Il6 and Acute Pressor Response to Psychological Stress

我们有新的数据显示，雄性小鼠在转换到先前由不同雄性小鼠占据的笼子中时出现了明显的心动过速和高血压反应。在白细胞介素-6（IL-6）基因敲除小鼠中，这种应激的升压效应显著减弱，但心率或活动没有减弱。我们也有新的证据表明，相当大的急性和慢性相互作用与交感神经和肾素血管紧张素系统。本项目将检验白细胞介素-6（IL-6）在交感神经和血管紧张素II介导的高血压对心理社会应激的反应中起主要作用的假设。具体目标是： 1)以验证IL-6在心理应激的急性升压反应中有重要作用的假设。我们将在小鼠中使用急性笼子转换压力测试来确定是否 a）与野生型（WT）小鼠相比，IL-6敲除（KO）小鼠具有钝性的血压增加; B）TNF-α敲除小鼠对笼子转换具有减弱的升压反应，类似于IL-6敲除; c）在KO小鼠中恢复IL-6将恢复对心理应激的正常升压反应; d）注射IL-6抗体的WT小鼠中的升压反应将模拟IL-6 KO小鼠中的反应。 2)确定IL-6在介导急性心理社会应激和慢性高血压之间的双向血压相互作用中的作用。这些实验将确定： a）在初始升压反应消退后，转换笼应激引起IL-6依赖性高血压; B）AngII高血压增加了心理社会应激诱导的升压反应对IL-6的依赖性; c）在WT与KO小鼠中，重复的换笼应激测试导致MAP随时间的更大增加。 3)为了检验交感神经系统在急性应激期间直接和通过刺激肾素-血管紧张素系统启动IL-6依赖性血压升高的假设。我们将研究急性换笼应激试验期间的血压升高，并检验以下假设： a）a-/b-肾上腺素能受体阻断剂将在WT中比在IL-6 KO小鼠中更多地阻断升压反应; B）与IL-6 KO小鼠相比，AngII受体阻断将在WT中更多地阻断升压反应; c）肾上腺素能阻断的作用在AngII系统正常夹紧的小鼠中将减弱。

We have new data showing marked tachycardic and hypertensive responses in male mice switched to cages previously occupied by a different male mouse. The pressor, but not the heart rate or activity, effect of this stress is blunted significantly in interleukin-6 (IL-6) knockout mice. We also have new evidence that shows considerable acute and chronic interaction with the sympathetic and renin-angiotensin systems. This project will test the hypothesis that interleukin-6 (IL-6) plays a major role in sympathetic- and angiotensin II-mediated hypertensive responses to psychosocial stress. The Specific Aims are: 1) to test the hypothesis that IL-6 contributes significantly to the acute pressor response to psychological stress. We will use acute cage-switch stress testing in mice to determine whether a) IL-6 knockout (KO) mice have a blunted increase in blood pressure compared to wild-type (WT) mice; b) TNF-a knockout mice have an attenuated pressor response to cage switch, similar to IL-6 knockout; c) restoring IL-6 in KO mice will restore a normal pressor response to psychological stress; d) the pressor response in WT mice injected with IL-6 antibody will mimic the response in IL-6 KO mice. 2) to determine the role of IL-6 in mediating the bi-directional blood pressure interactions between acute psychosocial stress and chronic hypertension. These experiments will determine whether: a) cage-switch stress causes IL-6-dependent hypertension after the initial pressor response has subsided; b) Angll hypertension increases the dependence of psychosocial stress-induced pressor responses on IL-6; c) repeated cage-switch stress testing causes a greater increase in MAP over time in WT versus KO mice. 3) to test the hypothesis that the sympathetic nervous system initiates IL-6-dependent blood pressure increases during acute stress, directly and through stimulation of the renin-angiotensin system. We will study the blood pressure increase during acute cage-switch stress testing and test the hypotheses that: a) a-/b-adrenergic receptor blockade will block the pressor response more in WT than in IL-6 KO mice; b) Angll receptor blockade will block the pressor response more in WT compared to IL-6 KO mice; c) the effect of adrenergic blockade will be blunted in mice with the Angll system clamped at normal.