Gender Difference And Underlying Mechanisms In Aortic Baroreceptor Neuron And Baroreflex Function

Gender differences of the incidence of cardiovascular diseases such as hypertension and the responses to the medications are becoming the hot topics in the field recently; however, it is largely unknown regarding to physiological action and significance of17β-estradiol (17b-E2) in aortic baroreceptor neurons, baroreflex the, and neuronal control of circulation. To investigate the gender differences of baroreceptor neurons in neuroanatomical, electrophysiological, pharmacological aspects, the regulation of17-E2, and underlie mechanisms in neurocontrol of blood pressure are the major Aims for this project and this study will provide theatrical essentials for clinical management of related cardiovascular diseases and therapeutic drug development. By using whole-cell patch-clamp technique and Vagus-nodose slicepreparation of adult male, female, and ovariectomized (OVX) rats, myelinated and unmyelinated baroreceptor (BR) neurons were identified by their afferent conduction velocities (CV) conjugated with retrograde fluorescent dye (Dil) labeling in order to study electrophysiological characteristics and distributions of each population of BR, therefore revealing the gender difference of BR neurons. By using electromicroscopy, the distribution of myelinated and unmyelinated afferents within aortic depressor nerve (ADN) was explored. These data were compared with data collected from electrophysiological study to further confirm the gender difference of BR neurons from the morphological points of view. BR neurons were isolated from adult intact and OVX female rats, electrophysiological characteristics and neuronal excitability of each category BR neurons were observed using whole-cell patch and immunohistochemical staining techniques to study the possible roles and mechanisms of17β-E2on action potential (AP) and ion channels and to discover the relationship of neuronal excitability and female hormone; By using Aorta-ADN preparation of OVX female rats, the discharge of single afferent fiber of ADN was observed and the instant firing frequency of recorded in order to test the gender difference in the discharge capability at baroreceptor terminals and if this gender difference is associated with17β-E2; By using whole-cell patch technique, the excitatory post-synaptic current (EPSC) was investigated in the second-order BR neurons located in nucleus of solitary tract (NTS) to confirm the gender difference in synaptic transduction at the level of NTS.The results showed that Myelinated Ah-type visceral afferent neurons (VANs), including BR neuron are a unique subpopulation that specifically and functionally distributes solely in female rats. They are characterized as lower threshold in action potential firings and stronger capability in frequency follow, suggesting relatively higher neuronal excitability. Myelinated Ah-type BR neuron is only BR subpopulation that its function is regulated by17-E2. The higher neuronal excitability of Ah-type BR neurons could be maintained and it is very likely that lower blood pressure change could activated Ah-type BR neurons in the presence of17-E2, consequently maintain the blood pressure at relatively lower level through the baroreflex compared with age-matched males. In OVX females, the distribution of Ah-type BR neurons remained the same but their neuronal excitability dramatically reduced and this reduction in excitability could be fully restored by physiological concentration of17-E2. Myelinated Ah-type BR neurons from female rats functionally express BK-type Ca2+-activated K+channel (BK-KCa) currents, which up-regulate by OVX. The reduction of neuronal excitability of Ah-type BR neurons due to OVX can be completely recovered by17-E2through inhibition of BK-KCa activity.17-E2are very likely to be involved in the functional expression of BK-KCa channels in presynaptic membrane of first order of BR neurons and participate the regulation of the afferent signal transduction between first and second order BR neurons.The results from this study revealed that gender differences in baroreflex and the regulatory effects of17-E2, provided novel theoretical essentials and practical significance for the neurocontrol of gender-based blood pressure regulation and application of replacement of hormone therapy in clinical managements of hypertension.