Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI
Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI
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DOI：
10.1152/ajpheart.00840.2004
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发表时间：
2005-05-01
影响因子：
4.8
通讯作者：
Leenen, FHH
中科院分区：
文献类型：
--
作者：
Huang, BS;Leenen, FHH
在大鼠心肌梗死（MI）后，交感神经功能亢进可以通过阻断脑盐皮质激素受体（MR）来预防。对醛固酮中枢输注的刺激反应可被苯扎明阻断，因此似乎是通过脑中的Na+通道（推测为上皮Na+通道（ENaC））介导的。为了评估MI后Wistar大鼠内源性盐皮质激素的概念，我们检测了阻断脑中MR和Na+通道的作用。在冠状动脉结扎后3天，使用渗透性微型泵开始侧脑室输注螺内酯（400 ng center dot kg（-1）center dot h（-1））或其溶剂，或苯扎明（4 ng center dot kg（-1）center dot h（-1））或其溶剂。以假结扎大鼠作为对照。4周后，在清醒大鼠中，记录静息时和对空气喷射应激、侧脑室注射α 2-肾上腺素受体激动剂胍那苄以及静脉输注苯肾上腺素和硝普钠的压力感受器反射功能的反应时的平均动脉压、心率和肾交感神经活动。MI大小在四组大鼠中相似（相似于31%）。在MI后用载体处理的大鼠中，心脏功能降低，交感神经反应性增强，压力反射功能受损。脑Na+通道或脑MR的阻断类似地防止交感神经过度活跃和压力反射功能的损害，并改善心脏功能。这些发现表明，在MI后的大鼠中，内源性激动剂与MR的结合增加会增加脑中的ENaC活性，从而导致交感神经活动过度和进行性左心室功能障碍。
In rats postmyocardial infarction ( MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors ( MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels ( ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post- MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone ( 400 ng center dot kg(-1)center dot h(-1)) or its vehicle, or with benzamil ( 4ng center dot kg (-1)center dot h(-1)) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air- jet stress, intracerebroventricular injection of the alpha(2)- adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats ( similar to 31%). In rats treated post- MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post- MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.