver concentrations stronger than systemic concentrations. In perfused rat livers associated with a gamma counter that measures liver concentrations continuously, we previously showed how fluxes across transporters generate the hepatocyte concentrations of two clinical imaging compounds, one with a low extraction ratio [gadobenate dimeglumine (BOPTA)] and one with a high extraction ratio [mebrofenin (MEB)]. BOPTA and MEB are transported by rat organic anion transporting polypeptide and multiple resistance-associated protein 2, which are both inhibited by rifampicin. The aim of the study is to measure how rifampicin modifies the hepatocyte concentrations and membrane clearances of BOPTA and MEB and to determine whether these compounds might be used to investigate transporter-mediated drug-drug interactions in clinical studies. We show that rifampicin coperfusion greatly decreases BOPTA hepatocyte concentrations, but increases those of MEB. Rifampicin strongly decreases BOPTA hepatic clearance. In contrast, rifampicin decreases moderately MEB hepatic clearance and blocks the biliary intrinsic clearance, increasing MEB hepatocyte concentrations. In conclusion, low concentrations prevent the quantification of BOPTA biliary intrinsic clearance, while MEB is a promising imaging probe substrate to evidence transporter-mediated drug-drug interactions when inhibitors act on influx and efflux transporters., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
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- 2019
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11. Liver Imaging and Hepatobiliary Contrast Media.
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Pastor CM, Langer O, and Van Beers BE
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- Animals, Contrast Media pharmacokinetics, Humans, Magnetic Resonance Imaging, Mice, Rats, Bile Ducts diagnostic imaging, Contrast Media chemistry, Liver diagnostic imaging, Molecular Imaging methods
- Published
- 2018
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12. Isolated Perfused Rat Livers to Quantify the Pharmacokinetics and Concentrations of Gd-BOPTA.
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Pastor CM
- Subjects
- ATP-Binding Cassette Transporters metabolism, Aniline Compounds, Animals, Bile Canaliculi metabolism, Biological Transport, Chronic Disease, Glycine, Hepatocytes metabolism, Imino Acids chemistry, Liver Cirrhosis, Biliary metabolism, Magnetic Resonance Imaging, Meglumine pharmacokinetics, Organotechnetium Compounds chemistry, Rats, Temperature, Tissue Distribution, Liver metabolism, Meglumine analogs & derivatives, Organometallic Compounds pharmacokinetics, Perfusion
- Abstract
With recent advances in liver imaging, the estimation of liver concentrations is now possible following the injection of hepatobiliary contrast agents and radiotracers. However, how these images are generated remains partially unknown. Most experiments that would be helpful to increase this understanding cannot be performed in vivo . For these reasons, we investigated the liver distribution of the magnetic resonance (MR) contrast agent gadobenate dimeglumine (Gd-BOPTA, MultiHance®, Bracco Imaging) in isolated perfused rat livers (IPRLs). In IPRL, we developed a new set up that quantifies simultaneously the Gd-BOPTA compartment concentrations and the transfer rates between these compartments. Concentrations were measured either by MR signal intensity or by count rates when the contrast agent was labelled by [
153 Gd]. With this experimental model, we show how the Gd-BOPTA hepatocyte concentrations are modified by temperature and liver flow rates. We define new pharmacokinetic parameters to quantify the canalicular transport of Gd-BOPTA. Finally, we present how transfer rates generate Gd-BOPTA concentrations in rat liver compartments. These findings better explain how liver imaging with hepatobiliary radiotracers and contrast agents is generated and improve the image interpretation by clinicians.- Published
- 2018
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13. Quantification of drug transport function across the multiple resistance-associated protein 2 (Mrp2) in rat livers.
