Splanchnic Circulation and Blood Pressure Regulation

 描述(由申请人提供)：内脏电容对血压调节的重要性早已被认识到，但由于实验方法的限制，临床研究一直滞后。我们已经组建了一个研究团队(由生理学家、临床药理学家、心脏病学家、生物医学工程师和统计学家组成)，他们可以获得独特的资源(使用三甲氧胺阻断神经节细胞，使用核医学和阻抗测定节段性体积变化，以及自主神经衰竭的患者)，以在这一领域取得进展。来自动物研究的大量证据表明，内脏循环有助于高血压。我们在高血压受试者中的初步研究表明，使用曲美沙潘的交感神经撤退通过减少每搏量来降低血压。这表明交感神经调节的内脏电容收缩有助于人类的高血压，我们将在特定的目标1检验这一假说。另一方面，内脏电容的反射性收缩是在直立姿势或热应激等刺激下保持足够血压的重要补偿机制。自主神经衰竭患者缺乏这些代偿反射，为研究这些现象提供了独特的资源。例如，自主神经衰竭患者对热应激很敏感，因为他们不能散热，也不能用反射交感神经激活来补偿。在特定的目标2中，我们将利用这些异常来确定控制热应用是否可以用于治疗自主神经衰竭所致的仰卧位高血压。最后，自主神经衰竭的临床表现主要是由内脏静脉淤积引起的直立性低血压。我们已经开发了一种设备，可以检测直立姿势，并通过伺服控制器自动充气腹部活页夹，将充气压力保持在40毫米汞。我们的初步结果表明，这种自动化的腹部粘合剂在改善立位耐力方面与米多君一样有效，米多君是目前的护理标准。我们将在特定的目标3中测试该设备的有效性。

 DESCRIPTION (provided by applicant): The importance of splanchnic capacitance to blood pressure regulation has long been recognized, but clinical research has lagged behind because of limitations in experimental methodology. We have put together a research team (of physiologists, clinical pharmacologists, cardiologists, biomedical engineers and statisticians) with access to unique resources (ganglionic blockade with trimethaphan, determination of segmental volume changes with nuclear medicine and impedance, patients with autonomic failure) to make progress in this field. Substantial evidence from animal studies indicates that the splanchnic circulation contributes to hypertension. Our preliminary studies in hypertensive subjects indicate that sympathetic withdrawal with trimethaphan lowers blood pressure by reducing stroke volume. This suggests that sympathetically mediated contraction of splanchnic capacitance contributes to hypertension in humans, a hypothesis that we will test in Specific Aim 1. On the other hand, reflex contraction of splanchnic capacitance is an important compensatory mechanism to maintain adequate blood pressure during stimuli such as upright posture or heat stress. Patients with autonomic failure lack these compensatory reflexes and provide a unique resource to study these phenomena. E.g., autonomic failure patients are sensitive to heat stress because they are unable to dissipate heat or to compensate with reflex sympathetic activation. In Specific Aim 2 we will take advantage of these abnormalities to determine if controlled heat application can be used to treat the supine hypertension of autonomic failure. Finally, the clinical picture of autonomic failure is dominated by orthostatic hypotension due primarily to splanchnic venous pooling. We have developed a device that detects upright posture and automatically inflates an abdominal binder with a servo controller that maintains inflation pressure to 40 mm Hg. Our preliminary results suggest that this automated abdominal binder is as effective as midodrine, the current standard of care in improving orthostatic tolerance. We will test the efficacy of this device in Specific Aim 3.