Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats
Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats
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DOI：
10.1113/jphysiol.2011.205575
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发表时间：
2011-04-01
影响因子：
5.5
通讯作者：
Brooks, Virginia L.
中科院分区：
文献类型：
--
作者：
Cassaglia, Priscila A.;Hermes, Sam M.;Brooks, Virginia L.
非技术摘要虽然已知胰腺激素胰岛素在大脑中发挥作用，增加交感神经活动和交感神经活动的压力反射控制，但其具体作用部位尚未确定。我们发现下丘脑的一个区域，即弓状核，是胰岛素作用开始的部位。这一新信息可能会让人们更好地了解胰岛素在大脑中在不良心血管并发症（如高血压和心脏病发作）中的作用，这些并发症与肥胖和糖尿病等胰岛素抵抗状态有关。尽管胰岛素激活交感神经系统和增强压力反射增益的中枢作用已众所周知，但胰岛素作用的特定大脑部位尚未确定。我们测试了以下假设：(1) 下丘脑室旁核 (PVN) 和弓状核 (ArcN) 是必要的大脑部位，(2) 胰岛素直接在 PVN 和/或 ArcN 中启动其作用。在α-氯醛糖麻醉的雌性Sprague-Dawley大鼠中，连续记录平均动脉压（MAP）、心率（HR）和腰交感神经活动（LSNA），并在高胰岛素-正常血糖钳夹之前和期间测量HR和LSNA的压力反射增益。 60 分钟后，静脉输注胰岛素（15 mU kg-1 min-1）而非生理盐水，显着增加（P < 0.05）基础 LSNA（至 228 +/- 28% 对照）和 LSNA 的压力反射控制增益（从 3.8 +/- 1.1 至 7.4 +/- 2.4% 对照 mmHg-1）。这些效应通过PVN（LSNA至124 +/- 8.8%对照；LSNA增益至3.9 +/- 1.7%对照mmHg-1）或ArcN（LSNA％对照：从100 +/- 0到198 +/- 24（胰岛素），然后133 +/- 的局部抑制（双侧显微注射musimol）逆转（P < 0.05） 23（蕈醇）LSNA 控制百分比 mmHg-1 增益：从 3.9 +/- 0.3 到 8.9 +/- 0.9（胰岛素），然后 5.1 +/- 0.5（蕈醇））。虽然在前自主性 PVN 亚核的神经元中发现了胰岛素受体免疫反应性，但将胰岛素（0.6、6 和 60 nU）微量注射到 PVN 中未能改变 LSNA 或 LSNA 增益。然而，ArcN 胰岛素增加 (P < 0.05) 基础 LSNA（控制百分比为 162 +/- 19, 0.6 nU；193 +/- 19, 6 nU；和 205 +/- 28, 60 nU）和 LSNA 压力反射增益（控制百分比 mmHg-1 从 4.3 +/- 1.2 增加到 6.9 +/- 1.0， 0.6nU；7.7+/-1.2，6nU；和7.8+/-1.3，60nU)。所有治疗均未改变 MAP、HR 或 HR 的压力感受反射控制。我们的研究结果确定 ArcN 是胰岛素通过包括 PVN 在内的神经通路激活交感神经系统并增加压力反射增益的部位。
Non-technical summaryThough the pancreatic hormone insulin is known to act in the brain to increase sympathetic nerve activity and baroreflex control of sympathetic nerve activity, its specific site of action had yet to be identified. We show that a region in the hypothalamus, the arcuate nucleus, is the site at which insulin's effects are initiated. This new information may lead to a greater understanding of the role of insulin in the brain in adverse cardiovascular complications, like hypertension and heart attacks, which are associated with insulin-resistant states, such as obesity and diabetes.Although the central effects of insulin to activate the sympathetic nervous system and enhance baroreflex gain are well known, the specific brain site(s) at which insulin acts has not been identified. We tested the hypotheses that (1) the paraventricular nucleus of the hypothalamus (PVN) and the arcuate nucleus (ArcN) are necessary brain sites and (2) insulin initiates its effects directly in the PVN and/or the ArcN. In alpha-chloralose anaesthetised female Sprague-Dawley rats, mean arterial pressure (MAP), heart rate (HR) and lumbar sympathetic nerve activity (LSNA) were recorded continuously, and baroreflex gain of HR and LSNA were measured before and during a hyperinsulinaemic-euglycaemic clamp. After 60 min, intravenous infusion of insulin (15 mU kg-1 min-1), but not saline, significantly increased (P < 0.05) basal LSNA (to 228 +/- 28% control) and gain of baroreflex control of LSNA (from 3.8 +/- 1.1 to 7.4 +/- 2.4% control mmHg-1). These effects were reversed (P < 0.05) by local inhibition (bilateral microinjection of musimol) of the PVN (LSNA to 124 +/- 8.8% control; LSNA gain to 3.9 +/- 1.7% control mmHg-1) or of the ArcN (LSNA in % control: from 100 +/- 0 to 198 +/- 24 (insulin), then 133 +/- 23 (muscimol) LSNA gain in % control mmHg-1: from 3.9 +/- 0.3 to 8.9 +/- 0.9 (insulin), then 5.1 +/- 0.5 (muscimol)). While insulin receptor immunoreactivity was identified in neurons in pre-autonomic PVN subnuclei, microinjection of insulin (0.6, 6 and 60 nU) into the PVN failed to alter LSNA or LSNA gain. However, ArcN insulin increased (P < 0.05) basal LSNA (in % control to 162 +/- 19, 0.6 nU; 193 +/- 19, 6 nU; and 205 +/- 28, 60 nU) and LSNA baroreflex gain (in % control mmHg-1 from 4.3 +/- 1.2 to 6.9 +/- 1.0, 0.6 nU; 7.7 +/- 1.2, 6 nU; and 7.8 +/- 1.3, 60 nU). None of the treatments altered MAP, HR, or baroreflex control of HR. Our findings identify the ArcN as the site at which insulin acts to activate the sympathetic nervous system and increase baroreflex gain, via a neural pathway that includes the PVN.