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Bonnaventure P and Pastor CM
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- Aniline Compounds, Animals, Bile metabolism, Biological Transport, Glycine, Hepatocytes metabolism, Imino Acids pharmacology, Liver drug effects, Meglumine analogs & derivatives, Meglumine pharmacology, Organometallic Compounds pharmacology, Organotechnetium Compounds pharmacology, Rats, ATP-Binding Cassette Transporters metabolism, Liver metabolism
- Abstract
To understand the transport function of drugs across the canalicular membrane of hepatocytes, it would be important to measure concentrations in hepatocytes and bile. However, these concentration gradients are rarely provided. The aim of the study is then to measure these concentrations and define parameters to quantify the canalicular transport of drugs through the multiple resistance associated-protein 2 (Mrp2) in entire rat livers. Besides drug bile excretion rates, we measured additional parameters to better define transport function across Mrp2: (1) Concentration gradients between hepatocyte and bile concentrations over time; and (2) a unique parameter (canalicular concentration ratio) that represents the slope of the non-linear regression curve between hepatocyte and bile concentrations. This information was obtained in isolated rat livers perfused with gadobenate dimeglumine (BOPTA) and mebrofenin (MEB), two hepatobiliary drugs used in clinical liver imaging. Interestingly, despite different transport characteristics including excretion rates into bile and hepatocyte clearance into bile, BOPTA and MEB have a similar canalicular concentration ratio. In contrast, the ratio was null when BOPTA was not excreted in bile in hepatocytes lacking Mrp2. The canalicular concentration ratio is more informative than bile excretion rates because it is independent of time, bile flows, and concentrations perfused in portal veins. It would be interesting to apply such information in human liver imaging where hepatobiliary compounds are increasingly investigated.
- Published
- 2014
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14. Experimental evidence of obesity as a risk factor for severe acute pancreatitis.
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Frossard JL, Lescuyer P, and Pastor CM
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- Acute Disease, Body Mass Index, Humans, Obesity pathology, Pancreatitis mortality, Prognosis, Risk Factors, Obesity complications, Pancreatitis complications
- Abstract
The incidence of acute pancreatitis, an inflammation of the pancreas, is increasing worldwide. Pancreatic injury is mild in 80%-90% of patients who recover without complications. The remaining patients may develop a severe disease with local complications such as acinar cell necrosis, abscess and remote organ injury including lung injury. The early prediction of the severity of the disease is an important goal for physicians in management of patients with acute pancreatitis in order to optimize the therapy and to prevent organ dysfunction and local complications. For that purpose, multiple clinical scale scores have been applied to patients with acute pancreatitis. Recently, a new problem has emerged: the increased severity of the disease in obese patients. However, the mechanisms by which obesity increases the severity of acute pancreatitis are unclear. Several hypotheses have been suggested: (1) obese patients have an increased inflammation within the pancreas; (2) obese patients have an increased accumulation of fat within and around the pancreas where necrosis is often located; (3) increase in both peri- and intra-pancreatic fat and inflammatory cells explain the high incidence of pancreatic inflammation and necrosis in obese patients; (4) hepatic dysfunction associated with obesity might enhance the systemic inflammatory response by altering the detoxification of inflammatory mediators; and (5) ventilation/perfusion mismatch leading to hypoxia associated with a low pancreatic flow might reduce the pancreatic oxygenation and further enhance pancreatic injury. Recent experimental investigations also show an increased mortality and morbidity in obese rodents with acute pancreatitis and the implication of the adipokines leptin and adiponectin. Such models are important to investigate whether the inflammatory response of the disease is enhanced by obesity. It is exciting to speculate that manipulation of the adipokine milieu has the potential to influence the severity of acute pancreatitis.
- Published
- 2009
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15. Opposite regulation of endothelial NO synthase by HSP90 and caveolin in liver and lungs of rats with hepatopulmonary syndrome.
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Frossard JL, Schiffer E, Cikirikcioglu B, Bourquin J, Morel DR, and Pastor CM
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- Acetylcholine pharmacology, Animals, Benzoquinones pharmacology, Bile Duct Diseases physiopathology, Caveolins biosynthesis, Common Bile Duct, HSP90 Heat-Shock Proteins biosynthesis, Hepatopulmonary Syndrome enzymology, In Vitro Techniques, Lactams, Macrocyclic pharmacology, Ligation, Lung drug effects, Norepinephrine pharmacology, Perfusion, Pulmonary Artery drug effects, Rats, Rats, Sprague-Dawley, Caveolins physiology, HSP90 Heat-Shock Proteins physiology, Hepatopulmonary Syndrome physiopathology, Liver enzymology, Lung enzymology, Nitric Oxide Synthase Type III physiology
- Abstract
The hepatopulmonary syndrome is a complication of cirrhosis that associates an overproduction of nitric oxide (NO) in lungs and a NO defect in the liver. Because endothelial NO synthase (eNOS) is regulated by caveolin that decreases and heat shock protein 90 (HSP90) that increases NO production, we hypothesized that an opposite regulation of eNOS by caveolin and HSP90 might explain the opposite NO production in both organs. Cirrhosis was induced by a chronic bile duct ligation (CBDL) performed 15, 30, and 60 days before sample collection and pharmacological tests. eNOS, caveolin, and HSP90 expression were measured in hepatic and lung tissues. Pharmacological tests to assess NO released by shear stress and by acetylcholine were performed in livers (n = 28) and lungs (n = 28) isolated from normal and CBDL rats. In lungs from CBDL rats, indirect evidence of high NO production induced by shear stress was associated with a high binding of HSP90 and a low binding of caveolin to eNOS. Opposite results were observed in livers from CBDL rats. Our study shows an opposite posttranslational regulation of eNOS by HSP90 and caveolin in lungs and liver from rats with CBDL. Such opposite posttranslational regulation of eNOS by regulatory proteins may explain in part the pulmonary overproduction of NO and the hepatic NO defect in rats with hepatopulmonary syndrome.
