Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca ²⁺ -dependent K ⁺ channels

Abstract

Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA), found abundantly in oily fish, may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems. However, the mechanisms underlying the purported health-promoting effects of DHA remain largely unclear, in part because molecular signaling pathways and effectors of DHA are only beginning to be revealed. In vascular smooth muscle cells, large-conductance Ca 2+ -and voltage-activated K + (BK) channels provide a critical vasodilatory influence. We report here that DHA with an EC 50 of ∼500 nM rapidly and reversibly activates BK channels composed of the pore-forming Slo1 subunit and the auxiliary subunit β1, increasing currents by up to ∼20-fold. The DHA action is observed in cell-free patches and does not require voltage-sensor activation or Ca 2+ binding but involves destabilization of the closed conformation of the ion conduction gate. DHA lowers blood pressure in anesthetized wildtype but not in Slo1 knockout mice. DHA ethyl ester, contained in dietary supplements, fails to activate BK channels and antagonizes the stimulatory effect of DHA. Slo1 BK channels are thus receptors for long-chain omega-3 fatty acids, and these fatty acids-unlike their ethyl ester derivatives-activate the channels and lower blood pressure. This finding has practical implications for the use of omega-3 fatty acids as nutraceuticals for the general public and also for the critically ill receiving omega-3-enriched formulas.fish oil | lipids | K Ca 1.1 | immunonutrition

Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA

“…We showed previously that DHA increased currents through native BK channels in vascular smooth muscle cells as well as heterologously expressed Slo1+β1 channels (27). Here we examined whether DHA stimulates Slo1 channels with other subunit compositions: Slo1 alone, Slo1+β2 (18,19), Slo1+β4 (6), and Slo1+LRRC26 (γ1) (3,4).…”

“…1A) found abundantly in oily fish (28). Injection of DHA into wild-type mice but not in Slo1 knockout mice significantly lowers blood pressure, clearly confirming the physiological significance of DHA-mediated modulation of Slo1+β1 channels (27). In addition to the roles in the cardiovascular system (29), omega-3 fatty acids are also important in other systems.…”

“…S1). Representative ionic currents recorded before and after application of DHA (3 μM), a functionally saturating concentration in Slo1+β1 (27), are shown in Fig. 1B.…”

“…We previously demonstrated that vascular Slo1+β1 channels are robustly and reversibly activated by DHA (27), a long-chain polyunsaturated omega-3 fatty acid with a 22-carbon chain (for structure, see Fig. 1A) found abundantly in oily fish (28).…”

Nutritional recommendations for individuals with Flammer syndrome

“…Omega-3 fatty acids are found in fish, such as salmon, tuna and halibut, other seafoods including algae and krill and flaxseed oil [78]. Omega-3 fatty acid prevents development of intracranial atherosclerosis [79], reduce inflammation [80,81], lower blood pressure [82], improve endothelial vascular function [83] and modulate intracellular calcium ion release and thereby the stabilization of circulation [84].…”