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Interlukin-1β Involved in the Regulatory Effect of Angiotensin Ⅱ on Blood Pressure in Paraventricular Nucleus and Its Mechanism

Author: LvYang
Tutor: ZhaoHua
School: Jilin University
Course: Physiology
Keywords: Paraventricular nucleus Interleukin -1β Angiotensin Ⅱ Angiotensin Type 1 Receptor Stress-induced hypertension
CLC: R544.1
Type: PhD thesis
Year: 2007
Downloads: 113
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Abstract

Psychological factor,or mental stress, is an important inducement in the formation and development of essential hypertension, it is the initiating agent to some extent. It is believed that the stressor acts on the central nervous system first, followed with the activation of some specific brain regions, then the arterial blood pressure elevates persistently under the effects of various neurotransmitters and/or neuromodulators and hormone, finally the hypertension arises. It is widely showed that when the human body is stimulated by the stress, a variety of active substances will release, including AngⅡ; IL-1β; Ach and so on, which can elevate the blood pressure, and mediate the cardiovascular effects in some brain regions. It is also known that these cardiovascular effects are closely related to stress-induced hypertension. In these nuclei, the hypothalamic paraventricular nuclei (PVN) play an important role in the cardiovascular responses elicited by the stimulation of stress such as horror. It is clear now that when the IL-1βimmunoreactive cells and the nerve fiber projection stress exist in the PVN, the expression of IL-1βmRNA and IL-1ramRNA in these areas are up-regulated and the activity of IL-1βincreases, then the IL-1βaffects the central nervous system, enhances blood pressure. The significance of IL-1βin stress responses is also shown by the local application of interleukin-1 receptor antagonist, which can inhibit pressor effect induced by stress. In addition, it has been proved that the elevated concentration of Ang II in blood and brain tissue is the pathologic basis of stress-induced hypertension in various stress condition. The central Ang II regulates the blood pressure by activating AT1R in the neurons. Therefore, when IL-1βor/and Ang II increase induced by stress or other factors, Ang II and IL-1βmay act on the neurons in the cardiovascular regulatory areas of PVN directly, or increase the release of other hypertensive substances in the periphery, or affect the regulation of cardiovascular activity through the stimulation of some receptors like AT1R, finally cause stress-induced hypertension. Applying several techniques such as central nuclei microinjection, neuro-electrophysiological technique, whole cell patch clamp technique, immunohistochemistry, etc, the purpose of this paper is to reveal the contribution and pathogenic mechanism of PVN and some other brain nuclei in the pathogenesis of hypertension, and further discuss the effects and mechanism of Ang II and IL-1βin the central cardiovascular activity. The main research results are as follows:1. Effects of stress on the concentration of IL-1βin cerebrospinal fluid and different brain regions of ratsThe intralcerebral IL-1βis a widely accepted proinflammatory cytokine, it is also a cytokine with diverse physiological regulation function and widely distributes in the central nervous system; it attracts much attention in the pathogenesis of stress-induced hypertension especially as a central stress mediator. It can be secreted by a variety of some cells in the central nervous system such as astrocytes; microglial cells; neuronal cells and endothelial cells. It has reported that the stress stimulation such as restraint stress, cerebral ischemia and tail electric shock could also elevate the concentration of central IL-1βand the expression of its mRNA. In recent years, and that the blood pressure of rats was induced to elevate by foot shock stress and noise. To further clarify the possible action of IL-1βin the formation of stress-induced hypertension and the related central region, we stimulated the rats with foot shock stress to observe its effect on the concentration of IL-1βin the cerebrospinal fluid and hypothalamus; amygdaloid nucleus; hippocampus; medulla oblongata; cerebellum.The results showed that the concentration of IL-1βin the cerebrospinal fluid collected 5min and 20 min after the stress increased significantly, and it responded quickly, so it was not likely that the IL-1βwas newly synthesized. We concluded that IL-1βwas synthesized in the central nervous system and then it was released with the stimulation of foot shock stress for 5min, But when the rats suffered from foot shock stress for 20min, the concentration of IL-1βin cerebrospinal fluid increased in 30~60min, which might result from the entering of peripheral IL-1βinto the central nervous system through active transport way from some regions with weaker blood-brain barrier, such as the organum vasculosum lamina terminalis, area postrema, choroid plexus, median eminence, et al. We also found that the concentration of IL-1βin amygdaloid nucleus and PVN increased. It explained that the foot shock stress could induce the synthesis of central IL-1βas well as the release of it. It proved that the central IL-1βwas one of the reasons for pressor response induced by foot shock stress. It further provided evidence on IL-1βacting as a central stress mediator, and associating with PVN and amygdaloid nucleus, the mechanism needed further research. 