Autonomic Determinants of Orthostatic Tolerance

在自主神经反射受损的人中，口服水会极大地提高血压。而当 效应平均为30-40毫米汞柱，个体间差异较大，偶尔增加100 毫米汞柱。我们最初对这种反应的规模感到震惊，但其他人现在也复制了这种反应，并 确认了它的强度。在接受治疗的高血压受试者和正常受试者中也发现了这种影响， 尽管震级较小。我们还发现，摄入水会增强升压的作用 药物苯丙醇胺(PPA)。鉴于其大小和坚固性，加压机对水的反应 可能是人类心血管调节中一种重要但迄今未被认识的机制的信号 在健康和疾病方面都是如此。水的反应可能具有重要的诊断和治疗意义。 特别是，它可能是血压评估中未被识别的主要决定因素 老年人群，可能是立位个体间和个体内差异的来源 宽容。 这项建议的目的是解决摄入水对心血管影响的机制， 并解决了这种胃压反应的个体间差异的基础。我们试图了解如果 交感神经系统在特定目标1中调节水的升压反应。在特定目标2中， 我们试图确定这种反应背后的宏观刺激因素。在具体目标3和4中，我们处理 在人类受试者和小鼠模型中更多分子水平的潜在传出机制 系统。最后，在特定的目标5中，我们试图确定升压者年龄依赖性的基础 对水的反应。 虽然水是日常生活的一部分，但我们认为我们观察到的胃压反应可能有 对健康和疾病的重要后果。

Oral ingestion of water greatly elevates blood pressure in individuals with impaired autonomic reflexes. While the effect averages 30-40 mmHg, there is large interindividual variation with occasional increases of 100 mmHg. We were initially startled by the magnitude of this response, but others have now replicated it and confirmed its magnitude. An effect is also found in treated hypertensive subjects and in normal subjects, albeit it at smaller magnitude. We have also found that ingestion of water potentiates the effect of the pressor drug phenylpropanolamine (PPA). In view of its magnitude and robustness, the pressor response to water may signal an important but heretofore unrecognized mechanism at work in human cardiovascular regulation both in health and disease. The water response may have important diagnostic and therapeutic implications. In particular, it may be the major unrecognized determinant of noise in blood pressure assessment in the older population, and might possibly be a source of interindividual and intraindividual variation in orthostatic tolerance. The purpose of this proposal is to address the mechanism of the cardiovascular effect of water ingestion, and address the basis of interindividual variation in this gastropressor response. We seek to understand if the sympathetic nervous system is mediating water's pressor response in Specific Aim 1. In Specific Aim 2, we try to determine the macroscopic stimulus underlying the response. In Specific Aims 3 and 4, we address potential efferent mechanisms at a more molecular level in both human subjects and in a mouse model system. Finally in Specific Aim 5 we try to determine the basis of the age dependency of the pressor response to water. Although water is a part of daily life, we believe the gastropressor response we have observed may have important consequences in health and disease.