Inhibitory Action of Fluvoxamine on Kv1.5 Currents

Abstract

Fluvoxamine is a selective serotonin reuptake inhibitor that exerts antidepressant activity by inhibiting the reuptake of serotonin, or 5-hydroxytryptamine, in the central nervous system. Fluvoxamine shows negligible affinity for other neurotransmitter reuptake systems, [1][2][3][4] so it may have advantages over other antidepressants in the treatment of depression. For example, tricyclic antidepressant (TCA) is associated with an increased risk of cardiovascular events. [5][6][7][8][9] However, accumulating evidence suggests that fluvoxamine may increase cardiovascular risk through inhibition of the human ether-a-go-go related (HERG) potassium channel. 10)The drug may also be associated with ventricular arrhythmia.11) Pharmacological blockade of cardiac muscle voltage-gated K ϩ channels (Kv channels) is associated with adverse cardiac arrhythmias, suggesting that fluvoxamine may interact with cardiac Kv channels. However, the exact effects of fluvoxamine on cardiac Kv channels remain to be elucidated.Kv1.5 is a cardiovascular-specific Kv channel isoform. It has an important role in determining the length of cardiac action potentials, and is a target of antiarrhythmic drugs. 12)Kv1.5 is rapidly activated and is difficult to inactivate, so it contributes to the repolarization of atrial action potentials. Kv1.5 dysfunction results in prolonged cardiac action potentials, eventually leading to cardiac arrhythmias with serious morbidity. [13][14][15] In this study, we investigated whether fluvoxamine interacts with Kv1.5 cloned from rat brain and determined the mechanisms by which fluvoxamine acts on Kv1.5. MATERIALS AND METHODS Stable Transfection and Cell CultureChinese hamster ovary (CHO) cells expressing Kv1.5 channels from rat brain were used for electrophysiological recordings.16) Kv1.5 cDNA 17) was cloned into the plasmid expression vector pCR3.1 (Invitrogen Corp., San Diego, CA, U.S.A.). CHO cells were transfected with Kv1.5 cDNA using FuGENE6 reagent (Boehringer Mannheim, Indianapolis, IN, U.S.A.).Transfected cells were cultured in Iscove's modified Dulbecco's medium (Invitrogen Corp.) supplemented with 10% fetal bovine serum, 2 mM glutamine, 0.1 mM hypoxanthine, 0.01 mM thymidine, and 300 mg/ml G418 (A.G. Scientific, San Diego, CA, U.S.A.) in 95% humidified air-5% CO 2 at 37°C. Cultures were passaged every 4-5 d by brief trypsinethylenediaminetetraacetic acid treatment, seeded onto glass coverslips (diameter: 12 mm, Fisher Scientific, Pittsburgh, PA, U.S.A.) in a Petri dish, and used for electrophysiological recordings after 12-24 h.Electrophysiological Recordings Kv1.5 currents were recorded from CHO cells using a whole-cell patch-clamp technique 18) at room temperature (22-23°C). Micropipettes fabricated from glass capillary tubing (PG10165-4; World Precision Instruments, Sarasota, FL, U.S.A.) with a doublestage vertical puller (PC-10; Narishige, Tokyo) had a tip resistance of 2-3 MW when filled with pipette solution. Wholecell currents were amplified with a MultiClamp 700B amplifier (Molecular Devices, S...

Comparison of the function of the serotonin transporter in the vasculature of male and female rats

“…This suggests that 5‐HT is actively taken up by SERT so that is no longer available to participate in contraction. Fluvoxamine has recently been shown to inhibit currents carried by the voltage‐gated K + channel Kv1.5, 22 raising the possibility that a leftward shift in responsiveness to 5‐HT could be because of inhibition of this important channel. However, this action of fluvoxamine is not consistent with our findings that fluvoxamine did not produce equivalent shifts in the 5‐HT curves in arteries from SERT‐KO and WT rats and there are no data suggesting that Kv1.5 function differs between these two strains.…”