Wood Susan K, Verhoeven Robert E, Savit Aaron Z, Rice Kenner C, Fischbach Peter S, Woods James H
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
Neuropsychopharmacology. 2006 Dec;31(12):2580-90. doi: 10.1038/sj.npp.1301085. Epub 2006 May 3.
Exposure to stressors that elicit fear and feelings of hopelessness can cause severe vagal activation leading to bradycardia, syncope, and sudden death. These phenomena though documented, are difficult to diagnose, treat clinically, and prevent. Therefore, an animal model incorporating these cardiovascular conditions could be useful. The present study examined 'sinking' during a 2-h swim stress, a phenomenon that occurs in 50% of rats during 25 degrees C water exposure. Concurrent measurements of body temperature, immobility, heart rate (HR), and PR interval (a measure of vagal activity) were made. Neither decreases in immobility nor variations in hypothermia during swim were correlated with sinking. Bradycardia was more severe in sinking rats (average minimum HR+/-SEM; 143+/-13 vs 247+/-14; p<0.01), and PR interval was elevated (p<0.0001). To examine potential modulation of vagal activity during stress, corticotropin-relasing factor (CRF) receptor antagonists (antalarmin, R121919 and astressin B), a glucocorticoid receptor antagonist (RU486), and a peripherally acting cholinergic antagonist (methylatropine nitrate) were administered. The centrally acting CRF antagonist, antalarmin (32 mg/kg), produced elongation of the PR interval (p<0.0001), robust bradycardia (135+/-18; p<0.001), and increased sinking (92%; p<0.05), and methylatropine nitrate (3.2 mg/kg) blocked these effects. Corroborating these data, two different CRF antagonists, R121919 (30 mg/kg) and astressin B (intracerebroventricular (i.c.v.), 0.03 mug/rat) increased sinking to 100%. RU486 (20 mg/kg) blocked HPA axis negative feedback and decreased percent sinking to 25%. From these studies, we concluded that sinking during a 2-h water exposure was a result of extreme vagal hyperactivity. Furthermore, stress-induced CRF release may serve to protect against elevated cardiac vagal activity.
暴露于引发恐惧和绝望感的应激源会导致严重的迷走神经激活，进而引发心动过缓、晕厥和猝死。这些现象虽有记录，但难以诊断、临床治疗和预防。因此，一种包含这些心血管状况的动物模型可能会有所帮助。本研究考察了在2小时游泳应激期间的“下沉”现象，该现象在25摄氏度水温下暴露时，50%的大鼠会出现。同时测量了体温、不动时间、心率（HR）和PR间期（迷走神经活动的一种测量指标）。游泳期间不动时间的减少和体温过低的变化均与下沉无关。下沉大鼠的心动过缓更为严重（平均最低心率±标准误；143±13对247±14；p<0.01），且PR间期延长（p<0.0001）。为了研究应激期间迷走神经活动的潜在调节作用，给予了促肾上腺皮质激素释放因子（CRF）受体拮抗剂（安他拉美、R121919和阿斯特辛B）、糖皮质激素受体拮抗剂（RU486）和外周作用的胆碱能拮抗剂（硝酸甲基阿托品）。中枢作用的CRF拮抗剂安他拉美（32毫克/千克）使PR间期延长（p<0.0001），出现强烈的心动过缓（135±18；p<0.001），并增加了下沉率（92%；p<0.05），而硝酸甲基阿托品（3.2毫克/千克）可阻断这些效应。与这些数据相符的是，两种不同的CRF拮抗剂R121919（30毫克/千克）和阿斯特辛B（脑室内注射（i.c.v.），0.03微克/只大鼠）使下沉率增加到100%。RU486（20毫克/千克）阻断了下丘脑-垂体-肾上腺（HPA）轴的负反馈，并使下沉百分比降至25%。从这些研究中，我们得出结论，在2小时水暴露期间的下沉是极度迷走神经活动亢进的结果。此外，应激诱导的CRF释放可能有助于抵御心脏迷走神经活动的升高。
