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: 8585081
• 负责人: WILLIAM BRYSON CAMPBELL
• 金额: $ 37.49万
• 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/8585081
• 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），一种血管收缩剂，刺激了肾上腺皮质的Zona glomerulosa（ZG）细胞的醛固酮释放。醛固酮调节钠和钾的平衡和血压。肾上腺血流（ABF）对于醛固酮合成和作用至关重要。 ABF将氧气，营养素，胆固醇酯和AII提供给ZG细胞，并将醛固酮带到其靶组织。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。众所周知，AII及其代谢物对肾上腺血管张力张力和类固醇发生的肾上腺内调节尚不清楚。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和类固醇生成的偶联。 ZG细胞与肾上腺皮质中的肾上腺小动脉的近端紧密相关，允许相互作用。我们已经定义了ZG细胞通过释放引起血管延缓的环氧树钠酸（EET）来调节肾上腺血管张力的新机制。在PM浓度中，AII通过两种机制松弛肾上腺动脉。 AII直接通过内皮释放一氧化氮（NO）的内皮释放，并通过ZG细胞释放EET的释放来放松肾上腺动脉。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细胞途径是氨基肽酶A（APA）转化为血管紧张素III（AIII）。 AIII在肾上腺皮质中具有新的作用。在刺激ZG细胞依赖性EET介导的松弛方面，AIII比AII高10倍。抑制AII代谢对AIII的抑制会阻止ZG细胞介导的松弛对AII。因此，AII对AIII的代谢对于调节肾上腺血管张力和AII的ABF至关重要。我们在该提案中的目标是了解ZG细胞在调节肾上腺血管张力，ABF和醛固酮释放方面代谢的重要性。中心假设是，APA对AIII的AII代谢是ZG细胞介导的血管汇总的强制性步骤，并且AII在ABF中增加了ABF。这表明APA在调节肾上腺血管张力和ABF中的重要作用。中央假设将以三个目标进行检验。 （1）我们将通过分离的ZG细胞以及AII代谢对EET和醛固酮释放的影响来鉴定AII代谢的途径。我们的假设是ZG细胞将AII代谢为AIII，从而调节AII刺激EET，但不是醛固酮释放。 （2）我们将确定AII在孤立的肾上腺皮质动脉中调节血管张力的机制。我们的假设是，AII对AIII和APA活性的代谢对于ZG细胞依赖性，EET介导的血管延缓至关重要。 （3）我们将确定AII代谢和ZG细胞衍生的EET在麻醉大鼠体内调节体内的作用。我们的假设是，APA对AIII的AII代谢对于ABF的AII增加至关重要。这些研究将表明AII与AIII的代谢是否是调节肾上腺血管张力和ZG细胞ABF的强制性步骤。 APA可以确定ZG细胞介导的EET和/或内皮介导的无机制是否反对AII的收缩并在高肾素状态下维持ABF。