Alosetron and the rapid component of delayed rectifying potassium current in cardiac cells.
Some drugs acting on 5-hydroxytryptamine receptors inhibit the rapid component of delayed rectifying potassium currents (I(Kr)) in cardiac muscle cells. This is associated with lengthening of the QT interval in the cardiac cycle and can lead to fatal arrhythmias. We investigated whether alosetron, a novel 5HT3 antagonist proposed for treatment of irritable bowel syndrome (IBS), blocks I(Kr) in guinea pig cardiac myocytes. I(Kr) was isolated under whole-cell voltage clamp, and was identified by its sensitivity to the selective I(Kr) antagonist E4031. Cisapride (10(-6) M) inhibited the E4031-sensitive current while alosetron (10(-10)-10(-6) M) had no effect on I(Kr). We also found that alosetron did not inhibit I(Ks). Therefore, use of alosetron for treatment of IBS should not be confounded by long QT syndrome.
Department of Physiology & Cell Biology, University of Nevada School of Medicine, Reno 89557, USA. andreas@physio.unr.edu
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Carl
K M
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Sanders
J L
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Kenyon
D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D020117:Cisapride / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*
D002243:Carbolines; D051668:Delayed Rectifier Potassium Channels; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C063968:E 4031; C090840:alosetron; D020117:Cisapride