Walker B R, Yau J L, Brett L P, Seckl J R, Monder C, Williams B C, Edwards C R
University of Edinburgh, Department of Medicine, Western General Hospital, United Kingdom.
Endocrinology. 1991 Dec;129(6):3305-12. doi: 10.1210/endo-129-6-3305.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in the rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. We have previously demonstrated that cortisol-induced cutaneous vasoconstriction in man is potentiated by the 11 beta-OHSD inhibitor glycyrrhetinic acid, suggesting that 11 beta-OHSD may protect vascular corticosteroid receptors. In this study we report quantitation of 11 beta-OHSD bioactivity in homogenates of rat aorta, mesenteric artery, caudal artery, and heart, expressed as the percent in vitro conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone. Nicotinamide adenine dinucleotide phosphate (NADP+)-dependent 11 beta-OHSD activity was found in all of these tissues and was significantly higher in resistance vessels than aorta (P less than 0.05) [without NADP+: caudal artery (4.2 +/- 0.2%) greater than mesenteric artery (2.5 +/- 0.7%) = heart (1.67 +/- 0.2%) greater than aorta (0.79 +/- 0.2%); with 200 microM NADP+: caudal artery (43.9 +/- 2.1%) greater than heart (20.6 +/- 1.0%) = mesenteric artery (17.7 +/- 3.1%) = aorta (11.4 +/- 0.4%); heart greater than aorta]. All of these were lower than renal cortex (29.4 +/- 1.8% without NADP+; 82.4 +/- 0.4% with NADP+; P less than 0.001). 3H-11-dehydrocorticosterone was the major metabolite of 3H-corticosterone (greater than 97% of 3H-corticosterone metabolized). Reduction of 3H-11-dehydrocorticosterone to 3H-corticosterone was not detected in these experiments. We also report localization of 11 beta-OHSD-like immunoreactivity by immunohistochemistry using antisera raised against rat liver 11 beta-OHSD, and of 11 beta-OHSD messenger RNA expression by in situ hybridization using complementary RNA probes transcribed from complementary DNA encoding rat liver 11 beta-OHSD. We found 11 beta-OHSD immunoreactivity and messenger RNA expression in vascular and cardiac smooth muscle cytoplasm but not in endothelium. Thus, 11 beta-OHSD is appropriately sited to modulate access of corticosterone to vascular receptors and could influence vascular resistance, cardiac output and thereby blood pressure.
11β-羟类固醇脱氢酶（11β-OHSD）可将活性糖皮质激素皮质酮转化为无活性的11-脱氢皮质酮（在大鼠中）或皮质醇转化为可的松（在人类中），从而保护肾脏盐皮质激素受体免受皮质酮或皮质醇的影响，使醛固酮能够优先与之结合。我们之前已经证明，11β-OHSD抑制剂甘草次酸可增强皮质醇诱导的人体皮肤血管收缩，这表明11β-OHSD可能保护血管皮质类固醇受体。在本研究中，我们报告了大鼠主动脉、肠系膜动脉、尾动脉和心脏匀浆中11β-OHSD生物活性的定量结果，以3H-皮质酮体外转化为3H-11-脱氢皮质酮的百分比表示。在所有这些组织中均发现了烟酰胺腺嘌呤二核苷酸磷酸（NADP+）依赖性11β-OHSD活性，且阻力血管中的活性显著高于主动脉（P<0.05）[无NADP+时：尾动脉（4.2±0.2%）>肠系膜动脉（2.5±0.7%）=心脏（1.67±0.2%）>主动脉（0.79±0.2%）；有200μM NADP+时：尾动脉（43.9±2.1%）>心脏（20.6±1.0%）=肠系膜动脉（17.7±3.1%）=主动脉（11.4±0.4%）；心脏>主动脉]。所有这些活性均低于肾皮质（无NADP+时为29.4±1.8%；有NADP+时为82.4±0.4%；P<0.001）。3H-11-脱氢皮质酮是3H-皮质酮的主要代谢产物（超过97%的3H-皮质酮被代谢）。在这些实验中未检测到3H-11-脱氢皮质酮还原为3H-皮质酮的过程。我们还通过免疫组织化学方法，使用针对大鼠肝脏11β-OHSD产生的抗血清，报告了11β-OHSD样免疫反应性的定位情况，并通过原位杂交方法，使用从编码大鼠肝脏11β-OHSD的互补DNA转录的互补RNA探针，报告了11β-OHSD信使核糖核酸表达情况。我们发现血管和心脏平滑肌细胞质中有11β-OHSD免疫反应性和信使核糖核酸表达，但内皮细胞中没有。因此，11β-OHSD的定位适当，可调节皮质酮与血管受体的结合，可能影响血管阻力、心输出量，进而影响血压。
