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Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes.
Eur J Pharmacol. 2002 Oct 11; 452(3):269-77.EJ

Abstract

The human ether-a-go-go related gene (HERG) product encodes for the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel that mediates repolarization of cardiac action potential. HERG channels are also potential targets of a large variety of pharmacological agents most of which tend to block HERG currents. In this study, we examined the effects of the non-steroidal anti-inflammatory agents, flufenamic acid and niflumic acid, on heterologously expressed HERG channels in oocytes. The cRNA of HERG (30 ng) was injected into Xenopus oocytes and currents were recorded using two-electrode voltage clamp technique in a low Cl(-) solution. Flufenamic and niflumic acids (10(-4)-5 x 10 (-4) M) enhanced the amplitude of outward currents evoked by depolarizing pulses. At potentials positive to 0 mV, an initial transient component was also evident in the presence of fenamates. Fenamates accelerated the activation rate of HERG channels and decelerated their deactivation. Flufenamic acid (5 x 10 (-4) M) shifted the I(tail)-V relationship from -26.7+/-0.1 to -31.4+/-0.2 mV. Neither flufenamic acid or niflumic acid affected the kinetics of HERG channel inactivation. Using a voltage protocol that mimicked the cardiac action potential, both fenamates increased the outward current during the plateau and during the phase 3 repolarization of action potential. The effects of the fenamates were blocked by the HERG channel blocker, E-4031 and were also not observed in water-injected oocytes. Our data suggest that fenamates enhance HERG currents and affect the action potential duration in the heart.

Authors+Show Affiliations

Department of Physiology, University of Oklahoma Health Sciences Center, BMSB 603, 940 Stanton L Young Blvd, Oklahoma City, OK 73104, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12359267

Citation

Malykhina, Anna P., et al. "Fenamate-induced Enhancement of Heterologously Expressed HERG Currents in Xenopus Oocytes." European Journal of Pharmacology, vol. 452, no. 3, 2002, pp. 269-77.
Malykhina AP, Shoeb F, Akbarali HI. Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes. Eur J Pharmacol. 2002;452(3):269-77.
Malykhina, A. P., Shoeb, F., & Akbarali, H. I. (2002). Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes. European Journal of Pharmacology, 452(3), 269-77.
Malykhina AP, Shoeb F, Akbarali HI. Fenamate-induced Enhancement of Heterologously Expressed HERG Currents in Xenopus Oocytes. Eur J Pharmacol. 2002 Oct 11;452(3):269-77. PubMed PMID: 12359267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes. AU - Malykhina,Anna P, AU - Shoeb,Fouzia, AU - Akbarali,Hamid I, PY - 2002/10/3/pubmed PY - 2003/4/4/medline PY - 2002/10/3/entrez SP - 269 EP - 77 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 452 IS - 3 N2 - The human ether-a-go-go related gene (HERG) product encodes for the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel that mediates repolarization of cardiac action potential. HERG channels are also potential targets of a large variety of pharmacological agents most of which tend to block HERG currents. In this study, we examined the effects of the non-steroidal anti-inflammatory agents, flufenamic acid and niflumic acid, on heterologously expressed HERG channels in oocytes. The cRNA of HERG (30 ng) was injected into Xenopus oocytes and currents were recorded using two-electrode voltage clamp technique in a low Cl(-) solution. Flufenamic and niflumic acids (10(-4)-5 x 10 (-4) M) enhanced the amplitude of outward currents evoked by depolarizing pulses. At potentials positive to 0 mV, an initial transient component was also evident in the presence of fenamates. Fenamates accelerated the activation rate of HERG channels and decelerated their deactivation. Flufenamic acid (5 x 10 (-4) M) shifted the I(tail)-V relationship from -26.7+/-0.1 to -31.4+/-0.2 mV. Neither flufenamic acid or niflumic acid affected the kinetics of HERG channel inactivation. Using a voltage protocol that mimicked the cardiac action potential, both fenamates increased the outward current during the plateau and during the phase 3 repolarization of action potential. The effects of the fenamates were blocked by the HERG channel blocker, E-4031 and were also not observed in water-injected oocytes. Our data suggest that fenamates enhance HERG currents and affect the action potential duration in the heart. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/12359267/Fenamate_induced_enhancement_of_heterologously_expressed_HERG_currents_in_Xenopus_oocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014299902023300 DB - PRIME DP - Unbound Medicine ER -