title: Heart failure modulates electropharmacological characteristics of sinoatrial nodes.
abstract: The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca2+release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.
authors.affiliation: Division of Cardiology, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C.; Department of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan, R.O.C.
authors.forename: Shih-Lin
authors.initials: SL
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C.; Department of Physiology, National Yang-Ming University School of Medicine, Taipei 112, Taiwan, R.O.C.
authors.forename: Hui-Lun
authors.initials: HL
authors.lastname: Chuang
authors.affiliation: Department of Biomedical Engineering, National Defense Medical Center, Taipei 114, Taiwan, R.O.C.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C.; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C.
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.affiliation: The First Cardiovascular Division, Chang-Gung Memorial Hospital and Chang-Gung University, Tao-Yuan 244, Taiwan, R.O.C.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.affiliation: Division of Cardiology, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C.; Department of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan, R.O.C.
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
keywords: KN-93; heart failure; ivabradine; ranolazine; ryanodine; tetrodotoxin