Tallo Fernando Sabia, de Santana Patricia Oliveira, Pinto Sandra Augusta Gordinho, Lima Rildo Yamaguti, de Araújo Erisvaldo Amarante, Tavares José Gustavo Padrão, Pires-Oliveira Marcelo, Nicolau Lucas Antonio Duarte, Medeiros Jand Venes Rolim, Taha Murched Omar, David André Ibrahim, Luna-Filho Bráulio, Filho Carlos Eduardo Braga, Barbosa Adriano Henrique Pereira, Silva Célia Maria Camelo, Wanderley Almir Gonçalves, Caixeta Adriano, Caricati-Neto Afonso, Menezes-Rodrigues Francisco Sandro
Department of Urgency and Emergency Care, Universidade Federal de São Paulo (UNIFESP), São Paulo 04024-000, SP, Brazil.
Postgraduate Program in Cardiology, Universidade Federal de São Paulo (UNIFESP), São Paulo 04024-000, SP, Brazil.
Pharmaceuticals (Basel). 2023 Oct 16;16(10):1473. doi: 10.3390/ph16101473.
Acute myocardial infarction (AMI) is the main cause of morbidity and mortality worldwide and is characterized by severe and fatal arrhythmias induced by cardiac ischemia/reperfusion (CIR). However, the molecular mechanisms involved in these arrhythmias are still little understood. To investigate the cardioprotective role of the cardiac Ca/cAMP/adenosine signaling pathway in AMI, L-type Ca channels (LTCC) were blocked with either nifedipine (NIF) or verapamil (VER), with or without A-adenosine (ADO), receptors (AR), antagonist (DPCPX), or cAMP efflux blocker probenecid (PROB), and the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) induced by CIR in rats was evaluated. VA, AVB and LET incidences were evaluated by ECG analysis and compared between control (CIR group) and intravenously treated 5 min before CIR with NIF 1, 10, and 30 mg/kg and VER 1 mg/kg in the presence or absence of PROB 100 mg/kg or DPCPX 100 µg/kg. The serum levels of cardiac injury biomarkers total creatine kinase (CK) and CK-MB were quantified. Both NIF and VER treatment were able to attenuate cardiac arrhythmias caused by CIR; however, these antiarrhythmic effects were abolished by pretreatment with PROB and DPCPX. The total serum CK and CK-MB were similar in all groups. These results indicate that the pharmacological modulation of Ca/cAMP/ADO in cardiac cells by means of attenuation of Ca influx via LTCC and the activation of AR by endogenous ADO could be a promising therapeutic strategy to reduce the incidence of severe and fatal arrhythmias caused by AMI in humans.
急性心肌梗死（AMI）是全球发病和死亡的主要原因，其特征是心脏缺血/再灌注（CIR）诱导的严重致命性心律失常。然而，这些心律失常所涉及的分子机制仍鲜为人知。为了研究心脏Ca/cAMP/腺苷信号通路在AMI中的心脏保护作用，用硝苯地平（NIF）或维拉帕米（VER）阻断L型钙通道（LTCC），同时或不同时使用A-腺苷（ADO）、受体（AR）拮抗剂（DPCPX）或cAMP外排阻滞剂丙磺舒（PROB），并评估CIR诱导的大鼠室性心律失常（VA）、房室传导阻滞（AVB）和致死率（LET）的发生率。通过心电图分析评估VA、AVB和LET的发生率，并在对照组（CIR组）与在CIR前5分钟静脉注射1、10和30 mg/kg NIF以及1 mg/kg VER的组之间进行比较，这些组分别存在或不存在100 mg/kg PROB或100 μg/kg DPCPX。对心脏损伤生物标志物总肌酸激酶（CK）和CK-MB的血清水平进行定量。NIF和VER治疗均能够减轻CIR引起的心律失常；然而，PROB和DPCPX预处理消除了这些抗心律失常作用。所有组的血清总CK和CK-MB相似。这些结果表明，通过减少LTCC的钙内流以及内源性ADO激活AR来对心脏细胞中的Ca/cAMP/ADO进行药理学调节，可能是一种有前景的治疗策略，可降低人类AMI引起的严重致命性心律失常的发生率。
