VASOMOTOR CONTROL OF DESCENDING VASA RECTA

降血管直肠的血管舒缩控制

• 批准号: 6604310
• 负责人: THOMAS L PALLONE
• 金额: $ 26.61万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604310
• 关键词: adenylate cyclase; angiotensin II; angiotensin receptor; calcium flux; calcium indicator; enzyme inhibitors; kidney circulation; kidney pharmacology; laboratory rat; macrophage; membrane potentials; microcirculation; nitric oxide; polymerase chain reaction; protein tyrosine kinase; protein tyrosine phosphatase; receptor expression; renal medulla; renal tubule; thromboxanes; vascular endothelium permeability; vasomotion; voltage /patch clamp; voltage gated channel

DESCRIPTION: (Adapted from the Investigator's Abstract) Descending vasa recta (DVR) are resistance vessels through which blood flow to the renal medulla is supplied. Angiotensin II (ANGII) appears to have tonic effects to constrict the medullary microcirculation and stimulate medullary NO production. The PI offers preliminary data suggesting that ANGII stimulates both AT1 and AT2 receptor subtypes on DVR, that ANGII-induced constriction is mediated by a cyclooxygenase product, and that the AT1-induced constriction is abrogated by AT2 receptor activation. Moreover, the DVR endothelium appears to respond to AT1 activation by increasing intracellular [Ca] only when AT2 receptors are blocked. Finally, AT2 receptor activation appears to hyperpolarize DVR endothelium, while having no effect on membrane potential of neighboring pericytes. The following specific aims are provided: Aim 1-Utilize both RT-PCR and a pharmacological assessment of responsiveness to AT2 receptor blockers to verify expression of the AT2 receptor in DVR. Aim 2-Measure ANGII-induced intracellular [Ca] responses and NO generation by DVR and interbundle nephron segments isolated from the renal outer medulla, and the effect of dietary salt loading on these responses. Aim 3-Utilize membrane permeant cyclic nucleotide analogues and guanylate or adenylate cyclase inhibitors to test the hypothesis that blockade of AT1-mediated calcium signaling in DVR endothelia by AT2 receptor activation involves cyclic nucleotides. The role of intracellular phosphorylation events and tyrosine phosphatase or kinase activity in this phenomenon will also be examined. Aim 4-Utilize patch clamp and Mn-quench of fura2 to examine the ability of AT1 and AT2 receptor activation to modulate endothelial Ca influx. Aim 5-Test the hypothesis that DVR pericytes lack L-type voltage operated Ca channels by examining the ability of nifedipine to block vasoconstriction, the effect of ANGII on pericyte membrane potential, and the effect of membrane depolarization on whole call Ca currents. Additional experiments will test the hypothesis that AT1 and AT2 stimulation modulates pericyte intracellular [Ca]. Finally, the PI hypothesizes that ANGII constricts OMDVR via thromboxane generation. This postulate will be tested by examining the ability of a PGH2-TxA2 receptor antagonist to block ANGII-induced vasoconstriction, the ability of a TxA2 analogue to cause vasoconstriction, and the ability of ANGII to stimulate TxB2 production in isolated vessels.

描述：（改编自研究者摘要）降直血管 (DVR)是阻力血管，血液通过这些血管流向肾髓质， 供应。血管紧张素II（ANGII）似乎具有紧张作用， 延髓微循环和刺激延髓NO的产生。PI提供 初步数据表明ANGII刺激AT 1和AT 2受体 亚型的DVR，ANGII诱导的收缩是由介导的， 环氧合酶产物，AT 1诱导的收缩被废除， AT 2受体激活。此外，DVR内皮似乎对 只有当AT 2受体被激活时，AT 1才通过增加细胞内[Ca]激活。 被挡出.最后，AT 2受体激活似乎使DVR过度兴奋， 内皮细胞，而不影响相邻的膜电位 周细胞提供了以下具体目标：目标1-利用RT-PCR 以及对AT 2受体阻滞剂的反应性的药理学评估， 验证DVR中AT 2受体的表达。目的2-测量ANGII诱导的 DVR和束间肾单位细胞内[Ca]反应和NO生成 从肾外髓质分离的节段，以及膳食盐的影响 加载这些响应。目的3-利用膜渗透性环核苷酸 类似物和鸟苷酸或腺苷酸环化酶抑制剂来检验这一假设 AT 2阻断AT 1介导的DVR内皮细胞钙信号， 受体活化涉及环核苷酸。细胞内的作用 磷酸化事件和酪氨酸磷酸酶或激酶活性 现象也将被研究。目的4-利用膜片钳和锰淬灭 fura 2检测AT 1和AT 2受体激活调节 内皮钙内流。目的5-检验DVR周细胞缺乏L型的假设 通过检测硝苯地平阻断电压操纵性钙通道的能力， 血管收缩，血管紧张素Ⅱ对周细胞膜电位的影响， 膜去极化对全钙电流影响。额外 实验将检验AT 1和AT 2刺激调节 周细胞胞内[Ca]。最后，PI假设ANGII收缩 通过血栓素生成的OMDVR。这一假设将通过检验 PGH 2-TxA 2受体拮抗剂阻断ANGII诱导的血管生成的能力 血管收缩，TxA 2类似物引起血管收缩的能力，和 ANGII刺激离体血管中TxB 2产生的能力。

项目成果

Interstitial water and solute recovery by inner medullary vasa recta.

内髓直肠血管间质水和溶质的回收。

• DOI: 10.1152/ajprenal.2000.278.2.f257
• 发表时间: 2000
• 期刊: American journal of physiology. Renal physiology
• 作者: Edwards,A;Delong,MJ;Pallone,TL
• 通讯作者: Pallone,TL

Control of descending vasa recta pericyte membrane potential by angiotensin II.

血管紧张素 II 对降直血管周细胞膜电位的控制。

• DOI: 10.1152/ajprenal.00306.2001
• 发表时间: 2002
• 期刊: American journal of physiology. Renal physiology
• 作者: Pallone,ThomasL;Huang,JamesM-C
• 通讯作者: Huang,JamesM-C

Expression of TRPC4 channel protein that interacts with NHERF-2 in rat descending vasa recta.

• DOI: 10.1152/ajpcell.00417.2004
• 发表时间: 2005-04
• 期刊: American journal of physiology. Cell physiology
• 作者: W. Lee‐Kwon;J. Wade;Zhong Zhang;T. Pallone;E. Weinman

Inhibition of calcium signaling in descending vasa recta endothelia by ANG II.

• DOI: 10.1152/ajpheart.2000.278.4.h1248
• 发表时间: 2000-04
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: T. Pallone;E. Silldorff;Z. Zhang

Role of chloride in constriction of descending vasa recta by angiotensin II.

氯化物在血管紧张素 II 导致的直降血管收缩中的作用。

• DOI: 10.1152/ajpregu.2001.280.6.r1878
• 发表时间: 2001
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Zhang,Z;Huang,JM;Turner,MR;Rhinehart,KL;Pallone,TL
• 通讯作者: Pallone,TL