- Published
- 2007
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16. Hepatopulmonary syndrome increases the postoperative mortality rate following liver transplantation: a prospective study in 90 patients.
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Schiffer E, Majno P, Mentha G, Giostra E, Burri H, Klopfenstein CE, Beaussier M, Morel P, Hadengue A, and Pastor CM
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- Adult, Aged, Blood Gas Analysis, Female, Follow-Up Studies, Hepatopulmonary Syndrome blood, Hepatopulmonary Syndrome diagnostic imaging, Hepatopulmonary Syndrome mortality, Humans, Male, Middle Aged, Patient Selection, Prospective Studies, Survival Rate, Time Factors, Ultrasonography, Hepatopulmonary Syndrome surgery, Liver Transplantation mortality
- Abstract
Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of patients with end-stage liver diseases. HPS is diagnosed by hypoxemia and pulmonary vascular dilatation and is an independent risk factor of mortality. Orthotopic liver transplantation (OLT) is the only factor that modifies the natural course of HPS. Once patients with HPS have been transplanted, their long-term survival rate is similar to transplanted patients without HPS. Consequently, HPS is an indication of OLT whatever the severity of hypoxemia. However, besides the favorable long-term survival of HPS patients with OLT, a high postoperative mortality (mostly within 6 months) has been suggested. The aim of our study was to analyze the incidence of HPS and postoperative outcome after OLT in 90 consecutive patients. All patients were prospectively included and had blood gas analysis to detect HPS. Patients with hypoxemia had contrast echocardiography to confirm HPS. Nine patients had HPS with a 50 = PaO(2)= 70 mmHg. Among them 3 (33%) died while the mortality rate was 9.2% in the group without HPS (7 over 76 patients). In the HPS patients who survived, the syndrome completely recovered within 6 months. In conclusion, our study shows a high postoperative mortality rate following OLT even though the preoperative PaO(2) was >50 mmHg in all HPS patients transplanted.
- Published
- 2006
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17. Neutrophil depletion--but not prevention of Kupffer cell activation--decreases the severity of cerulein-induced acute pancreatitis.
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Pastor CM, Vonlaufen A, Georgi F, Hadengue A, Morel P, and Frossard JL
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- Acute Disease, Amylases blood, Animals, Cell Count, Ceruletide, Gadolinium pharmacology, Interleukins analysis, Interleukins blood, Kupffer Cells drug effects, Liver chemistry, Liver pathology, Lung chemistry, Lung pathology, Lung physiopathology, Male, Mice, Mice, Inbred C57BL, Neutrophil Activation, Pancreas chemistry, Pancreas pathology, Pancreatitis chemically induced, Peroxidase analysis, Random Allocation, Severity of Illness Index, Kupffer Cells physiology, Macrophage Activation, Neutrophils immunology, Pancreatitis immunology, Pancreatitis pathology
- Abstract
Aim: To determine whether neutrophil depletion and Kupffer cell inhibition might combine their protective effects to decrease the severity of acute pancreatitis., Methods: Mice had cerulein administration to induce acute pancreatitis and were pretreated with either anti-mouse neutrophil serum or gadolinium chloride (GdCl3) to prevent Kupffer cell activation, or both treatments. Injury was assessed in pancreas and lungs. Myeloperoxidases (MPO) assessed neutrophil infiltration. Interleukin-6 (IL-6) and IL-10 were measured in serum, pancreas, lungs and liver., Results: In mice with acute pancreatitis, neutrophil depletion reduced the severity of pancreatitis and pancreatitis-associated lung injury. Kupffer cell inactivation by GdCl3 had less protective effect, although IL-6 and IL-10 concentrations were significantly decreased. The protective treatment brought by neutrophil depletion was not enhanced by Kupffer cell inactivation and both treatments did not combine their protective effects., Conclusion: Our results confirm the role of activated neutrophils in aggravating organ injury in acute pancreatitis while the role of Kupffer cell activation is less obvious.
