Thapa Shiwani, Morales Rika, Mysiewicz Steven, Hawks Sydney, Tolley Elizabeth, Dopico Alex M, Bukiya Anna N
Department of Pharmacology, Addiction Science and Toxicology, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Department of Preventive Medicine, Division of Biostatistics, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Alcohol Clin Exp Res (Hoboken). 2025 Jul;49(7):1396-1411. doi: 10.1111/acer.70073. Epub 2025 May 26.
Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid used as a dietary supplement with health benefits. Alcohol in moderate-to-high concentrations constricts cerebral arteries and triggers brain ischemia. Here, we probed the ability of DHA to protect against alcohol action on cerebral artery diameter and on the activity of calcium-/voltage-gated potassium channels of large conductance (BKs) in vasculature.
Adult Sprague-Dawley rats received daily oral DHA supplementation for up to 18-23 weeks. Constriction of middle cerebral artery (MCA) pial branches was probed using a cranial window upon infusion of 50 mM alcohol into the cerebral circulation. DHA and alcohol were also probed ex vivo in MCAs upon vessel pressurization at 60 mmHg. DHA's effect on alcohol-induced inhibition of BK channels in MCA myocytes was probed using patch-clamp recording of BK currents at physiological membrane voltage and intracellular calcium.
DHA protected males but not females against alcohol-induced vasoconstriction in vivo. Oral DHA increased DHA levels in the MCA of male but not female rats. Arteries from male rats on control chow that were pressurized ex vivo and perfused with 3 μM DHA lost their constriction by alcohol. Incubation of freshly isolated myocytes of male MCAs in DHA prevented alcohol-induced inhibition of BK channels. However, DHA protection was absent when DHA was perfused to excised patches. DHA did not alter the amount of BK channel subunits within the myocyte plasmalemma of male MCAs. DHA protection against alcohol-induced constriction persisted in arteries expressing BK channel with a mutation on a previously identified fatty acid-sensing site.
DHA protects against alcohol-induced cerebral artery constriction and BK channel inhibition in a sexually dimorphic manner via cellular mechanisms in vascular myocytes. This action of DHA is independent of changes in BK subunit membrane levels and of a previously identified fatty acid-sensing site in the BK channel.
二十二碳六烯酸（DHA）是一种ω-3多不饱和脂肪酸，用作具有健康益处的膳食补充剂。中高浓度的酒精会收缩脑动脉并引发脑缺血。在此，我们探究了DHA对酒精作用于脑动脉直径以及血管中钙/电压门控大电导钾通道（BKs）活性的保护能力。
成年Sprague-Dawley大鼠每日口服补充DHA，持续18 - 23周。在向脑循环中注入50 mM酒精后，使用颅窗探测大脑中动脉（MCA）软脑膜分支的收缩情况。在60 mmHg的血管压力下，还对离体的MCA进行了DHA和酒精的探究。使用膜片钳记录生理膜电压和细胞内钙条件下的BK电流，探究DHA对酒精诱导的MCA肌细胞中BK通道抑制的影响。
DHA在体内对雄性而非雌性具有保护作用，可防止酒精诱导的血管收缩。口服DHA可提高雄性大鼠而非雌性大鼠MCA中的DHA水平。在体外对喂食对照饲料的雄性大鼠的动脉施加压力并用3 μM DHA灌注后，酒精引起的收缩消失。将雄性MCA新鲜分离的肌细胞在DHA中孵育可防止酒精诱导的BK通道抑制。然而，当将DHA灌注到切除的膜片时，DHA的保护作用消失。DHA并未改变雄性MCA肌细胞质膜内BK通道亚基的数量。在表达BK通道且先前鉴定的脂肪酸感应位点发生突变的动脉中，DHA对酒精诱导的收缩仍具有保护作用。
DHA通过血管肌细胞中的细胞机制以性别二态性方式保护机体免受酒精诱导的脑动脉收缩和BK通道抑制。DHA的这种作用独立于BK亚基膜水平的变化以及BK通道中先前鉴定的脂肪酸感应位点。
