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: 8399061
• 负责人: WILLIAM BRYSON CAMPBELL
• 金额: $ 36.41万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399061
• 关键词: Acids; Adrenal Cortex; Adrenal Glands; Aldosterone; Angiotensin II; Angiotensin II Receptor; Angiotensin III; Arachidonic Acids; Arteries; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cell Proliferation; Cells; Cholesterol Esters; Congestive; Congestive Heart Failure; Coupling; Cytochrome P450; Data; Dilator; Disease; Equilibrium; Excretory function; Fibrosis; Goals; Grant; Heart Hypertrophy; Heart failure; Hypertension; Kidney; Knowledge; Learning; Life; Mediating; Metabolism; Nitric Oxide; Nutrient; Oxygen; Pathway interactions; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Physiological; Plasma; Potassium; Rattus; Regulation; Relaxation; Renin; Resistance; Role; Slice; Sodium; Sodium Chloride; Steroid biosynthesis; Testing; Tissues; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Water; Work; Zona Glomerulosa; arteriole; blood pressure regulation; constriction; glutamyl aminopeptidase; in vivo; inhibitor/antagonist; insight; kidney vascular structure; novel; novel strategies; research study; steroid hormone; tensin

DESCRIPTION (provided by applicant): Angiotensin II (AII), a vasoconstrictor, stimulates aldosterone release from the zona glomerulosa (ZG) cells of the adrenal cortex. Aldosterone regulates sodium and potassium balance and blood pressure. Adrenal blood flow (ABF) is critical to both aldosterone synthesis and action. ABF delivers oxygen, nutrients, cholesterol esters and AII to ZG cells and carries aldosterone to its target tissues. Thus, mechanisms that influence adrenal vascular tone are important to ABF regulation and steroidogenesis. The intra-adrenal regulation of adrenal vascular tone and steroidogenesis by AII and its metabolites is poorly understood. The long-term goal is to understand the intraadrenal regulation of vascular tone, ABF and steroidogenesis and the coupling of ABF and steroidogenesis. ZG cells are in close anatomical proximity to the adrenal arterioles in the adrenal cortex allowing interactions. We have defined the novel mechanism that ZG cells regulate adrenal vascular tone by releasing epoxyeicosatrienoic acids (EETs) that cause vasorelaxation. In pM concentrations, AII relaxes adrenal arteries by two mechanisms. AII relaxes adrenal arteries directly by endothelial release of nitric oxide (NO) and indirectly by ZG cell release of EETs. These findings indicate the central role of ZG cells in regulating both adrenal vascular tone and steroidogenesis. The major ZG cell pathway for AII metabolism is its conversion to angiotensin III (AIII) by aminopeptidase A (APA). AIII has a new role in the adrenal cortex. AIII is 10-fold more potent than AII in stimulating ZG cell-dependent, EET-mediated relaxation. Inhibition of AII metabolism to AIII blocks the ZG cell-mediated relaxation to AII. Thus, AII metabolism to AIII is critical for the regulation of adrenal vascular tone and ABF by AII. Our objective in this proposal is to understand the importance of AII metabolism by ZG cells in regulating adrenal vascular tone, ABF and aldosterone release. The central hypothesis is that AII metabolism to AIII by APA is an obligatory step for ZG cell-mediated vasorelaxation and increases in ABF by AII. This indicates an important role for APA in regulating adrenal vascular tone and ABF. The central hypothesis will be tested with three aims. (1) We will identify the pathways of AII metabolism by isolated ZG cells and the impact of AII metabolism on EET and aldosterone release. Our hypothesis is that ZG cells metabolize AII to AIII and thereby regulate AII stimulation of EET, but not aldosterone, release. (2) We will identify the mechanisms by which AII regulates vascular tone in isolated adrenal cortical arteries. Our hypothesis is that AII metabolism to AIII and APA activity are critical for ZG cell-dependent, EET-mediated vasorelaxation. (3) We will establish the role of AII metabolism and ZG cell-derived EETs in the regulation of ABF in vivo in anesthetized rats. Our hypothesis is that AII metabolism to AIII by APA is essential for AII increases in ABF. These studies will indicate if metabolism of AII to AIII is an obligatory step to the regulation of adrenal vascular tone and ABF by ZG cells. APA may determine whether ZG cell-mediated EET- and/or endothelial-mediated NO mechanisms oppose the constriction by AII and maintain ABF in high renin states.

