Il6 and Acute Pressor Response to Psychological Stress

我们有新的数据显示，在切换到之前由另一只雄鼠占据的笼子的雄鼠中，有明显的心动过速和高血压反应。在白介素6(IL-6)基因敲除的小鼠中，这种压力的升压效应显著减弱，而不是心率或活动。我们也有新的证据表明，交感神经系统和肾素-血管紧张素系统之间存在着相当大的急性和慢性相互作用。该项目将测试白介素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反应中起主要作用的假设。具体目标是： 1)检验IL-6在心理应激的急性升压反应中起重要作用的假设。我们将在小鼠身上使用急性笼子开关压力测试来确定 A)IL-6基因敲除(KO)小鼠与野生型(WT)小鼠相比，血压明显升高； B)肿瘤坏死因子-α基因敲除小鼠对笼状开关的升压反应减弱，类似于IL-6基因敲除小鼠； C)在KO小鼠体内恢复IL-6将恢复对心理应激的正常升压反应； D)WT小鼠注射IL-6抗体后的升压反应与IL-6 KO小鼠的升压反应相似。 2)探讨IL-6在急性社会心理应激与慢性高血压双向血压交互作用中的作用。这些实验将决定是否： A)笼式转换应激在初始升压反应消退后引起IL-6依赖性高血压； 2)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)重复笼式开关压力测试导致WT小鼠与KO小鼠的MAP随时间的增加更大。 3)验证交感神经系统启动IL-6依赖的血压在急性应激时直接或通过肾素-血管紧张素系统刺激升高的假说。我们将研究急性笼式开关压力测试期间的血压升高，并检验以下假设： A)阻断a-/b-肾上腺素能受体比阻断IL-6KO小鼠更能阻断WT小鼠的升压反应； B)与IL-6 KO小鼠相比，阻断血管紧张素Ⅱ受体可更多地阻断WT小鼠的升压反应； C)在正常阻断Angll系统的小鼠中，肾上腺素能阻断的作用将减弱。

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.