Zhang W, Huang B S, Leenen F H
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
Am J Physiol. 1999 May;276(5):H1608-15. doi: 10.1152/ajpheart.1999.276.5.H1608.
Blockade of brain "ouabain" prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain "ouabain" may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg. kg-1. day-1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the alpha2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.
阻断脑内“哇巴因”可预防充血性心力衰竭（CHF）大鼠的交感神经过度兴奋和压力反射功能受损。由于脑内“哇巴因”可能通过激活脑肾素-血管紧张素系统（RAS）发挥作用，本研究旨在评估心肌梗死后（MI）发生CHF的Wistar大鼠经脑室内给予AT1受体阻滞剂氯沙坦进行长期治疗是否能使交感神经过度兴奋和压力反射功能受损恢复正常。在左冠状动脉结扎（2或6周）后，大鼠通过渗透微型泵接受脑室内氯沙坦（1 mg·kg-1·天-1，CHF-Los）或溶剂（CHF-Veh）。为评估脑室内氯沙坦可能的外周作用，一组CHF大鼠皮下给予相同剂量的氯沙坦。假手术大鼠作为对照。治疗2周后，在清醒动物中测量静息时以及对喷气应激和脑室内注射α2肾上腺素能受体激动剂胍那苄的反应时的平均动脉压（MAP）、心率（HR）和肾交感神经活动（RSNA）。通过MAP的斜坡变化评估动脉压力反射功能。与假手术组相比，CHF-Veh组表现出对HR和RSNA的动脉压力反射控制受损、对喷气应激的交感兴奋和升压反应增加以及对胍那苄的交感抑制和降压反应增加。后者与交感抑制途径活性降低一致。长期脑室内输注氯沙坦可使这些异常情况基本恢复正常。在CHF大鼠中，皮下给予相同剂量的氯沙坦无效。在假手术大鼠中，脑室内或皮下给予氯沙坦均不影响交感神经活动。我们得出结论，CHF中交感兴奋的慢性增加、交感抑制的降低和压力反射功能的脱敏似乎均依赖于脑RAS，因为这种整体变化模式可通过氯沙坦进行长期中枢性AT1受体阻断而恢复正常。
