We elucidate the role of late Na+ current (INaL) for diastolic intracellular Ca2+ (DCa) accumulation in chronic heart failure (HF). HF was induced in 19 dogs by multiple coronary artery microembolizations; 6 normal dogs served as control. Ca2+ transients were recorded in field-paced (0.25 or 1.5 Hz) fluo-4-loaded ventricular myocytes (VM). INaL and action potentials were recorded by patch-clamp. Failing VM, but not normal VM, exhibited (1) prolonged action potentials and Ca2+ transients at 0.25 Hz, (2) substantial DCa accumulation at 1.5 Hz, and (3) spontaneous Ca2+ releases, which occurred after 1.5 Hz stimulation trains in ~31% cases. Selective INaL blocker ranolazine (10 microM) or the prototypical Na+ channel blocker tetrodotoxin (2 microM) reversibly improved function of failing VM. The DCa accumulation and the beneficial effect of INaL blockade were reproduced in silico using an excitation-contraction coupling model. We conclude that INaL contributes to diastolic Ca2+ accumulation and spontaneous Ca2+ release in HF.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891122 | PMC |
| http://dx.doi.org/10.1007/s12576-010-0092-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Studying the intracellular bile acid concentration and toxicity in drug-induced cholestasis: Comprehensive LC-MS/MS analysis with human liver slices.
Toxicol In Vitro
January 2025
University of Groningen, Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands. Electronic address:
Drug-induced cholestasis (DIC) is a leading cause of drug-induced liver injury post-drug marketing, characterized by bile flow obstruction and toxic bile constituent accumulation within hepatocytes. This study investigates the toxicity associated with intracellular bile acid (BA) accumulation during DIC development. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, we examined intracellular BA concentrations in human precision-cut liver slices (PCLS) following the administration of cyclosporin A and chlorpromazine, both with and without an established BA mixture.
View Article and Find Full Text PDFLactoferrin-functionalized PEGylation liposomes loaded with norcantharidin acid for targeted therapy of hepatocellular carcinoma.
Int J Pharm
January 2025
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110116, China.
Norcantharidin (NCTD), an antitumor agent with an increased leukocyte function, has been used for the treatment of hepatocellular carcinoma (HCC) in clinical. However, the clinical application of NCTD is limited due to its inadequate hydrophilicity and lipophilicity, short half-life (t), as well as adverse effects such as vascular irritation, cardiotoxicity, and nephrotoxicity. Herein, a lactoferrin (Lf) and DSPE-mPEG functionalized liposomes loaded with norcantharidic acid (NCA), an active metabolite of NCTD, was constructed for the targeted therapy of HCC.
View Article and Find Full Text PDFSecondary bile acid derivatives are contributors to the fecal bile acid pool and associated with bile acid modulating nutrients.
J Nutr
January 2025
Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA; University of Illinois Cancer Center, Chicago, Illinois, USA. Electronic address:
Objective: Accumulation of hydrophobic bile acids is linked with cancer development. However, derivatives of deoxycholic acid (DCA) and lithocholic acid (LCA) produced via bacterial metabolism may mitigate the proinflammatory and cytotoxic effects of hydrophobic bile acids. The impact of diet on secondary bile acid (BA) derivative production has not been determined.
View Article and Find Full Text PDFAn Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Deoxycholic Acid and Application to a Pharmacokinetic Study in Human Plasma.
Biomed Chromatogr
February 2025
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Deoxycholic acid (DCA) injection is applied in treating moderate to severe submental bulge or facial fullness caused by excessive submental fat accumulation. Using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technology, which was swiftly, precisely, and reliably confirmed, DCA was determined in human plasma with low quantification limits of 56 ng/mL. We selected six healthy individual blank human plasma with low concentrations of endogenous DCA and mixed them to prepare standard curve samples.
View Article and Find Full Text PDFMedium chain triglycerides alleviate non-alcoholic fatty liver disease through bile acid-mediated FXR signaling pathway: A comparative study with common vegetable edible oils.
J Food Sci
December 2024
Institute of Food & Nutrition Science and Technology, Shandong Engineering Research Center of Food for Special Medical Purpose, Key Laboratory of Agro-Products Processing Technology of Shandong Province, Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs, Shandong Academy of Agricultural Sciences, Shandong, P. R. China.
With the global epidemic trend of obesity, non-alcoholic fatty liver disease (NAFLD) has become a significant cause of chronic liver disease, seriously affecting human health. Medium-chain triglycerides (MCT) with a fatty acid chain length varying between 6 and 10 carbon atoms (most sources from coconut and palm kernel oils), which exhibited activities to improve lipid metabolism, prevent cardiovascular diseases, and enhance immunity. However, the efficacy differences and potential mechanisms between MCT and traditional long-chain vegetable oils (palm oil, PA; high oleic peanut oil, OA) in obesity-induced NAFLD were still unclear.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!