Gender differences in aortic baroreceptor function and neural integration

主动脉压力感受器功能和神经整合的性别差异

• 批准号: 8011980
• 负责人: JOHN H SCHILD
• 金额: $ 38.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011980
• 关键词: Afferent Neurons; Afferent Pathways; Age; Aging; Agreement; Autonomic nervous system; Baroreflex; Binding; Blood Pressure; Brain Stem; Calcium-Activated Potassium Channel; Cardiovascular Physiology; Cardiovascular system; Cells; Clinical; Clinical Research; Companions; Coupled; Data; Disease; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Exhibits; Female; Fiber; Foundations; GTP-Binding Proteins; Ganglia; Gender; Gonadal Steroid Hormones; Health; Heart Rate; Hormones; Hypertension; In Vitro; Investigation; Ion Channel; Killer Cells; Lead; Literature; Location; Measures; Mediating; Membrane; Methodology; Nerve; Nerve Fibers; Nervous System Physiology; Neurobiology; Neurons; Neurophysiology - biologic function; Nucleus solitarius; Outcome; Pathology; Pathway interactions; Physiological; Population; Potassium; Potassium Channel; Premenopause; Preparation; Pressoreceptors; Process; Property; Protein Isoforms; Protocols documentation; Rattus; Reflex action; Reflex control; Regulation; Role; Sensory; Sex Bias; Sex Characteristics; Slice; Synaptic Transmission; Testing; Time; Woman; aortic arch; male; men; neurophysiology; neuroregulation; neurotransmission; normotensive; novel; patch clamp; pressure; public health relevance; receptor; receptor function; relating to nervous system; research study; response; sex; sexual dimorphism; transmission process

DESCRIPTION (provided by applicant): Gender differences in cardiovascular function are well known. Hormones and related receptors are critically important factors, but clinical studies are revealing potential gender differences in afferent mediated autonomic nervous system (ANS) function. Some ANS assessments of cardiovagal reflexes have proven to be sexually dimorphic. In this study we investigate hypotheses related to possible neuroanatomical, neuophysiological and biophysical differences between aortic baroreceptors (BR) in male and female rats. A gender-related bias in aortic BR fiber type, pressure encoding and neurohormonal regulation may reveal as yet unrecognized mechanisms associated with noted gender differences in integrated cardiovagal control. This proposal builds upon our previous studies quantifying the differential composition of ionic channels in myelinated and unmyelinated BR afferents and the manner in which this defines the strikingly different reflex control of heart rate and blood pressure evoked by these neuroanatomically distinct afferent pathways. The first aim examines gender-related differences in rat aortic BR afferents. Morphometric analysis of aortic BR fibers and study of fluorescently identified aortic BR neurons (ABN) gives preliminary evidence that female rats have ~50% more myelinated BR, revealing, for the first time, a functionally distinct subtype of low threshold myelinated ABN rarely present (~2%) in age-matched males. The second aim quantifies the neuromodulatory capacity of estradiol (E2) upon this unique subtype of BR afferents. Nerve recordings show that E2 can increase the pressure-dependent discharge of single myelinated aortic BR fibers from female rats. Physiological levels of E2 (0.1 - 1 nM) acting, at least in part, via membrane bound estrogen receptors can selectively increase the excitability of this ABN subtype in female rats. Interestingly, E2 had no effect upon unmyelinated ABN from either gender. The third aim determines if E2 can alter K+ ion channel function in a manner consistent with the observed increased excitability. Our preliminary data show that, unlike all myelinated ABN in males and the balance of myelinated ABN from females, this unique subset expresses BKCa channels that provide ~25% of the whole cell potassium current. We further show that E2 selectively inhibits this BKCa current, offering one potential mechanism for the E2 sensitization of myelinated BR excitability in female rats. Finally, in aim four we determine if E2 can alter monosynaptic transmission of BR afferents onto 2nd-order BR neurons in the NTS. In male rats, monosynaptic transmission of myelinated afferents to the NTS does not involve BKCa channels. In stark contrast, E2 in female rats can increase monosynaptic transmission of myelinated afferent pathways with companion studies implicating a role for BKCa channels. Gender-related differences in the neural integration of BR sensory information from the afferent terminal through to 2nd-order BR neurons in the NTS could potentially lead to novel advances in the management of cardiovascular health and disease in the female population. PUBLIC HEALTH RELEVANCE: Gender differences in cardiovascular function are well known and while sex hormones are important contributing factors, there is growing evidence for alternative mechanisms. This project aims to determine if there are fundamental neuroanatomical and neurophysiological differences in the baroreceptor afferent pathway between men and women. Evidence for a gender-related difference in baroreceptors could potentially lead to novel advances in the effective management of cardiovascular health and disease in the female population.

描述(由申请人提供)：心血管功能的性别差异是众所周知的。激素和相关受体是至关重要的因素，但临床研究揭示了传入调节的自主神经系统(ANS)功能的潜在性别差异。一些ANS对心脏迷走神经反射的评估已被证明是两面性的。在这项研究中，我们调查了与雄性和雌性大鼠主动脉压力感受器(BR)之间可能的神经解剖学、神经生理学和生物物理差异有关的假说。在主动脉BR纤维类型、压力编码和神经激素调节方面的性别相关偏见可能揭示了与注意到的性别差异有关的心血管综合控制的机制。这一建议建立在我们之前的研究基础上，量化了有髓和无髓BR传入中离子通道的不同组成，以及这些神经解剖学上不同的传入通路对心率和血压的反射控制方式。第一个目的是研究大鼠主动脉BR传入的性别差异。对主动脉BR纤维的形态计量学分析和荧光标记的主动脉BR神经元(ABN)的研究初步证明，雌性大鼠的有髓BR增加了约50%，首次揭示了在年龄匹配的雄性大鼠中罕见的一种功能独特的低阈值有髓ABN亚型(~2%)。第二个目的是量化雌二醇(E2)对这种独特的BR传入亚型的神经调节能力。神经记录显示，雌二醇可增加雌性大鼠单个有髓主动脉BR纤维的压力依赖性放电。生理水平的E2(0.1-1 NM)至少部分通过膜结合的雌激素受体作用，可以选择性地增加雌性大鼠ABN亚型的兴奋性。有趣的是，雌激素E_2对男女的无髓ABN都没有影响。第三个目的是确定E2是否能以与观察到的兴奋性增加一致的方式改变K+离子通道功能。我们的初步数据显示，与男性的所有有髓ABN和女性的有髓ABN不同，这个独特的亚群表达BKCa通道，提供整个细胞约25%的钾电流。我们进一步证明，E_2选择性地抑制这一BKCa电流，为E_2敏化雌性大鼠有髓BR兴奋性提供了一种潜在的机制。最后，在第四个目标中，我们确定E_2是否能改变BR传入神经元向NTS内二阶BR神经元的单突触传递。在雄性大鼠，有髓传入传入NTS的单突触传递不涉及BKCa通道。与之形成鲜明对比的是，雌性大鼠体内的雌二醇可以增加有髓传入通路的单突触传递，相关研究表明BKCa通道也有作用。从传入终末到NTS内二阶BR神经元的BR感觉信息神经整合的性别差异可能会在女性人群的心血管健康和疾病管理方面带来新的进展。 公共卫生相关性：心血管功能的性别差异是众所周知的，虽然性激素是重要的促成因素，但越来越多的证据表明存在替代机制。该项目旨在确定男性和女性在压力感受器传入通路上是否存在根本的神经解剖学和神经生理学差异。压力感受器存在性别差异的证据可能会在女性人群中有效管理心血管健康和疾病方面带来新的进展。