Celecoxib Exacerbates Ligation – Induced Arrhythmias In Isolated Perfused Rat Hearts

Osama Mohamed, Abdulrahman Almotrefi. Department of Pharmacology,College of Medicine, King Saud University, Riyadh, 11472, Saudi Arabia

The COX-2 inhibitor celecoxib has been reported to inhibit delayed rectifier ( Kv2 ) potassium channels leading to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture ( Frolov etal.,2008 ). Moreover, tamoxifen selective deletion of COX-2 in mice cardiomyocytes enhanced susceptibility to induced arrhythmogenesis (Wang etal., 2009 ). Furthermore,celecoxib inhibited the hERG, SCN5A, KCNQ1 and KCNQ1/MinK channels expressed in HEK-293 cells and the KCND3/KChiP2 channels expressed in CHO cells (Frolov et al.,2011). These channels are critically involved in regulating human cardiac rhythm.This prompted us to investigate the putative arrhythmogenic effect of celecoxib using ligation –induced arrhythmias in the isolated rat heart. Hearts were cannulated via the aorta and perfused by the Langendorff’s method at a constant flow rate of 10ml/min using a peristaltic pump and a modified Kreb’s solution containing 5.9mM potassium and 2.5 mM calcium. After 10 minutes of stabilization, the left descending coronary artery was ligated. Heart rate, force of contraction (using a force displacement transducer , Harvard UFI transducer), perfusion pressure, the number of premature ventricular contractions (PVCs), incidence and duration of ventricular tachycardia (VT) and fibrillation(VF) were monitored for 30 minutes following ligation. Four groups (9 each) of albino rat (King Saud University breed) hearts were used. The first group was perfused with Kreb’s solution containing the celecoxib solvent polyethylene glycol 400 (PEG 400).The other three groups were perfused with Kreb’s solution containing 5µM ,10 µM, 20µM celecoxib respectively.

Celecoxib increased the number of PVCs significantly at 10µM (p<0.05). At 20 µM concentration there was less increase in the number of PVCs than at 10µM as the hearts went into ventricular fibrillation at this concentration which allowed less time for PVCs to occur. 20µM of celecoxib also increased significantly (p<0.05) the incidence of ventricular fibrillation and the duration of ventricular tachycardia. Celecoxib did not produce any effect on either the perfusion pressure or developed tension, but at 20µM it significantly decreased the heart rate (p<0.05).

These results suggest that celecoxib has significant arrhythmogenic effect on rat heart and support previous findings. This requires further confirmation by the use of other models of arrhythmia and by comparing celecoxib with other COX-2 inhibitors in order to establish whether this adverse effect pertains also to other drugs of this group or is specific for celecoxib. The significance of these results in the therapeutic use of celecoxib is discussed.

References:-

1- Frolov RV et al., (2008) J. Biol. Chem., 283,1518-24.

2- Frolov RV et al., (2011), PLoS ONE 6(10): e26344. doi:10.1371

3- Wang D et al., (2009) Proc. Natl. Acad. Sci. U S A., 106,7548-52.