Abstract:
Alcohol intake leading to blood ethanol concentrations (BEC) ≥ legal intoxication modifies brain blood flow with increases in some regions and decreases in others. Brain regions receive blood from the Willis\' circle branches: anterior, middle (MCA) and posterior cerebral (PCA), and basilar (BA) arteries. Rats and mice have been used to identify the targets mediating ethanol-induced effects on cerebral arteries, with conclusions being freely interchanged, albeit data were obtained in different species/arterial branches. We tested whether ethanol action on cerebral arteries differed between male rat and mouse and/or across different brain regions and identified the targets of alcohol action. In both species and all Willis\' circle branches, ethanol evoked reversible and concentration-dependent constriction (EC50s ≈ 37-86 mM; below lethal BEC in alcohol-naïve humans). Although showing similar constriction to depolarization, both species displayed differential responses to ethanol: in mice, MCA constriction was highly sensitive to the presence/absence of the endothelium, whereas in rat PCA was significantly more sensitive to ethanol than its mouse counterpart. In the rat, but not the mouse, BA was more ethanol sensitive than other branches. Both interspecies and regional variability were ameliorated by endothelium. Selective large conductance (BK) channel block in de-endothelialized vessels demonstrated that these channels were the effectors of alcohol-induced cerebral artery constriction across regions and species. Variabilities in alcohol actions did not fully matched KCNMB1 expression across vessels. However, immunofluorescence data from KCNMB1-/- mouse arteries electroporated with KCNMB1-coding cDNA demonstrate that KCNMB1 proteins, which regulate smooth muscle (SM) BK channel function and vasodilation, regulate interspecies and regional variability of brain artery responses to alcohol.
摘要:
酒精摄入导致血液乙醇浓度(BEC)≥法定中毒会改变脑血流量,在某些区域会增加,而在其他区域会减少。大脑区域从威利斯圈分支接收血液:前部,大脑中部(MCA)和大脑后部(PCA),和基底动脉(BA)。大鼠和小鼠已被用于确定介导乙醇诱导的脑动脉效应的靶标,结论可以自由互换,尽管数据是在不同的物种/动脉分支中获得的。我们测试了乙醇对脑动脉的作用是否在雄性大鼠和小鼠之间和/或在不同的大脑区域不同,并确定了酒精作用的目标。在这两个物种和所有威利斯圈分支中,乙醇引起可逆性和浓度依赖性收缩(EC50≈37-86mM;在未饮酒的人中低于致死性BEC)。虽然显示出类似于去极化的收缩,这两个物种对乙醇表现出不同的反应:在小鼠中,MCA收缩对内皮的存在/不存在高度敏感,而大鼠PCA对乙醇的敏感性明显高于小鼠。在老鼠身上,但不是老鼠,BA比其他分支对乙醇更敏感。内皮改善了种间和区域变异性。去内皮化血管中的选择性BK通道阻滞表明,这些通道是跨区域和物种的酒精诱导的脑动脉收缩的效应物。酒精作用的变异并不完全匹配血管中的KCNMB1表达。然而,用编码KCNMB1的cDNA电穿孔的KCNMB1-/-小鼠动脉的免疫荧光数据表明,KCNMB1蛋白,调节SMBK通道功能和血管舒张,调节大脑动脉对酒精反应的种间和区域变异性。