Stereospecific activation of cardiac ATP-sensitive K⁺ channels by epoxyeicosatrienoic acids: A structural determinant study

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 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 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 ω-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 ω-3 position. The results also suggest that fatty epoxides are important modulators of cardiac electrical excitability.