Adenosine in Renal Sympathetic Neurotransmission

腺苷在肾交感神经传递中的作用

• 批准号: 8897360
• 负责人: EDWIN Kerry JACKSON
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897360
• 关键词: Adenosine; Adenosine A1 Receptor; Adrenergic Receptor; Agonist; Amines; Angiotensin II; Blood Vessels; Diuretics; Enzymes; Functional disorder; Genes; Heart failure; Hypertension; Inosine; Kidney; Kidney Failure; Knock-out; Knockout Mice; Liver diseases; Mass Spectrum Analysis; Mediating; Mus; Nerve; Neuroeffector Junction; Norepinephrine; Outcome; Patients; Physiological; Process; Publishing; Purines; Rattus; Renal function; Reporting; Signal Transduction; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Sympathetic Nervous System; Tyramine; Vasoconstrictor Agents; Wild Type Mouse; Work; Xanthines; base; enantiomer; in vivo; kidney vascular structure; methylxanthine; neurotransmission; promoter; purine; receptor; reconstitution; response; small hairpin RNA; vasoconstriction

DESCRIPTION (provided by applicant): While investigating the renal effects of BG9928 (a selective antagonist of adenosine type A1 receptors that is being developed as a diuretic for heart failure patients) we observed that in vivo BG9928 profoundly reduces renal vasoconstriction induced by renal sympathetic nerve stimulation (RSNS). This finding suggests to us that A1 receptors in the renal neuroeffector junction augment renal sympathetic neurotransmission. Although this hypothesis is consistent with our published reports that RSNS increases adenosine release and published reports by others that sympathetic nerve stimulation releases the adenosine precursor ATP as well as enzymes that form adenosine from ATP, numerous studies by others clearly establish that prejunctional A1 receptors inhibit, not augment, NE release. Taken together, these observations suggest that if A1 receptors participate in enhancing renal sympathetic neurotransmission, the effect must be post-junctional. Because A1 receptors are well known to enhance angiotensin II-induced renal vasoconstriction, we postulate that RSNS increases adenosine and NE in the neuroeffector junction, and that adenosine, via the post-junctional A1 receptor, enhances NE-induced vasoconstriction (through coincident signaling, i.e., convergence of signaling) resulting in A1 receptor-intensification of RSNS-induced renal vasoconstriction. Accordingly, the overall objective of this project is to determine whether endogenous adenosine in the renal neuroeffector junction and via the A1 adenosine receptor significantly intensifies the renal vasoconstrictor response to renal sympathetic nerve stimulation. We will investigate this hypothesis using multiple approaches: 1) We will determine in rat and mouse kidneys the effects of selective A1 receptor antagonists on RSNS-induced renal vasoconstriction and purine release (by mass spectrometry); 2) We will determine in mouse kidneys the effects of A1 receptor knockout on RSNS-induced renal vasoconstriction and purine release; 3) We will determine in rat and mouse (both wild-type and A1 receptor knockout) kidneys the effects of a highly selective A1 receptor agonist on norepinephrine-induced renal vasoconstriction in the presence and absence of selective A1 receptor antagonists; 4) We will determine in mouse kidneys from A1 receptor knockout mice whether lentiviral-based reconstitution of the A1 receptor selectively in renal vascular smooth muscle cells augments renovascular responses to RSNS; and 5) We will determine in mouse kidneys from wild-type mice whether lentiviral-based shRNA knockdown of the A1 receptor selectively in renal vascular smooth muscle cells inhibits renovascular responses to RSNS. This project will identify a MAJOR mechanism that contributes to renal sympathetic neurotransmission. Because the renal sympathetic nervous system is involved in most renal physiological and pathophysiological processes, this discover would enlighten and inform renal physiologists working in all aspects of renal function and dysfunction and would provide a strong rationale for using A1 receptor blockers as diuretics in conditions associated with increased renal sympathetic tone.

描述（由申请人提供）：在研究BG9928的肾脏作用时（腺苷A1受体的选择性拮抗剂，作为心力衰竭患者的利尿剂开发的腺苷型拮抗剂），我们观察到，体内BG9928深刻地减少了肾脏血管促进的肾脏血管促进，并由肾脏促进型肾脏交感神经刺激（RSNS）。这一发现向我们表明，肾脏神经膜连接的A1受体增强肾交感神经传递。尽管这一假设与我们发表的报告相一致，即RSN增加了腺苷的释放，并由其他人发表的报告称，促进神经刺激释放腺苷前体ATP以及从ATP形成腺苷的酶，其他人的大量研究清楚地表明，这些研究明确地表明，术前的A1受体抑制了，而不是增强，而不是增强。综上所述，这些观察结果表明，如果A1受体参与增强肾交感神经传递，则效果必须是术后的。由于众所周知A1受体可以增强血管紧张素II诱导的肾血管收缩，因此我们假设RSN会增加神经反胶连接中的腺苷和NE，并且腺苷通过后官方的A1受体通过核能A1受体增强了NE NE NE诱导的血管促进（通过相一致的信号剂，I.EE.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E. RSN引起的肾血管收缩。因此，该项目的总体目的是确定肾脏神经反应器连接和通过A1腺苷受体中的内源性腺苷是否显着加强了对肾交感神经刺激的肾血管收缩剂反应。我们将使用多种方法研究这一假设：1）我们将在大鼠和小鼠肾脏中确定选择性A1受体拮抗剂对RSN诱导的肾血管收缩和嘌呤释放的影响（通过质谱法）； 2）我们将在小鼠肾脏中确定A1受体敲除对RSN诱导的肾血管收缩和嘌呤释放的影响； 3）我们将在大鼠和小鼠（野生型和A1受体基因敲除）中确定高度选择性A1受体激动剂对在存在和不存在选择性A1受体拮抗剂的情况下对去甲肾上腺素诱导的肾血管收缩的影响； 4）我们将在A1受体基因敲除小鼠的小鼠肾脏中确定肾血管平滑肌细胞中A1受体的基于慢病毒的重构是否会增强对RSN的肾血管反应； 5）我们将在野生型小鼠的小鼠肾脏中确定基于慢病毒的shRNA受体在肾血管平滑肌细胞中选择性地抑制了对RSN的肾血管反应。该项目将确定有助于肾同情神经传递的主要机制。由于肾交感神经系统参与了大多数肾脏生理和病理生理过程，因此该发现将启发并告知肾功能和功能障碍各个方面的肾脏生理学家，并将为在肾脏同情性增长的条件下用作利尿剂作为利尿剂提供强大的理由。