Stereospecific activation of cardiac ATP-sensitive K(+) channels by epoxyeicosatrienoic acids: a structural determinant study.

Abstract:

:The heart is richly endowed with K(ATP) channels, which function as biological sensors, regulating membrane potentials and electrical excitability in response to metabolic alterations. We recently reported that the cytochrome P450 metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), potently activate cardiac K(ATP) channels by reducing channel sensitivity to ATP. In the present study, we further demonstrate that 11(S),12(R)-EET activated the cardiac K(ATP) channels with an EC(50) of 39.5 nM, whereas 11(R),12(S)-EET was totally inactive. In addition, 11(S),12(R)-EET but not 11(R),12(S)-EET hyperpolarized the resting membrane potentials and shortened the duration of cardiomyocyte action potentials. By studying homologs and analogs of 11,12-EET, we also found that all four EET regioisomers are equipotent activators of the K(ATP) channels, reducing the ATP sensitivity by more than 10-fold; however, neither altered chain length, double bond number, epoxide position, nor methylation of the carboxyl group affected channel inhibitions by ATP. All the fatty epoxides studied are potent K(ATP) channel activators, but the omega-3 homolog was particularly potent, reducing ATP sensitivity 27-fold. Together, the results indicate that the presence of an epoxide group in a particular three-dimensional configuration is a critical determinant for K(ATP) channel activation, and its effect is augmented by a double bond at omega-3 position. The results also suggest that fatty epoxides are important modulators of cardiac electrical excitability.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Lu T,VanRollins M,Lee HC

doi

10.1124/mol.62.5.1076

keywords:

subject

Has Abstract

pub_date

2002-11-01 00:00:00

pages

1076-83

issue

5

eissn

0026-895X

issn

1521-0111

journal_volume

62

pub_type

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