- Published
- 2006
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18. Epidural anaesthesia restores pancreatic microcirculation and decreases the severity of acute pancreatitis.
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Demirag A, Pastor CM, Morel P, Jean-Christophe C, Sielenkämper AW, Güvener N, Mai G, Berney T, Frossard JL, and Bühler LH
- Subjects
- Acute Disease, Animals, Disease Models, Animal, Hindlimb, Isoflurane, Male, Motor Activity, Pancreatitis physiopathology, Rats, Rats, Wistar, Anesthesia, Epidural methods, Microcirculation drug effects, Pancreas blood supply, Pancreatitis drug therapy
- Abstract
Aim: To investigate the effect of epidural anaesthesia (EA) on pancreatic microcirculation during acute pancreatitis (AP)., Methods: AP was induced by injection of sodium taurocholate into the pancreatic duct of Sprague-Dawley rats. To realize EA, a catheter was introduced into the epidural space between T7 and T9 and bupivacaine was injected. Microcirculatory flow was measured by laser Doppler flowmetry. Arterial blood gas analyses were performed. At the end of the experiment (
- Published
- 2006
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19. Endothelial nitric oxide synthase regulation is altered in pancreas from cirrhotic rats.
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Frossard JL, Quadri R, Hadengue A, Morel P, and Pastor CM
- Subjects
- Animals, Caveolin 1 analysis, HSP90 Heat-Shock Proteins analysis, Immunohistochemistry, Immunoprecipitation, Nitric Oxide Synthase Type III metabolism, Phosphorylation, Rats, Rats, Sprague-Dawley, Liver Cirrhosis, Biliary enzymology, Nitric Oxide Synthase Type III analysis, Pancreas enzymology
- Abstract
Aim: To determine whether biliary cirrhosis could induce pancreatic dysfunction such as modifications in endothelial nitric oxide synthase(eNOS) expression and whether the regulation of eNOS could be altered by the regulatory proteins caveolin and heat shock protein 90 (Hsp90), as well as by the modifications of calmodulin binding to eNOS., Methods: Immunoprecipitations and Western blotting analysis were performed in pancreas isolated from sham and cirrhotic rats., Results: Pancreatic injury was minor in cirrhotic rats but eNOS expression importantly decreased with the length (and the severity) of the disease. Because co-immunoprecipitation of eNOS with both Hsp90 and caveolin similarly decreased in cirrhotic rats, eNOS activity was not modified by this mechanism. In contrast, cirrhosis decreased the calmodulin binding to eNOS with a concomitant decrease in eNOS activity., Conclusion: In biliary cirrhosis, pancreatic injury is minor but the pancreatic nitric oxide (NO) production is significantly decreased by two mechanisms: a decreased expression of the enzyme and a decreased binding of calmodulin to eNOS.
- Published
- 2006
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20. Perioperative management of patients with increased risk of laparoscopy-induced hepatic hypoperfusion.
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Clergue F, Morel P, and Pastor CM
- Subjects
- Humans, Laparoscopy adverse effects, Liver Diseases etiology, Perioperative Care
- Abstract
Because hepatic hypoperfusion induced by laparoscopy has been underestimated, the aim of this article is to review the numerous factors influencing hepatosplanchnic blood flow during laparoscopy and to alert clinicians to the adverse consequences of hepatic hypoperfusion in high risk patients undergoing this procedure.
