Recent findings suggest that modulation of
ion channels might be implicated in some of the clinical effects of
coxibs, selective inhibitors of
cyclooxygenase-2 (COX-2).
Celecoxib and its inactive analog
2,5-dimethyl-celecoxib, but not
rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human K(v)2.1 channels by a highly selective
COX-2 inhibitor SC-791. In this study we have further explored the
SC-791 action on
ion channels and heartbeat in Drosophila, which lacks
cyclooxygenases and thus can serve as a convenient model to study COX-2-independent mechanisms of
coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that
SC-791 inhibited voltage-activated K(+) and L-type Ca(2+) channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike
celecoxib and several other K(+) channel blockers,
SC-791 did not induce
arrhythmia. Instead, application of
SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat.
Isradipine, a selective blocker of L-type Ca(2+) channels, showed a similar pattern of
heart arrest, though no prolongation of contractions was observed.
Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like
SC-791,
ryanodine reduced heart rate without
arrhythmia. However, it could not stop heartbeat completely even at 500 µM, the highest concentration used. The magnitude of heart rate reduction, when
SC-791 and
ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that
SC-791 might be interfering with excitation-contraction coupling in Drosophila heart.