Effect of Vasopressin Receptor Agonist and Antagonist on Pulmonary Vein and Atrial Arrhythmogenesis

Atrial fibrillation (AF) is the most common sustained arrhythmia which associates the risk of heart failure and mortality. AF is associated with progressive structural and electrical remodeling of the substrate (atria) and initiator (pulmonary veins, PVs). Diuretics that use to treat heart failure change the balance of serum osmolarity and electrolyte. Hypertonicity is related to arrhythmogenesis. Arginine vasopressin (AVP) is synthesized in neurons in the hypothalamus and has several AVP receptor subtypes (V1a, V1b, and V2). The physiological functions of AVP are regulation of cardiovascular function on vascular smooth muscle via V1a receptors, and its antidiuretic actions on kidney via V2 receptors. Desmopressin (dDAVP), a V2 agonist for the treatment of diabetes insipidus in which there is a deficiency of circulating AVP. V2-receptor antagonist is a selective competitive vasopressin receptor 2 antagonist used to treat hyponatremia associated with congestive heart failure. PVs and left atrium (LA) are the most important AF triggers and substrate. However, the role of vasopressin receptors agonist and antagonist on PV and left atrium had not yet been elucidated. Moreover, it is not clear whether heart failure (HF) may change the effects of vasopressin receptors agonist and antagonist on sino-atrial node (SAN), PVs, right atrium (RA) and LA. Therefore, the purposes of this study are to investigate the effects of vasopressin agonist and antagonist on the electrophysiological characteristics in the SAN, PVs, RA and LA cardiomyocytes. In the first year, we will study the effects of vasopressin agonist and antagonist on control and HF SAN, PVs, RA and LA. In the second year, we will investigate the effects of vasopressin agonist and antagonist on ionic currents in isolated cardiomyoytes. In the third year, we will study the effects of vasopressin receptors agonist and antagonist on RA, LA, PV and SAN calcium regulation and conduction properties. Methods: The first year experiment: HF rabbits will be created by acute myocardial infarction. Conventional microelectrodes will be used to study the action potential morphology before and after different concentrations of vasopressin (10, 100, and 1000 nM), or vasopressin antagonist (O1266, 10, 100, and 1000 nM) in control and HF SAN, PVs, RA and LA tissue preparations. The Second year experiment: HF rabbits will be created by acute myocardial infarction. Whole-cell clamp techniques will be used to study the action potention, ionic currents (L-type calcium current, NCX currents, sodium current, late sodium current, apmin-sensetive small conductance Ca2+-activated potassium current, transient outward currents and delayed and inward rectified outward potassium) in enzyme digestive isolated HF SA, PVs, RA, and LA cardiomyocytes before and after different concentrations of vasopressin (10, 100, and 1000 nM), or vasopressin antagonist (O1266, 10, 100, and 1000 nM). Third year experiment: HF rabbits will be created by acute myocardial infarction. MED64 multi-electrode system, and high density optical mapping will be used to measure the conduction properties and electrophysiological characteristics between HF SAN, PVs, RA and LA tissue preparations before and after different concentrations of vasopressin (10, 100, and 1000 nM), or vasopressin antagonist (O1266, 10, 100, and 1000 nM). We will use confocal microscopy with fluorescence to study the calcium homeostasis in isolated single HF SA, PVs, RA, and LA cardiomyocytes before and after different concentrations of vasopressin (10, 100, and 1000 nM), or vasopressin antagonist (O1266, 10, 100, and 1000 nM).