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Vol. 62, Issue 5, 1076-1083, November 2002
Departments of Internal Medicine, Mayo Clinic, Rochester, Minnesota
(T.L., H.L.), and the University of Iowa, Iowa City, Iowa (M.V.)
The heart is richly endowed with KATP 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
KATP channels by reducing channel sensitivity to ATP. In
the present study, we further demonstrate that
11(S),12(R)-EET activated the cardiac
KATP channels with an EC50 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 KATP 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 KATP channel activators, but the 
-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
KATP channel activation, and its effect is augmented by a
double bond at -3 position. The results also suggest that fatty
epoxides are important modulators of cardiac electrical excitability.
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