RATIONALE:Central angiotensin (Ang) II inhibits baroreflex and plays an important role in the pathogenesis of hypertension. However, the underlying molecular mechanisms are still not fully understood. OBJECTIVE:Our objective in the present study was to characterize the signal transduction mechanism of phosphatidylinositol 3-kinase (PI3K) involvement in Ang II-induced stimulation of central neuronal activity in cultured neurons and Ang II-induced inhibition of baroreflex in spontaneously hypertensive rats (SHR) versus WKY rats. METHODS AND RESULTS:Application of Ang II to neurons produced a 42% greater increase in neuronal firing in cells from the SHR than the WKY rat. Although the Ang II-mediated increase in firing rate was abolished entirely by the protein kinase (PK)C inhibitor GF109230 in the WKY, blockade of both PKC and PI3K activity was necessary in the SHR. This was associated with an increased ability of Ang II to stimulate NADPH oxidase-reactive oxygen species (ROS)-mediated signaling involving phosphorylation of the p47phox subunit of the NADPH oxidase and was dependent on the activation of PI3K in the SHR. Inhibition of PI3K resulted in the reduction of levels of p47phox phosphorylation, NADPH oxidase activity, ROS levels, and ultimately neuronal activity in cells from the SHR but not the WKY rat. In addition, in working heart-brainstem preparations, inhibition of PKC activity in the nucleus of the solitary tract in situ abolished the Ang II-mediated depression of cardiac and sympathetic baroreceptor reflex gain in the WKY. In contrast, PKC inhibition in the nucleus of the solitary tract of SHR only partially reduced the effect of Ang II on the baroreceptor reflex gain. CONCLUSIONS:These observations demonstrate that PI3K in the cardiovascular brainstem regions of the SHR may be selectively involved in Ang II-mediated signaling that includes a reduction in baroreceptor reflex function, presumably via a NADPH-ROS mediated pathway.
原理: 中央血管紧张素 (Ang) ⅱ 抑制压力反射，在高血压的发病机制中起重要作用。然而，潜在的分子机制仍然没有完全理解。 目的: 本研究的目的是表征磷脂酰肌醇 3-激酶 (PI3K) 的信号转导机制参与 Ang ⅱ 诱导的对培养神经元中枢神经元活动的刺激和 Ang ⅱ 诱导的自发性高血压大鼠 (SHR) 与 WKY 大鼠的压力反射抑制。 方法和结果: 在神经元中应用 Ang ⅱ 比 WKY 大鼠在 SHR 细胞中产生了 42% 的神经元放电增加。尽管 Ang ⅱ 介导的放电速率增加在 WKY 中被蛋白激酶 (PK) C 抑制剂 GF109230 完全消除，但是在 SHR 中阻断 PKC 和 PI3K 活性是必要的。这与 Ang ⅱ 刺激 NADPH 氧化酶-活性氧 (ROS) 的能力增加有关介导的信号涉及 NADPH 氧化酶 p47phox 亚基的磷酸化，并依赖于 SHR 中 PI3K 的激活。抑制 PI3K 导致 SHR 而不是 WKY 大鼠细胞中 p47phox 磷酸化水平、 NADPH 氧化酶活性、 ROS 水平以及最终神经元活性的降低。此外，在工作的心脏脑干制剂中, 原位孤束核中 PKC 活性的抑制消除了 Ang ⅱ 介导的 WKY 心脏和交感压力感受器反射增益的抑制。相反，SHR 孤束核中的 PKC 抑制仅部分降低了 Ang ⅱ 对压力感受器反射增益的影响。 结论: 这些观察表明，SHR 心血管脑干区域的 PI3K 可能选择性地参与 Ang ⅱ 介导的信号，包括压力感受器反射功能的降低, 大概是通过 NADPH-ROS 介导的途径。
Shift to an involvement of phosphatidylinositol 3-kinase in angiotensin II actions on nucleus tractus solitarii neurons of the spontaneously hypertensive rat.
自发性高血压大鼠(SHR)主要亚系是卒中型自发性高血压大鼠(SHR- stroke prone strain, SHRsp)及抗卒中型SHR。SHR是Yamori于1970年起从自然死于卒中的SHR后代用近交方式培育的。SHR100%发生高血压80%发生脑卒中。SHR的对照是京都威斯特大鼠(WKY)。此为目前国际上应用最广泛的高血压动物模型。SHR的主要特点是：1.高血压高血压发生率100%，生后5周血压开始升高，25周龄达高峰，30周龄后稍下降。2.高血压并发症SHR的主要并发症与人类原发
Spontaneously 英 [spɒn'teɪnɪəslɪ] 美 [spɑːnˈteɪniəsli]
释 义 adv. 自发地；自然地；不由自主地
同根词 词根 spontaneous
adj. spontaneous 自发的；自然的；无意识的
n. spontaneity 自发性；自然发生
例 句 The mind quiets spontaneously in the company of a great soul.
释 义 adj. 高血压的；血压升高的
例 句 The most common site of hypertensive hemorrhage was basal ganglia. (91.06%).
Rat 英 [ræt] 美 [ræt]
释 义 n. 鼠；卑鄙小人，叛徒
短 语 rat poison 杀鼠剂，老鼠药；鼠毒
pack rat 不可靠的人，有敛癖的人
同根词 词根 rat
adj. ratty 像老鼠的；破烂的
n. ratter 捕鼠者；叛徒
例 句 The cat pats that rat under the mat.