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Rudolph T.K.,University of Cologne | Ravekes T.,University of Cologne | Klinke A.,University of Cologne | Klinke A.,St Annes University Hospital Brno | And 15 more authors.
Cardiovascular Research | Year: 2016

Aim Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF. Methods and results Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2-dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation. Conclusion OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs. © 2015 Published on behalf of the European Society of Cardiology.

Schwoerer A.P.,University of Hamburg | Schwoerer A.P.,German Center for Cardiovascular Research Hamburg Kiel Luebeck | Scheel H.,University of Hamburg | Friederich P.,TU Munich
Anesthesia and Analgesia | Year: 2015

BACKGROUND: Intoxication with local anesthetics may induce cardiac arrhythmias by interaction with ion channels. Ropivacaine has been introduced into clinical anesthesia as a safer alternative to bupivacaine, which is associated with a relatively high risk of cardiac arrhythmias. Diverging safety profiles may result from differences in the mode of interaction with cardiac Na+ channels. We conducted this study to test this hypothesis and to provide experimental basis for the ongoing discussion regarding the cardiotoxic profiles of these local anesthetics. METHODS: The influence of bupivacaine and ropivacaine on the electrophysiological properties of Na+ channels was investigated in human embryonic kidney-293 cells stably transfected with SCN5A channels cloned from the human heart using the patch-clamp technique in the outside-out configuration. RESULTS: Open-channel block of SCN5A channels was concentration dependent, with bupivacaine being approximately 4.5-fold more potent than ropivacaine (IC50 = 69.5 ± 8.2 μM vs IC50 = 322.2 ± 29.9 μM). Both drugs influenced the voltage dependency of channel activation and steady-state inactivation by shifting the membrane potential of half-maximal activation/inactivation toward somewhat more negative membrane potentials. In their inactivated state, SCN5A channels were slightly more sensitive toward bupivacaine than toward ropivacaine (IC50 = 2.18 ± 0.16 μM vs IC50 = 2.73 ± 0.27 μM). Blockade of inactivated channels developed in a concentration-dependent manner, with comparable time constants for both drugs, whereas recovery from block was approximately 2-fold faster for ropivacaine than for bupivacaine. CONCLUSIONS: Human cardiac Na+ channels show state-dependent inhibition by ropivacaine, and the mode of interaction is comparable to that of bupivacaine. Therefore, modest differences in cardiotoxicity between these local anesthetic drugs are compatible with subtle differences in their interaction with human cardiac Na+ channels. © 2015 International Anesthesia Research Society.

Schwoerer A.P.,University of Hamburg | Schwoerer A.P.,German Center for Cardiovascular Research Hamburg Kiel Luebeck | Neef S.,University of Gottingen | Broichhausen I.,University of Hamburg | And 25 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2013

Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca2+ transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca2+ transients, we investigated Ca2+ cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca2+ content was reduced by ~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca 2+ sparks and a diminished systolic Ca2+ release, even though the expression of ryanodine receptors was increased by ~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca2+ influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type Ca2+ channels (LTCC) were upregulated in atrophic myocardium. These data suggest that in early cardiac atrophy induced by mechanical unloading, an augmented sarcolemmal Ca2+ influx through LTCC fully compensates for a reduced systolic SR Ca2+ release to preserve the Ca2+ transient. This interplay involves an electrophysiological remodelling as well as changes in the expression of cardiac ion channels. © 2013 The Author(s).

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