Dietary Cholesterol Protects Against Alcohol-Induced Cerebral Artery Constriction

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2014-05, Vol.38 (5), p.1216-1226
• Main Authors: Bukiya, Anna, Dopico, Alejandro M., Leffler, Charles W., Fedinec, Alexander
• Format: Article
• Language: English
• Subjects: Animals; Cerebral Arteries - drug effects; Cerebral Artery; Cholesterol, Dietary - pharmacology; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Closed Cranial Window; Ethanol; Ethanol - pharmacology; Large-Conductance Calcium-Activated Potassium Channels - drug effects; Male; MaxiK Channel; Rats, Sprague-Dawley; Vascular Smooth Muscle; Vasoconstriction - drug effects
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.12373

Background Binge drinking represents the major form of excessive alcohol (ethanol [EtOH]) consumption in the United States. Episodic (such as binge) drinking results in blood alcohol levels (BAL) of 18 to 80 mM and leads to alcohol‐induced cerebral artery constriction (AICAC). AICAC was shown to arise from EtOH‐induced inhibition of large‐conductance, calcium/voltage‐gated potassium (BK) channels in the vascular smooth muscle. Factors that modulate BK channel‐mediated AICAC remain largely unknown. Methods Male Sprague Dawley rats were placed on high‐cholesterol (2% of cholesterol) diet for 18 to 23 weeks. Their littermates were placed on control iso‐caloric diet. AICAC was evaluated both in vivo and in vitro, by means of pial arteriole diameter monitoring through a closed cranial window and diameter measurements of isolated, pressurized cerebral arteries. Cholesterol level in the cerebral artery tissue was manipulated by methyl‐β‐cyclodextrin to reverse dietary‐induced accumulation of cholesterol. BK channel surface presence on the plasma membrane of cerebral artery myocytes was evaluated by immunofluorescence staining. BK channel function in pressurized cerebral artery was assessed using selective BK channel blocker paxilline. Results Within 5 minutes of 50 mM EtOH injection into carotid artery in vivo, arteriole diameter decreased by 20% in control group. Pial arteriole constriction was significantly reduced in rats on high‐cholesterol diet, resulting in only 10% reduction in diameter. BAL in both groups, however, remained the same. Significant reduction in AICAC in group on high‐cholesterol diet compared to control was also observed after middle cerebral artery dissection and in vitro pressurization at 60 mmHg, this reduction remaining after endothelium removal. Cholesterol level in de‐endothelialized cerebral arteries was significantly increased in rats on high‐cholesterol diet. Removal of excessive cholesterol content restored AICAC to the level observed in cerebral arteries of rats on normal diet. Immunofluorescence staining of BK channel‐forming and accessory, smooth muscle‐specific β1 subunit in freshly isolated cerebral artery myocyte showed that high‐cholesterol diet did not down‐regulate surface presence of BK protein. However, paxilline‐induced cerebral artery constriction was diminished in arteries from rats on high‐cholesterol diet. Conclusions Our data indicate that dietary cholesterol protects against AICAC. This protection is caused by cho