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Activation of ATP-sensitive K⁺ channels by epoxyeicosatrienoic acids in rat cardiac ventricular myocytes

Tong Lu *, Toshinori Hoshi †, Neal L. Weintraub *, Arthur A. Spector *‡ and Hon-Chi Lee *§

1. We examined the effects of epoxyeicosatrienoic acids (EETs), which are cytochrome P450 metabolites of arachidonic acid (AA), on the activities of the ATP-sensitive K⁺ (K_ATP) channels of rat cardiac myocytes, using the inside-out patch-clamp technique.
2. In the presence of 100 µM cytoplasmic ATP, the K_ATP channel open probability (P_o) was increased by 240 ± 60 % with 0.1 µM 11,12-EET and by 400 ± 54 % with 5 µM 11,12-EET (n = 5-10, P < 0.05 vs. control), whereas neither 5 µM AA nor 5 µM 11,12-dihydroxyeicosatrienoic acid (DHET), which is the epoxide hydrolysis product of 11,12-EET, had any effect on P_o.
3. The half-maximal activating concentration (EC₅₀) was 18.9 ± 2.6 nM for 11,12-EET (n = 5) and 19.1 ± 4.8 nM for 8,9-EET (n = 5, P = n.s. vs. 11,12-EET). Furthermore, 11,12-EET failed to alter the inhibition of K_ATP channels by glyburide.
4. Application of 11,12-EET markedly decreased the channel sensitivity to cytoplasmic ATP. The half-maximal inhibitory concentration of ATP (IC₅₀) was increased from 21.2 ± 2.0 µM at baseline to 240 ± 60 µM with 0.1 µM 11,12-EET (n = 5, P < 0.05 vs. control) and to 780 ± 30 µM with 5 µM 11,12-EET (n = 11, P < 0.05 vs. control).
5. Increasing the ATP concentration increased the number of kinetically distinguishable closed states, promoting prolonged closure durations. 11,12-EET antagonized the effects of ATP on the kinetics of the K_ATP channels in a dose- and voltage-dependent manner. 11,12-EET (1 µM) reduced the apparent association rate constant of ATP to the channel by 135-fold.
6. Application of 5 µM 11,12-EET resulted in hyperpolarization of the resting membrane potential in isolated cardiac myocytes, which could be blocked by glyburide.
7. These results suggest that EETs are potent activators of the cardiac K_ATP channels, modulating channel behaviour by reducing the channel sensitivity to ATP. Thus, EETs could be important endogenous regulators of cardiac electrical excitability.

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