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Inhibition of ion channels and heart beat in Drosophila by selective COX-2 inhibitor SC-791.

Frolov RV, Singh S - PLoS ONE (2012)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York, United States of America. rvfrolov@gmail.com

ABSTRACT
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.

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Heartbeat disruption by SC-791 and isradipine.Development of heartbeat stoppage in the presence of 50 μM SC-791 (A) or 3 μM isradipine (B). The corresponding averaged contraction waveforms demonstrate similarities (decrease in amplitude) and differences (prolongation of contraction) between the effects of SC-791 (C) and isradipine (D); each waveform is an average of 10 to 20 individual contraction waveforms.
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pone-0038759-g004: Heartbeat disruption by SC-791 and isradipine.Development of heartbeat stoppage in the presence of 50 μM SC-791 (A) or 3 μM isradipine (B). The corresponding averaged contraction waveforms demonstrate similarities (decrease in amplitude) and differences (prolongation of contraction) between the effects of SC-791 (C) and isradipine (D); each waveform is an average of 10 to 20 individual contraction waveforms.

Mentions: At 50 μM and higher concentrations, SC-791 progressively reduced heart rate, increased duration of heart contractions and decreased contraction amplitude up to the point when heartbeat could no longer be detected: at 100 μM SC-791 heartbeat ceased after 20 min exposure in 3 out of 6 cases, and at 300 μM heartbeat ceased in 3 out of 3 cases after 10 min exposure. Figure 4A demonstrates an example of a developing failure of heartbeat at 50 μM SC-791; note that the drug mainly increased the duration of the initial phase of contraction. Once again, this pattern was different from the effects of higher concentrations of celecoxib, which usually involved a sudden halt of beating, often against the background of severe arrhythmia [8].


Inhibition of ion channels and heart beat in Drosophila by selective COX-2 inhibitor SC-791.

Frolov RV, Singh S - PLoS ONE (2012)

Heartbeat disruption by SC-791 and isradipine.Development of heartbeat stoppage in the presence of 50 μM SC-791 (A) or 3 μM isradipine (B). The corresponding averaged contraction waveforms demonstrate similarities (decrease in amplitude) and differences (prolongation of contraction) between the effects of SC-791 (C) and isradipine (D); each waveform is an average of 10 to 20 individual contraction waveforms.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368905&req=5

pone-0038759-g004: Heartbeat disruption by SC-791 and isradipine.Development of heartbeat stoppage in the presence of 50 μM SC-791 (A) or 3 μM isradipine (B). The corresponding averaged contraction waveforms demonstrate similarities (decrease in amplitude) and differences (prolongation of contraction) between the effects of SC-791 (C) and isradipine (D); each waveform is an average of 10 to 20 individual contraction waveforms.
Mentions: At 50 μM and higher concentrations, SC-791 progressively reduced heart rate, increased duration of heart contractions and decreased contraction amplitude up to the point when heartbeat could no longer be detected: at 100 μM SC-791 heartbeat ceased after 20 min exposure in 3 out of 6 cases, and at 300 μM heartbeat ceased in 3 out of 3 cases after 10 min exposure. Figure 4A demonstrates an example of a developing failure of heartbeat at 50 μM SC-791; note that the drug mainly increased the duration of the initial phase of contraction. Once again, this pattern was different from the effects of higher concentrations of celecoxib, which usually involved a sudden halt of beating, often against the background of severe arrhythmia [8].

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York, United States of America. rvfrolov@gmail.com

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus