Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis. Am J Physiol Heart Circ Physiol 287: H1039 -H1045, 2004. First published April 22, 2004 10.1152/ajpheart.01016.2003.-The creatine kinase (CK) system is involved in the rapid transport of high-energy phosphates from the mitochondria to the sites of maximal energy requirements such as myofibrils and sarcolemmal ion pumps. Hearts of mice with a combined knockout of cytosolic M-CK and mitochondrial CK (M/Mito-CK Ϫ/Ϫ ) show unchanged basal left ventricular (LV) performance but reduced myocardial high-energy phosphate concentrations. Moreover, skeletal muscle from M/Mito-CK Ϫ/Ϫ mice demonstrates altered Ca 2ϩ homeostasis. Our hypothesis was that in CK-deficient hearts, a cardiac phenotype can be unmasked during acute stress conditions and that susceptibility to ischemia-reperfusion injury is increased because of altered Ca 2ϩ homeostasis. We simultaneously studied LV performance and myocardial Ca 2ϩ metabolism in isolated, perfused hearts of M/Mito-CK Ϫ/Ϫ (n ϭ 6) and wild-type (WT, n ϭ 8) mice during baseline, 20 min of no-flow ischemia, and recovery. Whereas LV performance was not different during baseline conditions, LV contracture during ischemia developed significantly earlier (408 Ϯ 72 vs. 678 Ϯ 54 s) and to a greater extent (50 Ϯ 2 vs. 36 Ϯ 3 mmHg) in M/Mito-CK Ϫ/Ϫ mice. During reperfusion, recovery of diastolic function was impaired (LV end-diastolic pressure: 22 Ϯ 3 vs. 10 Ϯ 2 mmHg), whereas recovery of systolic performance was delayed, in M/Mito-CK Ϫ/Ϫ mice. In parallel, Ca 2ϩ transients were similar during baseline conditions; however, M/Mito-CK Ϫ/Ϫ mice showed a greater increase in diastolic Ca 2ϩ concentration ([Ca 2ϩ ]) during ischemia (237 Ϯ 54% vs. 167 Ϯ 25% of basal [Ca 2ϩ ]) compared with WT mice. In conclusion, CK-deficient hearts show an increased susceptibility of LV performance and Ca 2ϩ homeostasis to ischemic injury, associated with a blunted postischemic recovery. This demonstrates a key function of an intact CK system for maintenance of Ca 2ϩ homeostasis and LV mechanics under metabolic stress conditions. aequorin bioluminescence; transgenic mouse THE CREATINE KINASE (CK) system comprises a family of mitochondrial (Mito-CK) and cytosolic (MM-, MB-, and BB-CK) isoenzymes that are critically involved in intracellular energy homeostasis. The primary role of CK is to catalyze the reversible transfer of a high-energy phosphoryl group between ATP and phosphocreatine (PCr; PCr ϩ ADP ϩ H ϩ 7 ATP ϩ creatine). The functional and physical coupling of certain members of the CK isoenzyme family to the sites of energy production and utilization has underscored the integrated properties of this important enzyme system in excitable tissue, particularly in muscle cells (26). MM-CK, for example, is present in membrane vesicles of the sarcoplasmic reticulum (SR) isolated from skeletal muscle (15), suggesting that an efficient and fast energy replenishing system is necessary for op...
Monitoring specific chemical properties is the key to chemical process control. Today, mainly optical online methods are applied, which require time- and cost-intensive calibration effort. NMR spectroscopy, with its advantage being a direct comparison method without need for calibration, has a high potential for enabling closed-loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and rough environments for process monitoring and advanced process control strategies. We present a fully automated data analysis approach which is completely based on physically motivated spectral models as first principles information (indirect hard modeling-IHM) and applied it to a given pharmaceutical lithiation reaction in the framework of the European Union's Horizon 2020 project CONSENS. Online low-field NMR (LF NMR) data was analyzed by IHM with low calibration effort, compared to a multivariate PLS-R (partial least squares regression) approach, and both validated using online high-field NMR (HF NMR) spectroscopy. Graphical abstract NMR sensor module for monitoring of the aromatic coupling of 1-fluoro-2-nitrobenzene (FNB) with aniline to 2-nitrodiphenylamine (NDPA) using lithium-bis(trimethylsilyl) amide (Li-HMDS) in continuous operation. Online 43.5 MHz low-field NMR (LF) was compared to 500 MHz high-field NMR spectroscopy (HF) as reference method.
Modular plants using intensified continuous processes represent an appealing concept for the production of pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes; besides, it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and is based on a compact nuclear magnetic resonance (NMR) spectrometer. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including robust evaluation of sensor data. Beyond monitoring the product quality, online NMR data was used in a new iterative optimization approach to maximize the plant profit and served as a reliable reference for the calibration of a near-infrared (NIR) spectrometer. The overall approach was demonstrated on a commercial-scale pilot plant using a metal-organic reaction with pharmaceutical relevance. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00216-019-01752-y) contains supplementary material, which is available to authorized users.
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