2. IL-1βin PVN participates in stress-induced high blood pressure and its interaction with AngⅡand AT1RTo further clarify the dynamic changes of expression of IL-1β, Ang II and AT1 receptors in PVN and their relation to blood pressure in the chronic stress-induced hypertension rats induced by foot shock stress. Thus, we investigate their dynamic changes and relation to blood pressure in stress in hypothalamic paraventricular nucleus. According to the results, as the stress goes on, the blood pressure increases gradually, the expression of IL-1β, Ang II and AT1 receptors in PVN is enhanced to different extent, which suggests that stress can activate the expression of IL-1β, Ang II and AT1 receptors as well as induce the blood pressure to rise, thus indicates that the formation of sustained hypertension of rats is associated with the enhanced function of angiotensin system of PVN and the activation of IL-1β.Our experiment studies the effect of IL-1βon blood pressure of stress rats and the intervention in the expression of Ang II and AT1 receptors in PVN. The results show a low expression of Ang II and AT1 receptors in PVN under normal basal condition, and it increases greatly with the application of IL-1β. The Ang II and AT1 receptors express widely in PVN of rats 15 days after stress, and the number of Ang II and AT1R positive cells and stained areas in cytoplasm decrease significantly when given anti-IL-1βantibody. Thereby we suppose that IL-1βcan up-regulate the Ang II level in hypothalamic paraventricular nucleus, leading to more synthesis and/or release, and IL-1βmay also up-regulate AT1 receptors by affecting their synthesis; storage; transport and release. These results indicate that the increase of endogenous IL-1βinduced by chronic stress and further activation of angiotensin system collaborate in the formation and maintenance of stress-induced hypertension, especially the chronic one, which demonstrates once again the significant role of central IL-1βand angiotensin system in the inducing and accelerating process of hypertension by stress.3. Effects of IL-1βon Ang II-induced cardiovascular activities in PVN of ratsIt is widely accepted that hypothalamic paraventricular nucleus plays an important role in cardiovascular regulation under normal and disease state, and it is a crucial site of central IL-1βin mediating the cardiovascular response elicited by stress. For the PVN of rats not only has IL-1β, Ang II immunopositive cells and plenty of nerve fiber projection, but also is one of the nuclei with highest AT1R density, we decide to study on the function of angiotensin system in the cardiovascular effects induced by administration of IL-1βin PVN.Our results show that microinjection of IL-1βinto PVN of rats can cause dose-related blood pressure elevation, and the pressor response to Ang II can be enhanced in the rats pretreated with IL-1β, which suggests that IL-1βmay elevate the response of cardiovascular neurons to Ang II, or reinforce the reactivity of central pressor response evoked by Ang II by increasing the synthesis and usage of AT1 receptors. Especially, we find that the pressor response induced by injection of IL-1βinto PVN can be attenuated by administration of losartan, a selective AT1 receptor antagonist, which demonstrates that the pressor effect is partially due to AT1 receptors in PVN. It provides evidence for the central interaction between IL-1βand Ang II, and indicates that the regulating effect of IL-1βon cardiovascular activities may result from direct function or integration of secondary effects of the rise of Ang II concentration and/or the up-regulation of its receptor in PVN. Moreover, our results show that significant acceleration of HR occurs only after microinjection of IL-1β(0.2ng) in the rats, which suggests that IL-1βmay promote the bradycardic effect by peripheral regulatory mechanisms. We also find that blockage of brain AT1 receptors does not change the pattern of HR to microinjection of IL-1βsignificantly, which indicates that AT1 receptors may not act in the regulation of HR.4. Effects of IL-1βon the discharge of paraventricular neurons in rats and the interaction with Ang II and AT1RTo further clarify the mechanism of IL-1βand Ang II in stress-induced hypertension, we observe the interrelation between IL-1βand Ang II in neural cells in PVN and their effect on electrical activities with extracellular recording technique in rat brain slices at cell level. The result shows that IL-1βcan stimulate the discharge of most of paraventricular neurons, which suggests that IL-1β, as neurotransmitters or neuromodulators, has stressful activation effect on the paraventricular neurons. It is the first time we observe the excitatory effect of IL-1βon the spontaneous discharge of paraventricular neurons in brain slices in vitro. We treat the brain slices in advance with low concentration IL-1β, resulting in higher expression of Ang II and AT1 receptor, and when adding Ang II, the unit discharge frequency increases significantly compared with the control. Moreover, Ang II loses its function with the application of anti- IL-1βantibody. The study also shows that when Ang II and anti-IL-1βantibody are added, following with the addition of Ang II and boiled anti-IL-1βantibody, the enhancing effect of Ang II on neural discharge is not influenced, which indicates that the function of IL-1βis specific and can be blocked by its antibody. These results further demonstrate that IL-1βcan enhance the stimulation effect of Ang II on the electrical activities of nervous cells specifically. In our early stage experiment, we have observed AT1 receptors in PVN mediating the pressor response to IL-1β, to further clarify the effect of AT1 receptors on IL-1βin the discharge of paraventricular neurons, we add losartan, a specific AT1 receptor antagonist, in advance, then IL-1β, and we find that the excitatory effect of IL-1βon most neurons can be blocked by losartan, which confirms that the excitatory effect of IL-1βin paraventricular neurons partially bases on AT1 receptors.Our research discusses in detail the pathogenesis of stress-induced hypertension at general and molecular level in hypothalamic paraventricular nucleus. It provides a first evidence for the cardiovascular mechanism of IL-1βin PVN and its interrelation with Ang II, and proves that IL-1βin PVN may be an important regulatory factor in cardiovascular activities evoked by Ang II, sets up a new research field of feedback regulation for Ang II, and then is of great significance in clarifying the mechanism of stress-induced hypertension and seeking new approach of prevention and treatment.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Abnormal blood pressure > Hypertension
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