Cholesterol and docosahexaenoic acid likely protect against alcohol-induced constriction of cerebral arteries via a common pathway.

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.