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）是一种血管收缩剂，刺激肾上腺皮质肾小球（ZG）细胞释放醛固酮。醛固酮调节钠钾平衡和血压。肾上腺血流量（ABF）对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输送到ZG细胞，并将醛固酮运送到其靶组织。因此，影响肾上腺血管张力的机制对ABF调节和类固醇生成很重要。AII及其代谢产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细胞在解剖学上靠近肾上腺皮质中的肾上腺小动脉，从而允许相互作用。我们已经确定了ZG细胞通过释放引起血管舒张的环氧二十碳三烯酸（E3）来调节肾上腺血管张力的新机制。在pM浓度下，AII通过两种机制舒张肾上腺动脉。AII通过内皮细胞释放一氧化氮（NO）直接舒张肾上腺动脉，并通过ZG细胞释放雌二醇间接舒张肾上腺动脉。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中心作用。AII代谢的主要ZG细胞途径是其通过氨肽酶A（阿帕）转化为血管紧张素III（AIII）。AIII在肾上腺皮质中具有新的作用。AIII在刺激ZG细胞依赖性、EET介导的松弛方面比AII有效10倍。抑制AII代谢为AIII阻断了ZG细胞介导的对AII的松弛。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。本研究的目的是了解ZG细胞代谢AII在调节肾上腺血管张力、ABF和醛固酮释放中的重要性。中心假设是，AII代谢AIII的阿帕是一个强制性的步骤ZG细胞介导的血管舒张和增加ABF的AII。这表明阿帕在调节肾上腺血管张力和ABF中具有重要作用。中心假设将通过三个目标进行检验。(1)我们将通过分离的ZG细胞确定AII代谢的途径以及AII代谢对EET和醛固酮释放的影响。我们的假设是，ZG细胞代谢AII到AIII，从而调节AII刺激EET，而不是醛固酮，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和阿帕活性是ZG细胞依赖性，EET介导的血管舒张的关键。(3)我们将在麻醉大鼠体内建立AII代谢和ZG细胞衍生的Ehrs在ABF调节中的作用。我们的假设是，AII代谢AIII的阿帕是必不可少的AII增加ABF。这些研究将表明AII代谢为AIII是否是ZG细胞调节肾上腺血管张力和ABF的必要步骤。阿帕可能决定ZG细胞介导的EET和/或内皮细胞介导的NO机制是否对抗AII的收缩并维持高肾素状态的ABF。