Abstract 20199: In the Absence of Muscarinic-Activation, Inhibition of Kir3.1/3.4 and Kir3.4/3.4, but Not Kir3.1/3.4-Alone Prolongs Repolarisation of Atrial Tissue From Patients With Atrial Fibrillation

Aim: In the human atrium K ir 3.1/3.4 conducts the ACh-activated potassium current I KACh . A number of studies have shown that K ir 3.4 can form homomers (K ir 3.4/3.4), however, their functional importance is unclear. This study set out to investigate the functional role of K ir 3.4/3.4 in the human atrium of patients in sinus rhythm (SR) and atrial fibrillation (AF). Method: The ion channel pharmacology of two drugs, XEN-R0706 and the substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol (NTC) was investigated using whole-cell patch-clamp (20°C) of HEK or CHO cells expressing the ion channel gene of interest. Sharp microelectrodes (37°C) were used to record ex vivo action potential duration (APD) and the effective refractory period (AERP) of human right atrial appendage (HRAA) from patients in either SR or AF. The study was approved by the university ethics committee and complied with the declaration of Helsinki. Results: XEN-R0706 inhibited K ir 3.1/3.4 and K ir 3.4/3.4 with similar potency (IC 50 29 nM, n H =0.9±0.1 v 18nM, n H =0.5±0.1 resp.). In contrast, NTC was >10,000-fold selective for K ir 3.1/3.4 over K ir 3.4/3.4 (IC 50 1.5nM, n H =0.7±0.2 v 19,750nM, n H =0.4±0.1, resp.). Both compounds displayed similar selectivity for K ir 3.1/3.4 (>100-fold) over other major cardiac ion channels K v 1.5, K v 4.3, K v 7.1/KCNE1, K v 11.1, Ca v 1.2, Na v 1.5, K ir 2.1, K ir 6.2/SUR2A. As such, these compounds represent good tools for investigating the role of K ir 3.4/3.4 in the heart. When applied to HRAA from SR patients, in the absence of a muscarinic agonist, neither compound (3μM) had an effect on APD 90 nor AERP at any frequency tested (n.s. at 1-5Hz, n=3 to 6). However, under identical conditions (absence of a muscarinic agonist), XEN-R0706 significantly prolonged APD 90 and AERP of HRAA from AF patients (P≤0.05 at 1-4Hz, n=6). However, NTC did not (ns. at 1-5Hz, n=6). Conclusion: XEN-R0706 and NTC have similar pharmacological profiles for the major cardiac ion channels except R0706 also inhibits the K ir 3.4/3.4-homomer. Both compounds failed to affect APD/AERP of SR tissue however, R0706 prolonged APD/AERP of AF tissue but NTC did not. Taken together these data suggest a functional role for K ir 3.4/3.4-homomer in the repolarisation of the AF remodelled human atria.