- Published
- 2004
- Full Text
- View/download PDF
21. Role of macrophage inflammatory peptide-2 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury.
- Author
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Pastor CM, Rubbia-Brandt L, Hadengue A, Jordan M, Morel P, and Frossard JL
- Subjects
- Acute Disease, Amylases blood, Animals, Ceruletide administration & dosage, Ceruletide toxicity, Chemokine CXCL2, Disease Models, Animal, Edema chemically induced, Edema pathology, Fluorescent Antibody Technique, Indirect, Gastrointestinal Agents administration & dosage, Gastrointestinal Agents toxicity, Injections, Intraperitoneal, Lung Diseases chemically induced, Lung Diseases complications, Male, Mice, Mice, Inbred Strains, Necrosis, Pancreas drug effects, Pancreas pathology, Pancreatitis chemically induced, Pancreatitis complications, Peroxidase blood, Lung Diseases metabolism, Monokines physiology, Pancreatitis metabolism
- Abstract
Acute pancreatitis is an inflammatory process of variable severity, and leukocytes are thought to play a key role in the development of pancreatitis and pancreatitis-associated lung injury. The effects of mediators released by these inflammatory cells may induce tissue damage. The aim of our study was to evaluate the role of the chemokine, macrophage inflammatory protein-2 (MIP-2), in the pathogenesis of cerulein-induced pancreatitis and pancreatitis-associated lung injury. The severity of pancreatitis was measured by serum amylase, pancreatic edema, acinar cell necrosis, and myeloperoxidase activity. Lung injury was quantitated by evaluating lung microvascular permeability and lung myeloperoxidase activity. To determine the role of MIP-2 in the pathophysiology of the disease, anti-MIP-2 antibody was administered either 1 hour before or 2 hours after the start of cerulein administration. MIP-2 concentrations increased in serum, pancreas, and lung tissues in mice treated with cerulein. Anti-MIP-2 antibody administrated either before or after cerulein partially protected against pancreas and lung injury. These results show that MIP-2 plays a key role in the pathophysiology of acute pancreatitis and that MIP-2 blockade may improve the outcome of the disease.
- Published
- 2003
- Full Text
- View/download PDF
22. Why clinical trials might succeed in acute pancreatitis when they failed in septic shock.
- Author
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Frossard JL, Morel P, and Pastor CM
- Subjects
- APACHE, Acute Disease, Anti-Inflammatory Agents therapeutic use, Humans, Research Design, Severity of Illness Index, Treatment Failure, Clinical Trials as Topic methods, Pancreatitis classification, Pancreatitis diagnosis, Pancreatitis drug therapy, Shock, Septic classification, Shock, Septic diagnosis, Shock, Septic drug therapy
- Published
- 2003
23. Hepatic kinetics of MRI contrast agents in the isolated perfused rat liver.
- Author
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Pastor CM, Terrier F, and Vallée JP
- Subjects
- Animals, Rats, Contrast Media pharmacokinetics, Gadolinium DTPA pharmacokinetics, Liver metabolism, Magnetic Resonance Imaging, Meglumine analogs & derivatives, Meglumine pharmacokinetics, Organometallic Compounds pharmacokinetics
- Published
- 2002
- Full Text
- View/download PDF
24. New serum markers for the detection of severe acute pancreatitis in humans.
- Author
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Frossard JL, Hadengue A, and Pastor CM
- Subjects
- Acute Disease, Biomarkers, Humans, Predictive Value of Tests, Severity of Illness Index, Cytokines blood, Pancreatitis blood, Pancreatitis classification, Pancreatitis metabolism, Pancreatitis physiopathology
- Published
- 2001
- Full Text
- View/download PDF
25. Effect of hyperthermia on NF-kappaB binding activity in cerulein-induced acute pancreatitis.
- Author
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Frossard JL, Pastor CM, and Hadengue A
- Subjects
- Acute Disease, Animals, Ceruletide, HSP70 Heat-Shock Proteins metabolism, Intercellular Adhesion Molecule-1 metabolism, Male, Osmolar Concentration, Pancreatitis chemically induced, Rats, Rats, Wistar, Reference Values, Tumor Necrosis Factor-alpha metabolism, Fever metabolism, NF-kappa B metabolism, Pancreatitis metabolism
- Abstract
Although the pancreatic heat shock response has already been reported to confer protective effects during experimental pancreatitis, the mechanism of action remains unknown. We investigated the effects of hyperthermia in cerulein-induced pancreatitis. Heat shock protein 70 (HSP70) expression in rats was induced by a 20-min period of water immersion (42 degrees C). The severity of pancreatitis as well as the pancreatic expression of cytokines, nuclear factor-kappaB (NF-kappaB), and inhibitory factor kappaB-alpha (IkappaB-alpha) were evaluated in the presence and absence of hyperthermia. We found that hyperthermia resulted in time-dependent expression of HSP70 within the pancreas associated with a reduction in the severity of acute pancreatitis. Tumor necrosis factor-alpha and intercellular adhesion molecule-1 expression was significantly reduced in the presence of hyperthermia. Moreover, NF-kappaB activity was delayed in the presence of hyperthermia whereas IkappaB-alpha was stabilized in the cytoplasm. These results suggest that hyperthermia decreases the severity of cerulein-induced pancreatitis by decreasing cytokine expression in the pancreas through the modulation of NF-kappaB activity.
