Neural Mechanisms in Cardiorenal Regulation

心肾调节的神经机制

• 批准号: 8374561
• 负责人: THOMAS E LOHMEIER
• 金额: $ 28.64万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8374561
• 关键词: Accounting; Acute; Adrenergic Agents; Animals; Attenuated; Baroreflex; Bypass; Canis familiaris; Cardiac; Cardiovascular system; Chronic; Clinical; Denervation; Electric Stimulation; Essential Hypertension; Evaluation; Excretory function; Financial compensation; Functional disorder; Goals; Heart failure; Human; Hypertension; Hypotension; Isotopes; Kidney; Light; Limb structure; Link; Long-Term Effects; Measures; Mediating; Methodology; Methods; Nature; Nerve; Nervous system structure; Neuraxis; Norepinephrine; Obesity; Organ; Pathogenesis; Pattern; Peripheral; Physiological; Physiology; Pilot Projects; Plasma; Play; Pressoreceptors; Process; Quantitative Evaluations; Reflex action; Regulation; Reporting; Role; Severities; Signal Transduction; Sodium; Sympathetic Nervous System; Techniques; Technology; Testing; Time; adrenergic; arm; attenuation; carotid sinus; discount; indexing; innovation; insight; instrument; interest; neuromechanism; normotensive; novel strategies; pressure; research study; response

The sympathetic nervous system plays an important role in the pathogenesis of hypertension, yet the precise determinants of sympathetic activation are unresolved. Furthermore, the efferent mechanisms that account for long-term sympathetically-induced alterations in arterial pressure are unclear. In this regard, there is considerable controversy as to whether alterations in renal excretory function are of paramount importance in mediating the chronic effects of the nervous system on arterial pressure. In short, progress in understanding the above issues has been limited by the lack of clinical and experimental methods for critically studying sympathetic function in the chronic regulation of arterial pressure. Because of the crucial role of the baroreflex in acute regulation of arterial pressure, there has been a long-standing interest in the possibility that baroreflexes might chronically influence the level of sympathetic activity and arterial pressure in hypertension. The potential importance of such a relationship has been highlighted by clinical observations demonstrating that the sympathetic arm of the baroreflex is impaired in primary hypertension. However, because the baroreflex resets in the direction of the ambient pressure, a role for the baroreflex in long-term pressure control is often discounted. On the other hand, because of technical limitations, it is important to emphasize that there is little empirical evidence from chronic studies that supports the notion that baroreflex resetting is complete in hypertension. In fact, recent innovative studies in animals with experimentally-induced hypertension suggest that the baroreflex does not totally reset and has sustained sympathoinhibitory effects in hypertension. These studies further indicate baroreflex activation chronically suppresses renal sympathetic nerve activity and promotes sodium excretion, responses expected to attenuate the severity of hypertension. The relevance of these studies to clinical hypertension, however, is limited by their relatively short duration (most commonly one week). In the proposed studies, we will use a novel approach to evaluate several aspects of baroreflex function over at least 3 weeks of controlled baroreflex activation. We will use a combination of sophisticated techniques in chronically instrumented dogs to determine whether the central nervous system contributes to chronic resetting of the baroreflex and whether chronic activation of the baroreflex does indeed have sustained effects to inhibit renal sympathetic nerve activity and promote sodium excretion. To achieve these goals, the carotid baroreflex will be chronically activated by electrical stimulation of the carotid sinuses. Chronic electrical activation of the carotid baroreflex leads to sustained suppression of sympathetic activity and arterial pressure and is an ideal technique for determining the importance of central resetting in attenuating the sympathoinhibition induced by increased baroreceptor activity because it allows for precise control of central afferent input patterns. Additionally, in combination with other measures, this methodology permits direct evaluation of the chronic effects of baroreflex activation on renal sympathetic outflow and excretory function. Isotope dilution methodology will be used in these studies to determine whole body and renal norepinephrine spillover to plasma as indices of central and renal specific sympathetic outflow. These studies will provide unique insight into the chronic functional effects of the baroreflex in hypertension and the importance of the kidneys in mediating long-term changes in-arterial pressure during alterations in central sympathetic outflow.

交感神经系统在高血压的发病机制中起着重要作用，但确切的 交感神经激活的决定因素尚未解决。此外，解释 长期交感神经诱导的动脉压变化尚不清楚。在这方面， 关于肾排泄功能的改变是否在肾衰竭中具有至关重要的意义， 调节神经系统对动脉压的慢性影响。简而言之， 由于缺乏临床和实验方法进行批判性研究， 交感神经在动脉压慢性调节中的作用。因为压力感受器反射的重要作用 在动脉压的急性调节中，长期以来人们对以下可能性感兴趣， 压力反射可能会长期影响高血压患者的交感神经活动水平和动脉压。 这种关系的潜在重要性已被临床观察所强调， 压力反射的交感神经臂在原发性高血压中受损。但由于 压力反射在环境压力的方向上重置，这是压力反射在长期压力控制中的作用 往往被低估。另一方面，由于技术限制，必须强调， 很少有来自慢性研究的经验证据支持压力反射重置是完全的这一观点， 高血压事实上，最近对实验性高血压动物的创新研究表明， 压力感受性反射在高血压中不会完全复位，并具有持续的交感神经抑制作用。这些 研究进一步表明压力反射激活长期抑制肾交感神经活动， 促进钠排泄，预期减轻高血压严重程度的反应。的相关性 然而，这些临床高血压的研究受到其相对较短的持续时间的限制（最常见的是 周）。在这些研究中，我们将使用一种新的方法来评估压力反射功能的几个方面 在至少3周的受控压力反射激活中。我们将使用复杂的技术 以确定中枢神经系统是否有助于慢性 压力感受器反射的重置以及压力感受器反射的慢性激活是否确实具有持续效应 抑制肾交感神经活动，促进钠排泄。为了实现这些目标，颈动脉 压力感受器反射将被颈动脉窦的电刺激慢性激活。慢性电 颈动脉压力感受器反射的激活导致交感神经活动和动脉压的持续抑制 并且是用于确定中枢复位在衰减脑电活动中的重要性的理想技术。 压力感受器活动增加引起的交感神经抑制，因为它允许精确控制中枢神经系统。 传入输入模式此外，结合其他措施，这种方法可以直接 评价压力反射激活对肾交感神经流出和排泄功能的慢性影响。 在这些研究中将使用同位素稀释法测定全身和肾脏去甲肾上腺素 溢出到血浆作为中枢和肾特异性交感神经流出的指标。这些研究将提供 独特的洞察力慢性功能的影响，压力反射在高血压和重要性， 在中枢交感神经流出改变期间，肾脏介导动脉压的长期变化。