Department of Emergency Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Laboratory for Epidemiology, Department of Health Care Management, and Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan.
PLoS One. 2021 Apr 1;16(4):e0234591. doi: 10.1371/journal.pone.0234591. eCollection 2021.
Paraquat (PQ) is a highly lethal herbicide. Ingestion of large quantities of PQ usually results in cardiovascular collapse and eventual mortality. Recent pieces of evidence indicate possible involvement of oxidative stress- and inflammation-related factors in PQ-induced cardiac toxicity. However, little information exists on the relationship between hemodynamic and cardiac electromechanical effects involved in acute PQ poisoning. The present study investigated the effects of acute PQ exposure on hemodynamics and electrocardiogram (ECG) in vivo, left ventricular (LV) pressure in isolated hearts, as well as contractile and intracellular Ca2+ properties and ionic currents in ventricular myocytes in a rat model. In anesthetized rats, intravenous PQ administration (100 or 180 mg/kg) induced dose-dependent decreases in heart rate, blood pressure, and cardiac contractility (LV +dP/dtmax). Furthermore, PQ administration prolonged the PR, QRS, QT, and rate-corrected QT (QTc) intervals. In Langendorff-perfused isolated hearts, PQ (33 or 60 μM) decreased LV pressure and contractility (LV +dP/dtmax). PQ (10-60 μM) reduced the amplitudes of Ca2+ transients and fractional cell shortening in a concentration-dependent manner in isolated ventricular myocytes. Moreover, whole-cell patch-clamp experiments demonstrated that PQ decreased the current amplitude and availability of the transient outward K+ channel (Ito) and altered its gating kinetics. These results suggest that PQ-induced cardiotoxicity results mainly from diminished Ca2+ transients and inhibited K+ channels in cardiomyocytes, which lead to LV contractile force suppression and QTc interval prolongation. These findings should provide novel cues to understand PQ-induced cardiac suppression and electrical disturbances and may aid in the development of new treatment modalities.
百草枯（PQ）是一种高毒除草剂。大量摄入 PQ 通常会导致心血管崩溃，最终导致死亡。最近的一些证据表明，氧化应激和炎症相关因素可能参与了 PQ 诱导的心脏毒性。然而，关于急性 PQ 中毒涉及的血液动力学和心脏机电效应之间的关系，信息很少。本研究在大鼠模型中研究了急性 PQ 暴露对体内血流动力学和心电图（ECG）、分离心脏左心室（LV）压力、心室肌细胞收缩和细胞内 Ca2+特性以及离子电流的影响。在麻醉大鼠中，静脉内给予 PQ（100 或 180mg/kg）可诱导剂量依赖性的心率、血压和心脏收缩力（LV + dP/dtmax）下降。此外，PQ 给药延长了 PR、QRS、QT 和心率校正 QT（QTc）间期。在 Langendorff 灌流分离心脏中，PQ（33 或 60μM）降低 LV 压力和收缩力（LV + dP/dtmax）。PQ（10-60μM）以浓度依赖性方式降低分离心室肌细胞中 Ca2+瞬变和分数细胞缩短的幅度。此外，全细胞膜片钳实验表明，PQ 降低了瞬时外向 K+通道（Ito）的电流幅度和可及性，并改变了其门控动力学。这些结果表明，PQ 诱导的心脏毒性主要是由于心肌细胞中 Ca2+瞬变减少和 K+通道抑制，导致 LV 收缩力抑制和 QTc 间期延长。这些发现应该为理解 PQ 诱导的心脏抑制和电干扰提供新的线索，并可能有助于开发新的治疗方法。
