Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

• Kijtawornrat Anusak

  Department of Veterinary Biosciences, The Ohio State University

• Ziolo Mark T.

  Department of Physiology and Cell Biology, The Ohio State University

• Nishijima Yoshinori

  Department of Veterinary Biosciences, The Ohio State University QTest Labs, LLC., 6456 Fiesta Drive

• Roche Brian M.

  QTest Labs, LLC., 6456 Fiesta Drive

• Hamlin Robert L.

  Department of Veterinary Biosciences, The Ohio State University

抄録

QT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca²⁺ cycling is the proximate cause of EADs, and Ca²⁺ cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP. <br>In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 ± 1.3 minutes and 10.3 ± 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01). KB-R7943, W-7, and KN-93 accelerated onset of TdP. Blockades of L-type Ca²⁺ channel, ryanodine channel, and protein kinase A prevent dofetilide-induced TdP, suggesting roles for intracellular Ca²⁺ overload and Ca²⁺ signaling pathways in drug-induced TdP.

収録刊行物

• International Heart Journal

  International Heart Journal 51 (4), 285-290, 2010

  一般社団法人 インターナショナル・ハート・ジャーナル刊行会

キーワード

• Calcium
• QT
• Heart failure
• Protein kinase A
• Rabbit
• Torsades de Pointes

詳細情報

• CRID: 1390282680203172864
• NII論文ID: 130000299285
• DOI: 10.1536/ihj.51.285
• ISSN: 13493299
• ISSN: 13492365
• Web Site: http://www.jstage.jst.go.jp/article/ihj/51/4/51_4_285/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2011013557
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可