COX-2 inhibitors like Celecoxib have come under scrutiny lately due to
adverse cardiovascular side-effects stemming from COX-2 reduction. In
both fruit fly and rat models, researchers reveal another adverse effect
of Celecoxib; this drug can induce arrhythmia. More interestingly, this
effect is independent of the COX-2 enzyme.
The attached image shows the larval heart from
Drosophila on which many of the experiments were done. The arrows
point to the walls of the heart. The upper frame shows the heart
in its dilated form and the lower frame shows the heart after
contraction.
Image by Satpal Singh
Satpal Singh and colleagues tested various
Celecoxib doses on the heart rate of Drosophila, a good model for
human cardiac pharmacology. To their surprise, administering 3 ��m
Celecoxib (not much higher than the plasma levels in humans taking the
drug) reduced heart rate and increased beating irregularities, while
30 ��m was enough to stop the heart within a minute.
The surprise arises from the fact that Drosophila do not have COX-2
enzymes. Rather, Celecoxib could directly inhibit the potassium
channels that help generate the electric current that drives heartbeat.
The researchers could achieve similar heart-stopping results in rat
cardiac cells, whereas aspirin, another potent COX-2 inhibitor, had no
effect, confirming that another mechanism is at work. The drug also
inhibited rat and human potassium channels expressed in a human cell
line.
Singh and colleagues point out that since these arrhythmia effects
bypass COX-2, it is unclear if other COX-2 inhibitors would yield
similar results. They also stress it is too early to speculate on
human effects, although their results suggest Drosophila are a
valuable tool to investigate other COX-2 drugs.
Further Information
and Source:
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Roman V. Frolov, Ilya G. Berim, and Satpal Singh: Inhibition of delayed rectifier potassium channels and induction
of arrhythmia - a novel effect of celecoxib and the mechanism
underlying it.
In: Journal of Biological Chemistry; J. Biol. Chem., Vol.
283, Issue 3, 1518-1524, January 18, 2008;
doi: 10.1074/jbc.M708100200.
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Source: The
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