Regulation of Adrenal Vascular Tone by Steroidogenic Cells

类固醇生成细胞对肾上腺血管张力的调节

• 批准号: 7624598
• 负责人: WILLIAM BRYSON CAMPBELL
• 金额: $ 33.1万
• 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/7624598
• 关键词: Acetylcholine; Acids; Adrenal Cortex; Adrenal Glands; Agonist; Aldosterone; Angiotensin II; Arachidonic Acids; Architecture; Arteries; Blood Vessels; Blood flow; Carbon; Cattle; Cell membrane; Cells; Cholesterol; Comparative Study; Conditioned Culture Media; Congestive Heart Failure; Corticotropin; Cytochrome P450; Dilator; Endocrine Glands; Endogenous Factors; Endothelium; Equilibrium; Excision; Fatty Acids; Fibroblasts; Flowmeters; Glucocorticoids; Glucose; Heart Hypertrophy; High Pressure Liquid Chromatography; Histamine; Hydrocortisone; Hypertension; In Vitro; Incubated; Lasers; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Membrane Potentials; Metabolism; Modeling; Nitric Oxide; Nitric Oxide Synthase; Nutrient; Oxygen; Pathway interactions; Potassium; Potassium Channel; Prostaglandins; Rattus; Regulation; Relaxation; Reporting; Research Personnel; Role; Slice; Smooth Muscle Myocytes; Sodium; Source; Steroid biosynthesis; Stimulus; Testing; Tissues; Vasodilation; Vasodilator Agents; Zona Fasciculata; Zona Glomerulosa; adrenic acid; extracellular; in vivo; inhibitor/antagonist; insight; progesterone 11-hemisuccinate-(2-iodohistamine); programs; protein metabolism; release factor; research study; response

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球状带（ZG）细胞合成。它调节钠和钾 (K) 平衡，并与高血压、心脏肥大和充血性心力衰竭有关。血管紧张素 II (All)、促肾上腺皮质激素 (ACTH) 和钾 (K) 是醛固酮释放的主要刺激物。流向肾上腺皮质的血流将营养物质输送至 ZG 细胞，并将醛固酮输送至目标组织。因此，了解调节肾上腺血流量（ABF）和肾上腺血管张力的因素非常重要。 ACTH 扩张肾上腺脉管系统并增加体内 ABF；然而，ACTH 在体外不会松弛孤立的肾上腺皮质动脉。我们想知道肾上腺皮质中的其他细胞是否会释放一种血管扩张剂来介导 ACTH 的扩张。当 ZG 细胞与分离的肾上腺动脉共孵育时，ACTH 会引起松弛。 ZG 细胞依赖性 ACTH 松弛受到高细胞外 K、K 通道抑制剂、细胞色素 P450 抑制剂和环氧二十碳三烯酸 (EET) 拮抗剂的抑制。 ZG 细胞同样增强了肾上腺动脉对 AII 的松弛作用。 ZG 细胞条件培养基 (ZG-CM) 还可放松肾上腺动脉并持续 EET 和前列腺素。这些研究表明，ZG 细胞释放可溶性因子，介导 ACTH 和 All 的松弛。该因子可以是 EET 或相关脂肪酸代谢物。我们将检验这样的假设：ZG 细胞在解剖学上与肾上腺皮质中的肾上腺动脉非常接近，会释放可溶性、可转移的因子，导致血管舒张。拟议的研究将调查 ZG 细胞和 ZG-CM 在体外松弛离体牛肾上腺皮质动脉并介导 ACTH 和 All 诱导的扩张的能力。将测试各种脂肪酸以及已知内源性扩张剂的抑制剂。平行研究将对束状带（ZF）细胞进行。为了维持 ZG 细胞和肾上腺动脉之间的解剖关系，将对嵌入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 提取物中分离和鉴定活性因子。将合成因子并测试扩张器活性。还将测试因子对 K 通道活性和平滑肌细胞膜电位的作用。我们将测量 ACTH 和 All 刺激下 ZG 细胞释放的因子。还将在麻醉大鼠体内进行研究，以确定 ZG 细胞因子在调节 ABF 中的作用。将通过激光多普勒流量计测量皮质 ABF，以响应 ACTH 和 All，并确定内源性血管舒张途径抑制剂的作用。 ZG 细胞对肾上腺血管张力的调节可能具有更广泛的意义。这可能代表了许多内分泌腺中血管张力调节的一般途径。