piperidines and Pericarditis

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 day before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K+ currents (IK); reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways; and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevented abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats; therefore, it might be a promising strategy to treat AF, particularly postoperative AF.

Topics: Action Potentials; Aged; Animals; Atrial Fibrillation; Atrial Remodeling; Female; Fibrosis; Heart Atria; Heart Rate; Humans; Inflammation; Male; Middle Aged; Myocytes, Cardiac; Pericarditis; Piperidines; Quinolines; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

Numerous studies have shown that E-4031 generally prolongs the atrial effective refractory period (AERP) without affecting cardiac conduction. The effects of E-4031 on AERP and cardiac conduction at short cycle lengths (CLs) close to the AERP were measured in 12 dogs with sterile pericarditis. Three pairs of electrodes were sutured at three sites in the atria 4 days after the model was created. We measured AERP and maximum conduction delay (MCD) after 8 beats train at CLs of 400, 300, 200 and 150 ms before and during continuous infusion of E-4031 (0.1 microgram/kg/min) that followed an initial dose of 10 micrograms/kg/min/5 min. E-4031 interrupted sustained atrial flutter (AF) (> or = 10 min) in 4 of 5 episodes and atrial fibrillation (> or = 10 min) in 4 of 4. The CL of AF defined as a rapid atrial rhythm (rate > or = 240 beats/min) in five episodes studied in the sterile pericarditis model was significantly (p < 0.005) prolonged from 120 +/- 8 to 160 +/- 17 ms. There were significant (p < 0.005) increases in AERP at each CL, and prolongation of AERP was 39 +/- 18, 31 +/- 14, 23 +/- 14, and 16 +/- 14 ms at CL 400, 300, 200, and 150 ms, respectively. E-4031 produced less prolongation of AERP at short pacing CLs and had no effect on conduction time during atrial rapid pacing at CLs > 150 ms. E-4031 did not prolong MCD at CL 400 ms, but did prolong MCD at CLs of 300, 200, and 150 ms, despite prolongation of AERP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Dogs; Electric Stimulation; Electrophysiology; Heart; Heart Conduction System; Models, Cardiovascular; Pericarditis; Piperidines; Pyridines