Docosahexaenoic acid protects against alcohol-induced constriction of cerebral arteries and inhibition of vascular smooth muscle BK channels.

IF 3 Q2 SUBSTANCE ABUSE
Shiwani Thapa, Rika Morales, Steven Mysiewicz, Sydney Hawks, Elizabeth Tolley, Alex M Dopico, Anna N Bukiya
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Abstract

Background: 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.

Methodology: 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.

Results: 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.

Conclusions: 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.

二十二碳六烯酸可防止酒精诱导的脑动脉收缩和血管平滑肌BK通道的抑制。
背景:二十二碳六烯酸(DHA)是一种omega-3多不饱和脂肪酸,被用作有益健康的膳食补充剂。中度至高浓度的酒精会收缩大脑动脉,引发脑缺血。在这里,我们探讨了DHA对酒精对脑动脉直径和血管中钙/电压门控大电导钾通道(BKs)活性的保护能力。方法:成年Sprague-Dawley大鼠每天口服DHA补充剂,持续18-23周。在脑循环中注入50 mM酒精后,使用颅窗探查大脑中动脉(MCA)枕支的收缩情况。在血管加压至60 mmHg时,还在MCAs体内检测DHA和酒精。通过膜片钳记录生理膜电压和细胞内钙离子下的BK电流,探讨DHA对酒精诱导的MCA肌细胞BK通道抑制的影响。结果:DHA在体内对酒精诱导的血管收缩有保护作用,而对雌性无保护作用。口服DHA增加了雄性大鼠MCA中的DHA水平,但没有增加雌性大鼠的DHA水平。在离体加压并灌注3 μM DHA的对照饲料中,雄性大鼠的动脉在酒精作用下失去收缩。在DHA中孵育新分离的雄性MCAs肌细胞可防止酒精诱导的BK通道抑制。然而,当DHA灌注到切除的斑块时,DHA没有保护作用。DHA没有改变雄性MCAs肌细胞质膜内BK通道亚基的数量。DHA对酒精诱导的收缩的保护作用在表达BK通道的动脉中持续存在,在先前确定的脂肪酸敏感位点发生突变。结论:DHA通过血管肌细胞的细胞机制,以两性二态的方式防止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亚基膜水平的变化和先前确定的BK通道中的脂肪酸敏感位点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
5.40
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