Division of Gastroenterology and Hepatology, VA Maryland Health Care System and University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2012;7(2):e32006. doi: 10.1371/journal.pone.0032006. Epub 2012 Feb 16.
Bile acids (BAs) regulate cardiovascular function via diverse mechanisms. Although in both health and disease serum glycine-conjugated BAs are more abundant than taurine-conjugated BAs, their effects on myogenic tone (MT), a key determinant of systemic vascular resistance (SVR), have not been examined.
METHODOLOGY/PRINCIPAL FINDINGS: Fourth-order mesenteric arteries (170-250 µm) isolated from Sprague-Dawley rats were pressurized at 70 mmHg and allowed to develop spontaneous constriction, i.e., MT. Deoxycholylglycine (DCG; 0.1-100 µM), a glycine-conjugated major secondary BA, induced reversible, concentration-dependent reduction of MT that was similar in endothelium-intact and -denuded arteries. DCG reduced the myogenic response to stepwise increase in pressure (20 to 100 mmHg). Neither atropine nor the combination of L-NAME (a NOS inhibitor) plus indomethacin altered DCG-mediated reduction of MT. K(+) channel blockade with glibenclamide (K(ATP)), 4-aminopyradine (K(V)), BaCl(2) (K(IR)) or tetraethylammonium (TEA, K(Ca)) were also ineffective. In Fluo-2-loaded arteries, DCG markedly reduced vascular smooth muscle cell (VSM) Ca(2+) fluorescence (∼50%). In arteries incubated with DCG, physiological salt solution (PSS) with high Ca(2+) (4 mM) restored myogenic response. DCG reduced vascular tone and VSM cytoplasmic Ca(2+) responses (∼50%) of phenylephrine (PE)- and Ang II-treated arteries, but did not affect KCl-induced vasoconstriction.
In rat mesenteric resistance arteries DCG reduces pressure- and agonist-induced vasoconstriction and VSM cytoplasmic Ca(2+) responses, independent of muscarinic receptor, NO or K(+) channel activation. We conclude that BAs alter vasomotor responses, an effect favoring reduced SVR. These findings are likely pertinent to vascular dysfunction in cirrhosis and other conditions associated with elevated serum BAs.
胆汁酸（BAs）通过多种机制调节心血管功能。尽管在健康和疾病中，血清甘氨酸结合胆汁酸比牛磺酸结合胆汁酸更为丰富，但它们对肌源性张力（MT）的影响尚未被研究，MT 是全身血管阻力（SVR）的关键决定因素。
方法/主要发现：从 Sprague-Dawley 大鼠分离出第四级肠系膜动脉（170-250μm），在 70mmHg 下加压并允许自发收缩，即 MT。脱氧胆酰甘氨酸（DCG；0.1-100μM），一种主要的甘氨酸结合次级 BA，诱导可逆的、浓度依赖性的 MT 减少，在完整内皮和去内皮动脉中相似。DCG 降低了对逐渐增加压力（20 至 100mmHg）的肌源性反应。阿托品或 L-NAME（NOS 抑制剂）加吲哚美辛的组合均不改变 DCG 介导的 MT 减少。用格列本脲（K(ATP)）、4-氨基吡啶（K(V)）、BaCl(2)（K(IR)）或四乙铵（TEA，K(Ca)）阻断 K+通道也无效。在 Fluo-2 加载的动脉中，DCG 显著降低血管平滑肌细胞（VSM）Ca(2+)荧光（约 50%）。在孵育 DCG 的动脉中，高 Ca(2+)（4mM）的生理盐溶液（PSS）恢复了肌源性反应。DCG 降低了苯肾上腺素（PE）和 Ang II 处理的动脉的血管张力和 VSM 细胞质 Ca(2+)反应（约 50%），但不影响 KCl 诱导的血管收缩。
在大鼠肠系膜阻力动脉中，DCG 降低了压力和激动剂诱导的血管收缩和 VSM 细胞质 Ca(2+)反应，与毒蕈碱受体、NO 或 K+通道激活无关。我们得出结论，BA 改变了血管舒缩反应，这有利于降低 SVR。这些发现可能与肝硬化和其他与血清 BA 升高相关的疾病中的血管功能障碍有关。
