Basic/Translational Science -> Whole Animal Electrophysiology and Pharmacology (includes Neurohumoral Modulation) D-PO06 - Poster Session VI (ID 26) Poster

D-PO06-011 - Acute Phosphodiesterase Type 5 Inhibition Decreases Vulnerability To Induced AF In Anaesthetised Sheep (ID 640)

Disclosure
 N.C. Denham: Nothing relevant to disclose.

Abstract

Background: Cyclic nucleotides are secondary messengers which regulate cardiomyocyte calcium cycling and ion channel function. These messengers are hydrolysed by phosphodiesterases (PDEs). Inhibitors of PDE type 5 have received interest for the treatment of heart failure and ventricular arrhythmias. However, it is uncertain whether PDE5 inhibitors (e.g. Sildenafil) affect atrial electrophysiology.
Objective: To determine the effects of acute PDE5 inhibition on atrial electrophysiology and vulnerability to atrial fibrillation (AF).
Methods: Electrophysiological studies were performed in anaesthetised adult female Welsh mountain sheep before and after administration of 10mg intravenous Sildenafil. The perforated patch clamp technique was used to assess action potential morphology and calcium transients in isolated atrial cardiomyocytes using 50nM Tadalafil, a more specific PDE5 inhibitor. Data are presented as mean ± SEM.
Results: Sildenafil prolonged the atrial effective refractory period (control 150±10ms vrs Sildenafil 170±10ms; p=0.03; n=9), reduced the duration of induced AF (48±19s vrs 5±2s; p=0.01; n=8) and reduced the proportion of induced AF episodes lasting >5s (38±6% vrs 19±5%; p=0.048; n=8). The dominant frequency of AF was lower in Sildenafil (5.43±0.27Hz vrs 3.67±1.8Hz; p=0.002; n=8). No differences were observed in P wave duration, the rate threshold for atrial alternans, atrial conduction velocity or monophasic action potential duration. Tadalafil reduced the calcium transient amplitude in single cells (baseline 234±25nmol/L vrs Tadalafil 160±21nmol/L; p=0.0001; n=16) with no effect on action potential duration at 50% of repolarisation (76±10ms vrs 77±9ms; p=0.07; n=19), or at 90% (285±25ms vrs 278±26ms; p=0.77, n=19).
Conclusion: Acute PDE5 inhibition decreases vulnerability to AF in sheep by prolonging the atrial effective refractory period and decreasing the dominant frequency of AF. The reduction in the calcium transient amplitude without an effect on action potential duration suggests PDE5 inhibition may produce an anti-arrhythmic effect by modifying calcium cycling. Future work should assess the effect of chronic PDE5 inhibition on the incidence of AF.
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