College of Pharmacy, The Ohio State University, Columbus, OH, USA; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Life Sci. 2020 Jan 1;240:117068. doi: 10.1016/j.lfs.2019.117068. Epub 2019 Nov 18.
Bradycardia contributes to tachy-brady arrhythmias or sinus arrest during heart failure (HF). Sinoatrial node (SAN) adenosine A1 receptors (ADO A1Rs) are upregulated in HF, and adenosine is known to exert negative chronotropic effects on the SAN. Here, we investigated the role of A1R signaling at physiologically relevant ADO concentrations on HF SAN pacemaker cells.
Dogs with tachypacing-induced chronic HF and normal controls (CTL) were studied. SAN tissue was collected for A1R and GIRK mRNA quantification. SAN cells were isolated for perforated patch clamp recordings and firing rate (bpm), slope of slow diastolic depolarization (SDD), and maximum diastolic potential (MDP) were measured. Action potentials (APs) and currents were recorded before and after addition of 1 and 10 μM ADO. To assess contributions of A1R and G protein-coupled Inward Rectifier Potassium Current (GIRK) to ADO effects, APs were measured after the addition of DPCPX (selective A1R antagonist) or TPQ (selective GIRK blocker).
A1R and GIRK mRNA expression were significantly increased in HF. In addition, ADO induced greater rate slowing and membrane hyperpolarization in HF vs CTL (p < 0.05). DPCPX prevented ADO-induced rate slowing in CTL and HF cells. The ADO-induced inward rectifying current, I, was observed significantly more frequently in HF than in CTL. TPQ prevented ADO-induced rate slowing in HF.
An increase in A1R and GIRK expression enhances I, causing hyperpolarization, and subsequent negative chronotropic effects in canine chronic HF at relevant [ADO]. GIRK blockade may be a useful strategy to mitigate bradycardia in HF.
在心力衰竭（HF）期间，心动过缓可导致心动过速-过缓性心律失常或窦性停搏。窦房结（SAN）腺苷 A1 受体（ADO A1R）在 HF 中上调，并且已知腺苷对 SAN 具有负性变时作用。在这里，我们研究了在生理相关 ADO 浓度下 A1R 信号对 HF SAN 起搏细胞的作用。
研究了患有快心率诱导性慢性 HF 和正常对照（CTL）的狗。收集 SAN 组织以进行 A1R 和 GIRK mRNA 定量。分离 SAN 细胞进行穿孔贴附记录，测量放电率（bpm）、慢舒张去极化（SDD）斜率和最大舒张电位（MDP）。在添加 1 和 10 μM ADO 前后记录动作电位（AP）和电流。为了评估 A1R 和 G 蛋白偶联内向整流钾电流（GIRK）对 ADO 作用的贡献，在添加 DPCPX（选择性 A1R 拮抗剂）或 TPQ（选择性 GIRK 阻断剂）后测量 AP。
A1R 和 GIRK mRNA 表达在 HF 中显著增加。此外，与 CTL 相比，ADO 在 HF 中诱导的速率减慢和膜超极化更大（p < 0.05）。DPCPX 可防止 ADO 在 CTL 和 HF 细胞中诱导的速率减慢。在 HF 中比在 CTL 中更频繁地观察到 ADO 诱导的内向整流电流 I。TPQ 可防止 ADO 在 HF 中诱导的速率减慢。
A1R 和 GIRK 表达的增加增强了 I，导致超极化，从而在犬慢性 HF 中在相关的 [ADO] 下产生负性变时作用。GIRK 阻断可能是减轻 HF 中心动过缓的有用策略。
