Central endothelin: effects on vasopressin and the arterial baroreflex in doxorubicin heart failure rats.
Central endothelin: effects on vasopressin and the arterial baroreflex in doxorubicin heart failure rats.
复制标题
中枢内皮素：对阿霉素心力衰竭大鼠加压素和动脉压力反射的影响。
DOI：
10.1139/y08-027
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发表时间：
2008
影响因子：
2.1
通讯作者：
Chen,Haiping
中科院分区：
文献类型：
--
作者：
Rossi,NoreenF;Maliszewska-Scislo,Maria;Chen,Haiping
内皮素1 （ET-1）在心力衰竭时血浆和中枢神经系统内均升高。中枢，ET-1诱导交感神经亢进和精氨酸加压素（AVP）分泌。交感神经活动和AVP分泌都受到动脉压力反射的调节，而动脉压力反射在心力衰竭中是典型的受损。我们假设中枢阻滞剂（ETAR）改变心肌病心力衰竭模型中心率、肾交感神经活动（RSNA）和血浆AVP水平的压力反射反应。雌性Sprague-Dawley大鼠每周腹腔注射阿霉素2.5 mg·kg-1（阿霉素心力衰竭，doxo-HF）或生理盐水（对照组）。8周后，他们被仪器化，适应学习环境，然后在清醒，不受约束的状态下学习。两组的基线平均动脉压（MAP）、RSNA和血浆渗透压相似，但doxo-HF组的心率（p< 0.02）、左心室压（p< 0.001）和血浆AVP （p< 0.01）较高。ET-1剂量依赖性地增加MAP，但在所有剂量的doxo-HF大鼠中，MAP的增加都明显减弱。两组心率和RSNA的基线压反射控制相似。以4 nmol BQ123 icc.v阻断ETAR可显著降低doxo-HF大鼠的上平台值（p< 0.05）及心率和RSNA的压力反射反应幅度（p< 0.05），而对照组无明显差异。尽管基础血浆AVP水平较高，ET-1引起doxo-HF大鼠血浆AVP升高13.6±3.2 pg·ml -1，而对照组为0.4±0.4 pg·ml -1 （p< 0.001）。为了解释dodo - hf大鼠对ET-1的降压反应减弱，AVP释放的增益计算为ΔAVP/ΔMAP，并且在dodo - hf大鼠中也发现明显更大（p< 0.001）。BQ123阻止了AVP的升高，并使doxo-HF大鼠的AVP恢复到对照组的水平。因此，在阿霉素心肌病引起的心力衰竭中，中枢性ETAR有助于交感神经兴奋和AVP反应。
Endothelin 1 (ET-1) is increased in heart failure, both in plasma and within the central nervous system. Centrally, ET-1 induces sympathetic hyperactivity and arginine vasopressin (AVP) secretion. Both sympathetic activity and AVP secretion are regulated by the arterial baroreflex, which is typically impaired in heart failure. We hypothesized that central blockade of ETAreceptors (ETAR) alters the baroreflex response of heart rate, renal sympathetic nerve activity (RSNA), and plasma AVP levels in a cardiomyopathic model of heart failure. Female Sprague–Dawley rats received weekly intraperitoneal injections of doxorubicin 2.5 mg·kg–1(doxorubicin heart failure, doxo-HF) or saline vehicle (control). After 8 weeks, they were instrumented, conditioned to the study environment, and then studied in the awake, non-restrained state. Baseline mean arterial pressure (MAP), RSNA, and plasma osmolality were similar in both groups, but heart rate (p< 0.02), left ventricular pressure (p< 0.001), and plasma AVP (p< 0.01) were higher in the doxo-HF group. ET-1 dose dependently increased MAP, but the rise was significantly attenuated in doxo-HF rats at all doses. Baseline baroreflex control of heart rate and RSNA was similar in both groups. ETAR blockade with 4 nmol BQ123 i.c.v. significantly decreased both the upper plateau (p< 0.05) and the range (p< 0.05) of the baroreflex response of both heart rate and RSNA in doxo-HF but not in control rats. Despite higher basal plasma levels of AVP, ET-1 evoked a rise in plasma AVP of 13.6 ± 3.2 pg·mL–1in doxo-HF compared with 0.4 ± 0.4 pg·mL–1in control rats (p< 0.001). To account for the blunted pressor response to ET-1 in the doxo-HF rats, gain of AVP release was calculated as ΔAVP/ΔMAP and was also found to be significantly greater in the doxo-HF rats (p< 0.001). BQ123 prevented the rise in AVP and restored the gain in doxo-HF rats to that seen in controls. Thus, central ETAR contribute to the sympathoexcitation and AVP responses observed in heart failure due to doxorubicin cardiomyopathy.