title: Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat.
abstract: 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., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. 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 Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-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 ± 1 ms vs. ENA 72 ± 2 ms; 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 Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). 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.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic.
authors: Marek
authors: M
authors: Matus
authors: Dana
authors: D
authors: Kucerova
authors: Peter
authors: P
authors: Kruzliak
authors: Adriana
authors: A
authors: Adameova
authors: Gabriel
authors: G
authors: Doka
authors: Katarina
authors: K
authors: Turcekova
authors: Jana
authors: J
authors: Kmecova
authors: Jan
authors: J
authors: Kyselovic
authors: Peter
authors: P
authors: Krenek
authors: Uwe
authors: U
authors: Kirchhefer
authors: Frank U
authors: FU
authors: Mueller
authors: Peter
authors: P
authors: Boknik
authors: Jan
authors: J
authors: Klimas
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation; D004573:Electrolytes / Q000097:blood; D015773:Enalaprilat / Q000008:administration & dosage / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D004573:Electrolytes; D015221:Potassium Channels; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015773:Enalaprilat; D007545:Isoproterenol