- Published
- 2001
- Full Text
- View/download PDF
26. Minor involvement of nitric oxide during chronic endotoxemia in anesthetized pigs.
- Author
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Pastor CM, Hadengue A, and Nussler AK
- Subjects
- Acetylcholine pharmacology, Animals, Blood Pressure drug effects, Chronic Disease, Endotoxemia blood, Endotoxemia metabolism, Female, Hemodynamics, Liver metabolism, Liver physiopathology, Liver Circulation drug effects, Male, Nitric Oxide Synthase genetics, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type II, Oxygen Consumption, RNA, Messenger metabolism, Reference Values, Swine, Swine, Miniature, Vasodilator Agents pharmacology, Endotoxemia physiopathology, Nitric Oxide physiology
- Abstract
To study the modifications of hepatic blood flow and hepatic function over time during endotoxemia, 10 pigs received a continuous intravenous infusion of endotoxin (Endo, 160 ng. kg(-1). h(-1)) over 18 h and 7 control (Ctrl) animals received a saline infusion. The involvement of nitric oxide (NO) in this endotoxic model was assessed by measuring plasma concentrations of NO(-)(2), NO(-)(3), and cGMP, by testing vascular reactivity to ACh, and by evaluating inducible NO synthase (NOS 2) expression in hepatic biopsies. Endotoxin induced hypotensive and normokinetic shock in association with few modifications of hepatic blood flow, and hepatic injury was observed in both groups. Endotoxin did not increase plasma concentrations of NO(-)(2), NO(-)(3), and cGMP. The ACh-dependent decrease of mean arterial pressure was reduced in Endo pigs, whereas a minor difference was observed between Ctrl and Endo pigs for ACh-dependent modification of hepatic perfusion. Hepatic NOS 2 mRNA was not detected in Ctrl pigs. In Endo pigs, NOS 2 protein expression was detected only in tissues surrounding the portal vein and the inferior vena cava, whereas NOS 2 mRNA was expressed in all hepatic biopsies. Thus, although endotoxemia induces NOS 2 expression in the liver, our findings show that NO involvement is lower in pigs than in rodents during endotoxemia.
- Published
- 2000
- Full Text
- View/download PDF
27. Hepatic vascular response to norepinephrine during endotoxemia in anesthetized pigs.
- Author
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Mastrangelo D and Pastor CM
- Subjects
- Anesthetics, Animals, Chronic Disease, Female, Hemodynamics drug effects, Male, Portal Vein drug effects, Swine, Swine, Miniature, Endotoxemia drug therapy, Hepatic Veins drug effects, Norepinephrine pharmacology, Vasoconstrictor Agents pharmacology
- Abstract
To investigate the systemic and hepatic reactivity to norepinephrine (NE) during chronic endotoxemia, we measured the reactivity of the drug in pigs infused with endotoxin (End, 160 ng/kg/min) during an 18-h period. At the end of the experiments, the hepatic vessels were removed to test the hepatic vascular reactivity in vitro. The pressive response to NE did not change over time in control (Ctrl) pigs, but endotoxin infusion decreased the response at t = 11 and 17 h. The reactivity of the portal vein blood flow did not change in Ctrl pigs but was significantly increased in End pigs at t = 5 h. Finally, endotoxin decreased the contractile response to NE only in transversal strips of portal veins isolated from End pigs. Thus, in this model, the decreased pressive response to NE develops over time, but the modifications of the hepatic vascular reactivity remain minor.
- Published
- 1999
- Full Text
- View/download PDF
28. Beneficial effects of leukocyte-depleted blood and low-potassium dextran solutions on microvascular permeability in preserved porcine lung.
