Advances in Drug and Alcohol Research · Published 2026-07-17 · DOI 10.3389/adar.2026.16302
Shiwani Thapa, Steven Mysiewicz, Alex M. Dopico, Anna N. Bukiya
Binge alcohol drinking is significantly associated with an increased risk of cerebrovascular dysfunction. Within cerebral artery smooth muscle, alcohol inhibits calcium- and voltage-gated potassium (BK) channels of large-conductance, leading to cerebrovascular constriction. Administration of high-cholesterol diet or docosahexaenoic acid (DHA) supplementation independently protects against alcohol-induced constriction of cerebral arteries. However, whether these interventions act additively or through a shared mechanism(s) remains unclear. Here, we examined the combined effects of cholesterol and DHA dietary supplementation in vivo and their combined administration ex vivo on alcohol-induced changes in rat cerebral artery diameter. DHA dietary supplementation in vivo and application to rat cerebral arteries ex vivo did not further modify protective action of high-cholesterol diet and cholesterol-enrichment, respectively. Lack of additivity may point to a shared mechanism(s) that drives cholesterol- and DHA-driven protection against alcohol constriction of cerebral arteries. Considering a prior report of BK channel α-subunit (slo1) residue tyrosine 450 mediating cholesterol protection against alcohol cerebrovascular action, we probed slo1Y450 role in DHA protection against alcohol effect on cerebral artery diameter. DHA protection against alcohol-induced constriction vanished in cerebral arteries harvested from male slo1Y450F knock-in mice. Yet DHA protection against alcohol was still present in arteries harvested from female slo1Y450F knock-in mice. Combined with previous observations, our current findings identify slo1Y450 as a potentially shared target involved in a sexually dimorphic pathway between alcohol effect on cerebral artery diameter and its sensitivity to cholesterol- and DHA-driven interventions.
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Thapa, S., Mysiewicz, S., Dopico, A., et al. (2026). Cholesterol and docosahexaenoic acid likely protect against alcohol-induced constriction of cerebral arteries via a common pathway. Advances in Drug and Alcohol Research. https://doi.org/10.3389/adar.2026.16302