Chronic heart failure increases negative chronotropic effects of adenosine in canine sinoatrial cells via A1R stimulation and GIRK-mediated IKado

• Published in: Life sciences (1973) 2020-01, Vol.240, p.117068-117068, Article 117068
• Main Authors: Long, Victor P., Bonilla, Ingrid M., Baine, Stephen, Glynn, Patric, Kumar, Sanjay, Schober, Karsten, Mowrey, Kent, Weiss, Raul, Lee, Nam Y., Mohler, Peter J., Györke, Sandor, Hund, Thomas J., Fedorov, Vadim V., Carnes, Cynthia A.
• Format: Article
• Language: English
• Subjects: action potentials; Adenosine; antagonists; arrhythmia; Bradycardia; Cellular electrophysiology; dogs; gene expression; Heart failure; messenger RNA; potassium; purinergic receptors; Sinoatrial node
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.117068

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