- Author
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Schneuwly OD, Licker M, Pastor CM, Schweizer A, Slosman DO, Kapanci Y, Nicod LP, Robert J, Spiliopoulos A, and Morel DR
- Subjects
- Animals, Capillary Permeability drug effects, Capillary Permeability physiology, Female, Hypertonic Solutions pharmacology, Lung drug effects, Lung pathology, Lung physiopathology, Lung Compliance physiology, Lung Transplantation pathology, Lung Volume Measurements, Male, Oxygen blood, Reperfusion Injury pathology, Reperfusion Injury physiopathology, Respiratory Mechanics physiology, Swine, Blood, Dextrans pharmacology, Lung Transplantation physiology, Lymphocyte Depletion, Organ Preservation, Organ Preservation Solutions pharmacology, Potassium pharmacology
- Abstract
Modified Euro-Collins (EC) solution, a crystalloid intracellular-type solution, has been commonly used for pulmonary preservation. Several experimental studies have shown the advantages of using extracellular colloid-based solutions. The aim of this study was to compare the quality of preservation of two extracellular colloid solutions, leukocyte-depleted blood (BL) and low-potassium dextran (LPD) solutions, with that of EC solution. Lungs of 22 domestic pigs were flushed and preserved with EC (n = 8), BL (n = 7), or LPD (n = 7) solution. After harvesting, one of the lungs was reperfused immediately in an ex vivo circuit (control lungs), whereas the contralateral lung was reperfused after 8 h of cold (4 degrees C) storage (preserved lungs). Besides the lung function parameters (gas exchange, pulmonary hemodynamics and mechanics), the permeability of the endothelial-epithelial barrier was assessed by determining the transferrin leak index (TLI) using a double radioisotopic method, by measuring the alveolar/arterial protein concentration ratio, and by analyzing histopathologic changes. The functional quality (oxygenation, airway resistance, dynamic compliance [CL, dyn]) of both BL and LPD lungs was slightly but significantly superior to that of EC lungs. However, pulmonary vascular resistance was lower in BL-preserved than in EC- or LPD-preserved lungs. The TLI was increased in EC control and preserved lungs, whereas it was low in BL and LPD control lungs and did not increase after preservation. The alveolar/arterial protein concentration ratio was not different between control groups, but was increased fourfold in EC-preserved compared with BL- or LPD-preserved lungs. Finally, EC-preserved lungs presented a weight gain about twice that of BL- and LPD-preserved lungs. Morphologic analysis confirmed these results, because in the EC-preserved lungs, rupture of alveolar septa and severe alveolar edema and hemorrhage were observed, whereas BL- and LPD-preserved lungs showed a relatively well-preserved structure. The results demonstrate that both BL and LPD flush solutions preserve the endothelial-epithelial barrier better than does EC solution. Although the quality of preservation is similar, pulmonary vascular resistance is higher in LPD-preserved than in BL-preserved lungs.
- Published
- 1999
- Full Text
- View/download PDF
29. Hepatic hemodynamics and cell functions in human and experimental sepsis.
- Author
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Pastor CM and Suter PM
- Subjects
- Animals, Humans, Lactates metabolism, Liver metabolism, Liver Circulation, Oxygen Consumption, Shock, Septic physiopathology, Splanchnic Circulation, Liver physiopathology, Sepsis physiopathology
- Published
- 1999
- Full Text
- View/download PDF
30. Oxygen supply dependence of urea production in the isolated perfused rat liver.
- Author
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Pastor CM, Morel DR, and Billiar TR
- Subjects
- Ammonium Chloride administration & dosage, Ammonium Chloride metabolism, Animals, Buffers, Glucose, Glutamine administration & dosage, Glutamine metabolism, L-Lactate Dehydrogenase metabolism, Lactates metabolism, Linear Models, Liver enzymology, Male, Organ Preservation Solutions, Oxygen administration & dosage, Oxygen Consumption, Perfusion, Potassium metabolism, Rats, Rats, Sprague-Dawley, Regional Blood Flow, Tromethamine, Liver metabolism, Oxygen blood, Urea metabolism
- Abstract
To determine whether hepatic urea production is limited at low hepatic O2 delivery (DO2) by O2 itself or by the availability of substrate for urea synthesis, we isolated livers from normal rats and perfused them with Krebs-Henseleit bicarbonate (KHB) buffer, KHB + 5 mM NH4Cl, or KHB + 5 mM glutamine (Gln) as an NH3 donor. The pump flow was lowered in stages, and we determined at each flow rate inflow and outflow O2 content and urea levels in the outflow perfusate. Urea production in Gln-perfused livers remained constant at high DO2 and declined in direct proportion to DO2 below a critical oxygen delivery (DO2crit, the point below which the hepatic O2 consumption [VO2] becomes limited by the hepatic DO2). The DO2crit calculated from the urea release-DO2 relationship (147 +/- 32 microl/min/dry g) was similar to the DO2crit calculated from the VO2-DO2 relationship (158 +/- 26 microl/min/dry g). When Gln concentration and flow rate were maintained constant while decreasing PO2 in the inflow perfusate (as well as hepatic DO2), urea production declined below the DO2crit. Furthermore, when Gln concentration in the perfusate was gradually reduced while keeping hepatic DO2 constant, urea production decreased proportionally with Gln concentrations in the perfusate. Consequently, urea production is dependent on Gln and O2 availability and becomes limited at the same DO2crit determined by the VO2-DO2 relationship.
