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Dihydroxyeicosatrienoic acids are potent activators of Ca²⁺-activated K⁺ channels in isolated rat coronary arterial myocytes

Tong Lu *, Prasad V. G. Katakam *, Mike VanRollins *, Neal L. Weintraub *, Arthur A. Spector *† and Hon-Chi Lee *‡

1. Dihydroxyeicosatrienoic acids (DHETs), which are metabolites of arachidonic acid (AA) and epoxyeicosatrienoic acids (EETs), have been identified as highly potent endogenous vasodilators, but the mechanisms by which DHETs induce relaxation of vascular smooth muscle are unknown. Using inside-out patch clamp techniques, we examined the effects of DHETs on the large conductance Ca²⁺-activated K⁺ (BK) channels in smooth muscle cells from rat small coronary arteries (150-300 µm diameter).
2. 11,12-DHET potently activated BK channels with an EC₅₀ of 1.87 ± 0.57 nM (n = 5). Moreover, the three other regioisomers 5,6-, 8,9- and 14,15-DHET were equipotent with 11,12-DHET in activating BK channels. The efficacy of 11,12-DHET in opening BK channels was much greater than that of its immediate precursor 11,12-EET. In contrast, AA did not significantly affect BK channel activity.
3. The voltage dependence of BK channels was dramatically modulated by 11,12-DHET. With physiological concentrations of cytoplasmic Ca²⁺ (200 nM), the voltage at which the channel open probability was half-maximal (V_1/2) was shifted from a baseline of 115.6 ± 6.5 mV to 95.0 ± 10.1 mV with 5 nM 11,12-DHET, and to 60.0 ± 8.4 mV with 50 nM 11,12-DHET.
4. 11,12-DHET also enhanced the sensitivity of BK channels to Ca²⁺ but did not activate the channels in the absence of Ca²⁺. 11,12-DHET (50 nM) reduced the Ca²⁺ EC₅₀ of BK channels from a baseline of 1.02 ± 0.07 µM to 0.42 ± 0.11 µM.
5. Single channel kinetic analysis indicated that 11,12-DHET did not alter BK channel conductance but did reduce the first latency of BK channel openings in response to a voltage step. 11,12-DHET dose-dependently increased the open dwell times, abbreviated the closed dwell times, and decreased the transition rates from open to closed states.
6. We conclude that DHETs hyperpolarize vascular smooth muscle cells through modulation of the BK channel gating behaviour, and by enhancing the channel sensitivities to Ca²⁺ and voltage. Hence, like EETs, DHETs may function as endothelium-derived hyperpolarizing factors.

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