描述（由申请人提供）：血管紧张素 II (AII) 是一种血管收缩剂，刺激肾上腺皮质肾小球带 (ZG) 细胞释放醛固酮。醛固酮调节钠和钾平衡以及血压。肾上腺血流量 (ABF) 对于醛固酮的合成和作用至关重要。 ABF 将氧气、营养物质、胆固醇酯和 AII 输送至 ZG 细胞，并将醛固酮输送至其靶组织。因此，影响肾上腺血管张力的机制对于 ABF 调节和类固醇生成很重要。 AII 及其代谢物对肾上腺血管张力和类固醇生成的肾上腺内调节作用尚不清楚。长期目标是了解血管张力、ABF 和类固醇生成的肾上腺内调节以及 ABF 和类固醇生成的耦合。 ZG 细胞在解剖学上与肾上腺皮质中的肾上腺小动脉非常接近，可以相互作用。我们已经定义了 ZG 细胞通过释放引起血管舒张的环氧二十碳三烯酸（EET）来调节肾上腺血管张力的新机制。在下午浓度下，AII 通过两种机制放松肾上腺动脉。 AII 通过内皮释放一氧化氮 (NO) 直接放松肾上腺动脉，并通过 ZG 细胞释放 EET 间接放松肾上腺动脉。这些发现表明 ZG 细胞在调节肾上腺血管张力和类固醇生成中的核心作用。 AII 代谢的主要 ZG 细胞途径是通过氨肽酶 A (APA) 转化为血管紧张素 III (AIII)。 AIII 在肾上腺皮质中发挥了新作用。 AIII 在刺激 ZG 细胞依赖性、EET 介导的放松方面比 AII 更有效 10 倍。抑制 AII 代谢为 AIII 可阻断 ZG 细胞介导的 AII 松弛。因此，AII 代谢为 AIII 对于 AII 调节肾上腺血管张力和 ABF 至关重要。我们本提案的目的是了解 ZG 细胞 AII 代谢在调节肾上腺血管张力、ABF 和醛固酮释放中的重要性。核心假设是，APA 将 AII 代谢为 AIII，是 ZG 细胞介导的血管舒张和 AII 增加 ABF 的必要步骤。这表明 APA 在调节肾上腺血管张力和 ABF 中发挥着重要作用。中心假设将通过三个目标进行检验。 (1)我们将鉴定分离的ZG细胞的AII代谢途径以及AII代谢对EET和醛固酮释放的影响。我们的假设是，ZG 细胞将 AII 代谢为 AIII，从而调节 AII 对 EET 的刺激，但不调节醛固酮的释放。 (2) 我们将确定 AII 调节离体肾上腺皮质动脉血管张力的机制。我们的假设是，AII 代谢为 AIII 和 APA 活性对于 ZG 细胞依赖性、EET 介导的血管舒张至关重要。 (3)我们将建立AII代谢和ZG细胞衍生的EET在麻醉大鼠体内ABF调节中的作用。我们的假设是，AII 通过 APA 代谢为 AIII 对于 ABF 中 AII 的增加至关重要。这些研究将表明 AII 到 AIII 的代谢是否是 ZG 细胞调节肾上腺血管张力和 ABF 的必要步骤。 APA 可以确定 ZG 细胞介导的 EET 和/或内皮介导的 NO 机制是否对抗 AII 的收缩并维持 ABF 处于高肾素状态。