- Published
- 1998
- Full Text
- View/download PDF
31. Competition for tetrahydrobiopterin between phenylalanine hydroxylase and nitric oxide synthase in rat liver.
- Author
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Pastor CM, Williams D, Yoneyama T, Hatakeyama K, Singleton S, Naylor E, and Billiar TR
- Subjects
- Animals, Binding, Competitive, Biopterins metabolism, Liver enzymology, Male, Rats, Rats, Sprague-Dawley, Biopterins analogs & derivatives, Liver metabolism, Nitric Oxide Synthase metabolism, Phenylalanine metabolism
- Abstract
Tetrahydrobiopterin (BH4) is an important cofactor for two hepatic enzymes, inducible nitric oxide synthase (iNOS) and phenylalanine hydroxylase (PAH), and competition for BH4 between the two enzymes might limit hepatic iNOS or PAH activity. To test this hypothesis, we determined whether conversion of phenylalanine to tyrosine was modified by changes in NO synthase activity, and conversely whether NO synthesis was limited by the rate of phenylalanine conversion to tyrosine in rat hepatocytes and perfused livers. NO production was decreased only slightly, when flux through PAH was maximized in isolated perfused livers, and in isolated hepatocytes only when BH4 synthesis was inhibited. Increases in NO synthesis did not reduce tyrosine formation from phenylalanine. Phenylalanine markedly increased biopterin synthesis, whereas arginine had no effect. Thus, basal BH4 synthesis appears to be adequate to support iNOS activity, whereas BH4 synthesis is increased to support PAH activity.
- Published
- 1996
- Full Text
- View/download PDF
32. Effect of modifying nitric oxide pathway on liver circulation in a rabbit endotoxin shock model.
- Author
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Pastor CM and Payen DM
- Subjects
- Animals, Blood Flow Velocity drug effects, Blood Pressure drug effects, Hepatic Artery drug effects, Hepatic Artery physiology, Hepatic Artery physiopathology, Liver Circulation drug effects, Male, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Mesenteric Arteries physiopathology, Molsidomine analogs & derivatives, Molsidomine pharmacology, Nitric Oxide antagonists & inhibitors, Nitroarginine, Portal Vein drug effects, Portal Vein physiology, Portal Vein physiopathology, Rabbits, Vasodilator Agents pharmacology, Arginine analogs & derivatives, Arginine pharmacology, Liver Circulation physiology, Nitric Oxide physiology, Shock, Septic physiopathology
- Abstract
The role of nitric oxide (NO) inhibition on liver circulation during sepsis is unknown. To answer this question, we studied the effects of L-arginine (the substrate for the NO synthase), linsidomine (a direct NO donor), and N omega-nitro-L-arginine (an NO inhibitor) on the liver circulation in anesthetized rabbits previously injected with endotoxin (Escherichia coli, Salmonella enteridis, and Salmonella minnesota, 400 micrograms each). After endotoxin administration, and without fluid resuscitation, rabbits showed a hypodynamic shock with decrease in mean arterial pressure (MAP) and aortic blood flow velocity. Portal vein blood flow velocity decreased, whereas hepatic artery blood flow velocity increased. Saline or treatments were injected, 75 min after endotoxin administration. In saline-treated rabbits, MAP, aortic and portal vein blood flow velocities remained steady but hepatic artery blood flow velocity decreased. Only N omega-nitro-L-arginine (7.5 mg/kg, intravenously) significantly increased MAP compared to saline treatment. However, aortic, portal vein, and hepatic artery blood flow velocities were lower in rabbits treated with N omega-nitro-L-arginine than in saline-treated rabbits. L-Arginine (600 mg/kg, intravenously) increased aortic blood flow and portal vein blood flow velocity with no change on hepatic artery blood flow velocity. In contrast, linsidomine (1 mg) increased both hepatic flows. These results show that NO inhibition after endotoxin injection reduces systemic and liver flows, while NO release from linsidomine improves them. These findings question the usefulness of NO inhibition during septic shock, particularly as hepatic failure frequently occurs in the evolution of the disease.
- Published
- 1994
- Full Text
- View/download PDF
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