Schaich Chris L, Wellman Theresa L, Koi Blanka, Erdos Benedek
Department of Pharmacology, University of Vermont, Burlington, VT, USA.
Department of Pharmacology, University of Vermont, Burlington, VT, USA.
Auton Neurosci. 2016 May;197:1-8. doi: 10.1016/j.autneu.2016.02.011. Epub 2016 Mar 2.
Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during hypertensive stimuli including stress and hyperosmolarity, but its role in PVN cardiovascular regulatory mechanisms is unclear. Chronic BDNF overexpression in the PVN has been shown to elevate sympathetic tone and blood pressure in part by modulating central angiotensin (Ang) II mechanisms. However, the cardiovascular effects of short-term increases in PVN levels of BDNF and the mechanisms governing them are unknown. Therefore, we investigated whether acute BDNF microinjections into the PVN of conscious and anesthetized Sprague-Dawley rats induce blood pressure elevations and whether Ang II signaling is involved in these hypertensive responses. In conscious rats, unilateral BDNF (12.5ng) microinjections into the PVN increased mean arterial pressure (MAP) by 27±1mmHg (P<0.001 vs vehicle), which was significantly attenuated by intracerebroventricular infusion of the Ang II-type-1 receptor (AT1R) antagonist losartan and by ganglionic blockade with intravenous hexamethonium infusion. In anesthetized rats, unilateral PVN microinjection of BDNF increased MAP by 31±4mmHg (P<0.001 vs vehicle), which was prevented by PVN microinjection pretreatments with the high-affinity BDNF receptor TrkB antagonist ANA-12, losartan, the angiotensin converting enzyme inhibitor lisinopril, or by intravenous hexamethonium. Additional experiments in hypothalamic samples including the PVN revealed that BDNF-induced TrkB receptor phosphorylation was prevented by ANA-12 and losartan pretreatments. Collectively, these data indicate that BDNF acting within the PVN acutely raises blood pressure under permissive control of Ang II-AT1R mechanisms and therefore may play an important role in mediating acute pressor responses to hypertensive stimuli.
在包括应激和高渗在内的高血压刺激过程中，脑源性神经营养因子（BDNF）在下丘脑室旁核（PVN）中的表达会增加，但其在PVN心血管调节机制中的作用尚不清楚。PVN中慢性BDNF过表达已被证明部分通过调节中枢血管紧张素（Ang）II机制来提高交感神经张力和血压。然而，PVN中BDNF水平短期升高的心血管效应及其调控机制尚不清楚。因此，我们研究了向清醒和麻醉的Sprague-Dawley大鼠的PVN中急性微量注射BDNF是否会导致血压升高，以及Ang II信号是否参与这些高血压反应。在清醒大鼠中，向PVN单侧微量注射BDNF（12.5 ng）可使平均动脉压（MAP）升高27±1 mmHg（与注射溶剂相比，P<0.001），脑室内注入Ang II 1型受体（AT1R）拮抗剂氯沙坦以及静脉输注六甲铵进行神经节阻滞可显著减弱这种升高。在麻醉大鼠中，向PVN单侧微量注射BDNF可使MAP升高31±4 mmHg（与注射溶剂相比，P<0.001），用高亲和力BDNF受体TrkB拮抗剂ANA-12、氯沙坦、血管紧张素转换酶抑制剂赖诺普利进行PVN微量注射预处理或静脉输注六甲铵可预防这种升高。在下丘脑包括PVN的样本中进行的额外实验表明，ANA-12和氯沙坦预处理可阻止BDNF诱导的TrkB受体磷酸化。总体而言，这些数据表明BDNF在PVN内起作用，在Ang II-AT1R机制的允许控制下急性升高血压，因此可能在介导对高血压刺激的急性升压反应中起重要作用。
