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Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0000000000000015
Original Article

Effects of Endothelin-1 Chronic Stimulation on Electrical Restitution, Beat-to-beat Variability of Repolarization, and Ventricular Arrhythmogenesis

Liu, Tao MD*,†; Qin, Mu MD*,†,‡; Shi, Shao Bo MD*,†; Chen, Zhen MMSc§; Wang, Teng MMSc; Huang, Cong-Xin MD, PhD*,†

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Abstract

Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1–S2 protocol and S1–S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD90), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD90 ratio, and increased the spatial dispersions of APD90, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

Copyright © 2013 by Lippincott Williams & Wilkins

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