Regulation Adrenal Vascular Tone by Steroidogenic Cells

类固醇生成细胞调节肾上腺血管张力

• 批准号: 7142185
• 负责人: WILLIAM BRYSON CAMPBELL
• 金额: $ 36.59万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142185
• 关键词: adrenal glands; adrenocorticotropic hormone; aldosterone; animal tissue; blood circulation; cytochrome P450; eicosanoid metabolism; endocrine pharmacology; high performance liquid chromatography; hormone regulation /control mechanism; laboratory rat; laser Doppler flowmetry; mass spectrometry; membrane potentials; nitric oxide; perfusion; potassium channel; prostaglandins; steroid biosynthesis; tissue /cell culture; vascular smooth muscle; vasodilation; vasodilators

DESCRIPTION (provided by applicant): Aldosterone is synthesized by zona glomerulosa (ZG) cells of the adrenal cortex. It regulates sodium and potassium (K) balance and is involved hypertension, cardiac hypertrophy and congestive heart failure. Angiotensin II (All), adrenocorticotropic hormone (ACTH) and potassium (K) are major stimuli for aldosterone release. Blood flow to the adrenal cortex delivers nutrients to ZG cells and carries aldosterone to its target tissues. Thus, understanding the factors regulating adrenal blood flow (ABF) and adrenal vascular tone is important. ACTH dilates the adrenal vasculature and increases ABF in vivo; however, ACTH does not relax isolated adrenal cortical arteries in vitro. We wondered if other cells in the adrenal cortex released a vasodilator that mediates the dilation by ACTH. When ZG cells were co-incubated with the isolated adrenal arteries, ACTH caused relaxation. The ZG cell-dependent relaxations to ACTH were inhibited by high extracellular K, a K channel inhibitor, a cytochrome P450 inhibitor and an epoxyeicosatrienoic acid (EET) antagonist. ZG cells similarly enhanced the relaxation of adrenal arteries to AII. ZG cell conditioned media (ZG-CM) also relaxed adrenal arteries and continued EETs and prostaglandins. These studies indicate that ZG cells release a soluble factor(s) that mediates the relaxations to ACTH and All. This factor(s) may be an EET or related fatty acid metabolite(s). We will test the hypothesis that ZG cells, which are in close anatomical proximity to adrenal arteries in the adrenal cortex, release soluble, transferable factors that cause vasodilation. The proposed studies will investigate the ability of ZG cells and ZG-CM to relax isolated bovine adrenal cortical arteries in vitro and mediate ACTH- and All-induced dilation. Various fatty acids as well as inhibitors of known endogenous dilators will be tested. Parallel studies will be conducted on zona fasciculata (ZF) cells. To maintain the anatomical relationship between ZG cells and adrenal arteries, parallel studies will be conducted with perfused adrenal arteries embedded in slices of the adrenal cortex. The active factor(s) will be isolated and identified from ZG-CM extracts using HPLC and mass spectrometry. The factor(s) will be synthesized and tested for dilator activity. The action of the factor(s) will also be tested on K channel activity and smooth muscle cell membrane potential. We will measure the release of the factor(s) from ZG cells with ACTH and All stimulation. Studies will also be performed in vivo in anesthetized rats to determine the role of the ZG cell factor(s) in regulating ABF. Cortical ABF will be measured by a laser Doppler flowmeter in response to ACTH and All and the effect of inhibitors of endogenous vasodilator pathways determined. The regulation of adrenal vascular tone by ZG cells may have broader implications. This may represent a general pathway for regulation of vascular tone in many endocrine glands.

描述（由申请人提供）：醛固酮由肾上腺皮质的Zona glomerulosa（ZG）细胞合成。它调节钠和钾（K）平衡，涉及高血压，心脏肥大和充血性心力衰竭。血管紧张素II（全），肾上腺皮质激素（ACTH）和钾（K）是醛固酮释放的主要刺激。流向肾上腺皮质的血流可为ZG细胞提供营养，并将醛固酮带到其靶组织。因此，了解调节肾上腺血流（ABF）和肾上腺血管张力的因素很重要。 ACTH扩张肾上腺脉管系统，并增加体内ABF；但是，ACTH在体外不会放松分离的肾上腺皮质动脉。我们想知道肾上腺皮质中的其他细胞是否释放了介导ACTH扩张的血管扩张剂。当ZG细胞与分离的肾上腺动脉共孵育时，ACTH引起了松弛。 ZG细胞依赖性弛豫与ACTH的弛豫受到高细胞外K，K通道抑制剂，细胞色素P450抑制剂和环氧酸磷脂酸（EET）拮抗剂的抑制。 ZG细胞类似地增强了肾上腺动脉对AII的松弛。 ZG细胞条件培养基（ZG-CM）还放松了肾上腺动脉，持续的Eets和前列腺素。这些研究表明，ZG细胞释放了可溶性因子，该因子介导了ACTH及所有方面的松弛。该因子可以是EET或相关的脂肪酸代谢产物（S）。我们将检验以下假设：ZG细胞在肾上腺皮质中与肾上腺动脉紧密的近端，释放引起血管舒张的可溶性因子释放。拟议的研究将研究ZG细胞和ZG-CM在体外放松分离的牛肾上腺皮质动脉的能力，并介导ACTH和全诱导的扩张。将测试各种脂肪酸以及已知内源扩张剂的抑制剂。平行研究将在Zona fasciculata（ZF）细胞上进行。为了维持ZG细胞与肾上腺动脉之间的解剖学关系，将使用灌注肾上腺皮质切片中的灌注肾上腺动脉进行平行研究。将使用HPLC和质谱法从ZG-CM提取物中分离活性因子。该因子将被合成并测试扩张器活性。该因子的作用也将在K通道活性和平滑肌细胞膜电位上进行测试。我们将测量具有ACTH和所有刺激的ZG细胞中因子的释放。研究还将在麻醉大鼠的体内进行，以确定ZG细胞因子在调节ABF中的作用。皮质ABF将通过激光多普勒流量计响应ACTH和ALL以及确定的内源性血管舒张途径的抑制剂的影响来测量。 ZG细胞对肾上腺血管张力的调节可能具有更广泛的影响。这可能代表了许多内分泌腺体血管张力调节的一般途径。