AUTHOR=North Kelsey C. , Shaw Andrew A. , Moreira Luiz , Bukiya Anna N. , Dopico Alex M. 

TITLE=Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle Ca2+- and voltage-gated K+ channels of big conductance

JOURNAL=Advances in Drug and Alcohol Research

VOLUME=Volume 3 - 2023

YEAR=2023

URL=https://www.frontierspartnerships.org/journals/advances-in-drug-and-alcohol-research/articles/10.3389/adar.2023.11735

DOI=10.3389/adar.2023.11735

ISSN=2674-0001

ABSTRACT=Despite the significant amount of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone+ethanol combinations on cerebral artery diameter.  We investigated this by evaluating the effect of this combination on the diameter of male and female C57BL/6J mouse middle cerebral arteries both in vivo and in vitro.  The use of de-endothelialized, in vitro-pressurized middle cerebral artery segments allowed us to conduct a concentration response to constriction by pregnenolone+/-ethanol where drug action could be evaluated independently of circulating and endothelial factors.  In both male and female animals, pregnenolone at lower concentrations (≤1 µM) synergized with 50 mM ethanol to cause vasoconstriction.  In both sexes, this synergism was lost as one or both vasoconstrictors approached their maximally effective concentrations (75 mM and 10 µM for ethanol and pregnenolone, respectively), whether evaluated in vitro or in vivo using a cranial window.  Vasoconstriction by pregnenolone+ethanol was abolished by 1 µM paxilline indicating BK channel involvement.  Moreover, cell-free recordings of BK channel activity in cerebral artery myocyte membranes showed that 10 µM pregnenolone and pregnenolone+50 mM ethanol reduced channel activity identically, suggesting that these drugs inhibit cerebrovascular BK channels via a common mechanism(s).  Indeed, pregnenolone disrupted allosteric coupling to Ca2+-driven gating, as previously reported for ethanol.