Molecular and cellular biochemistry
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Mol. Cell. Biochem. · Oct 1996
ReviewElucidating molecular mechanisms of septic cardiomyopathy--the cardiomyocyte model.
In the multiple organ dysfunction syndrome of sepsis and septic shock the heart is one of the organs subject to failure. Many new insights into the mechanisms underlying septic cardiomyopathy were gained in the last years. ⋯ These substances interfere at clinically relevant concentrations with several main inotropic axes, not only with the beta-adrenoceptor/adenylyl cyclase and with the NO-cGMP-system-on which most of the interest is focused at present-but also with the alpha 1-adrenoceptor/phosphoinositide pathway and the Ca2+ homeostasis of the cardiomyocyte, the latter representing the common final inotropic pathway. Not a single cardiodepressant factor, but more likely a total bunch of toxins and mediators with different attack mechanisms seem to contribute to the picture of septic cardiomyopathy.
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Mol. Cell. Biochem. · Oct 1996
Alterations in inotropy, nitric oxide and cyclic GMP synthesis, protein phosphorylation and ADP-ribosylation in the endotoxin-treated rat myocardium and cardiomyocytes.
To evaluate the effects of the in vivo endotoxin treatment of the rat on (1) the contractile responses in the subsequently isolated papillary muscle to adrenergic and cholinergic agonists and (2) the biochemical parameters (cyclic GMP, nitric oxide synthesis, protein phosphorylation and ADP-ribosyslation) in the subsequently isolated cardiomyocytes. Following the in vivo endotoxin treatment (4 mg/kg i.p., 18 h), contractile responses to increasing amounts of isoprenaline or to increasing amounts of oxotremorine in the presence of a fixed amount of isoprenaline were determined in isolated papillary strips. Activities of nitric oxide synthase, guanylyl cyclase, as well as phosphorylation of phospholamban and troponin-inhibitory subunit, and pertussis toxin-catalyzed and endogenous ADP-ribosylations were determined in the intact cardiomyocytes and subcellular fractions. ⋯ The activities of both nitric oxide synthase, primarily of the inducible form of the enzyme, and cytosolic guanylyl cyclase were higher while the phosphorylations of both phospholamban and troponin-inhibitory subunit were of lesser magnitude in the cardiomyocytes following the in vivo endotoxin treatment. Pertussis toxin-catalyzed ADP-ribosylation of the 41 kDa polypeptide, which is the alpha subunit of Gi, was also decreased. The results of the present study support the postulate that alterations in both the cyclic AMP and cyclic GMP signalling cascade contribute to the myocardial dysfunction caused by endotoxin and cytokines.
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Mol. Cell. Biochem. · Dec 1993
Dissociation between myocardial relaxation and diastolic stiffness in the stunned heart: its prevention by ischemic preconditioning.
The effects of myocardial stunning and ischemic preconditioning on left-ventricular developed pressure and end-diastolic pressure (diastolic stiffness) as well as on coronary-perfusion pressure were examined in isolated isovolumic rabbit hearts. The isovolumic relaxation was evaluated, and the time constant of pressure decay during the isovolumic period was calculated. Our experimental protocol comprised: 1) myocardial stunning-global ischemia (15 min) followed by reperfusion (30 min); 2) myocardial stunning-global ischemia (20 min) followed by reperfusion (30 min); and 3) ischemic preconditioning--a single cycle of brief global ischemia and reperfusion (5 min each), before a second ischemic period, of 20-min duration. ⋯ They were increased after stunning, as also was the coronary perfusion pressure. When the heart was preconditioned with a single episode of ischemia, the systolic and diastolic alterations were completely abolished. We thus concluded that diastolic abnormalities incurred by myocardial stunning consist in both an increase in diastolic stiffness and an early impairment of isovolumic relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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Mol. Cell. Biochem. · Jun 1993
Purification and partial characterisation of an alpha-tocopherol-binding protein from rabbit heart cytosol.
An alpha-tocopherol-binding protein has been isolated and purified from rabbit heart cytosol. The purified protein had an apparent molecular mass of 14,200, as derived from SDS-PAGE. ⋯ Neither gamma nor delta tocopherol could displace the bound alpha-tocopherol from the protein, suggesting a high specificity for alpha-tocopherol. alpha-Tocopherol-binding protein did not bind oleate. Transfer of alpha-tocopherol from liposomes to mitochondria was stimulated 8-fold in the presence of the binding protein, suggesting that this protein may be involved in the intracellular transport of alpha-tocopherol in the heart.
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Mol. Cell. Biochem. · Apr 1993
Biochemical and electron microscopy analysis of the endotoxin binding to microtubules in vitro.
The mechanisms involved in cellular activation and damage by bacterial endotoxins are not completely defined. In particular, there is little information about possible intracellular targets of endotoxins. Recently, the participation of a microtubule associated protein in endotoxin actions on macrophages has been suggested. ⋯ Electron microscopy showed that LPS binds to microtubules of tubulin + MAPs and to microtubules of purified tubulin (without MAPs) polymerized with taxol. Gel filtration experiments confirmed the binding of LPS to tubulin, and by ligand blot assays an interaction LPS-MAP-2 was detected. The ability of LPS to interact with microtubular proteins suggests a possible participation of microtubules on the cellular effects of endotoxins.