caa a22 4500 606236724 CHVBK 20210128101249.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s11010-015-2350-1 doi (NATIONALLICENCE)springer-10.1007/s11010-015-2350-1 Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat [Elektronische Daten] [Marek Matus, Dana Kucerova, Peter Kruzliak, Adriana Adameova, Gabriel Doka, Katarina Turcekova, Jana Kmecova, Jan Kyselovic, Peter Krenek, Uwe Kirchhefer, Frank Mueller, Peter Boknik, Jan Klimas] Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5mg/kg every 12h) or vehicle (CON) for 2weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca2+-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr17-PLB—phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2—voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P<0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P<0.05) and under beta-adrenergic stimulation (by 73%, P<0.05). Enalaprilat shortened QTc interval duration (CON 78±1ms vs. ENA 72±2ms; P<0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P<0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100±20 vs. ENA 304±13; P<0.05) and complete absence of basal Ca2+/calmodulin-dependent phosphorylation of PLB at Thr17. Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression. Springer Science+Business Media New York, 2015 ACE inhibition nationallicence SERCA2a nationallicence Phospholamban nationallicence Cacna1c nationallicence Cardiac repolarization nationallicence QT interval nationallicence Arrhythmogenesis nationallicence Matus Marek Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Kucerova Dana Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Kruzliak Peter Department of Cardiovascular Diseases, International Clinical Research Center, St. Anne's University Hospital and Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic aut Adameova Adriana Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Doka Gabriel Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Turcekova Katarina Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Kmecova Jana Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Kyselovic Jan Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Krenek Peter Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Kirchhefer Uwe Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany aut Mueller Frank Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany aut Boknik Peter Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany aut Klimas Jan Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 403/1-2(2015-05-01), 199-208 0300-8177 403:1-2<199 2015 403 11010 https://doi.org/10.1007/s11010-015-2350-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2350-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Matus Marek Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Kucerova Dana Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Kruzliak Peter Department of Cardiovascular Diseases, International Clinical Research Center, St. Anne's University Hospital and Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic aut NATIONALLICENCE 700 1- Adameova Adriana Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Doka Gabriel Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Turcekova Katarina Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Kmecova Jana Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Kyselovic Jan Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Krenek Peter Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 700 1- Kirchhefer Uwe Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany aut NATIONALLICENCE 700 1- Mueller Frank Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany aut NATIONALLICENCE 700 1- Boknik Peter Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany aut NATIONALLICENCE 700 1- Klimas Jan Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 403/1-2(2015-05-01), 199-208 0300-8177 403:1-2<199 2015 403 11010