Clifford Liam, Dampney Bruno W, Carrive Pascal
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Exp Physiol. 2015 Apr 1;100(4):388-98. doi: 10.1113/expphysiol.2014.084137. Epub 2015 Feb 20.
What is the central question of this study? Blockade of orexin receptors reduces blood pressure in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar-Kyoto (WKY) rats, suggesting that upregulation of orexin signalling underlies the hypertensive phenotype of the SHR. However, it is not known what causes this upregulation. What is the main finding and its importance? Using orexin immunolabelling, we show that SHRs have 20% more orexin neurons than normotensive WKY and Wistar rats in the medial hypothalamus, which is a good match to their blood pressure phenotype. In contrast, there is no such match for the orexin neurons of the lateral hypothalamus. Essential hypertension may be linked to an increase in orexin neurons in the medial hypothalamus. The neuropeptide orexin contributes to the regulation of blood pressure as part of its role in the control of arousal during wakefulness and motivated behaviour (including responses to psychological stress). Recent work shows that pharmacological blockade of orexin receptors reduces blood pressure in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar-Kyoto (WKY) rats. It is not clear why orexin signalling is upregulated in the SHR, but one possibility is that these animals have more orexin neurons than their normotensive WKY and Wistar relatives. To test this possibility, SHRs, WKY and Wistar male rats (6-16 weeks old) were killed, perfused and their brains sectioned and immunolabelled for orexin A. Labelled neurons were plotted and counted in the six best labelled hemisections (120 μm apart) of each brain. There were significantly more orexin neurons (+20%) in the medial hypothalamus (medial to fornix) of SHRs compared with WKY and Wistar rats (126 ± 4 versus 106 ± 5 and 104 ± 5 per hemisection, respectively, P < 0.05), which matches well the blood pressure phenotypes. In contrast, counts in the lateral hypothalamus did not match the blood pressure phenotypes (69 ± 2 versus 50 ± 3 and 76 ± 4, respectively). The results support the idea that orexin signalling is upregulated in the SHR and suggest that this is due, at least in part, to a greater number of orexin neurons in the medial hypothalamus. These medial orexin neurons, which are also involved in hyperarousal and stress responses, may contribute to the development of essential hypertension.
本研究的核心问题是什么？食欲素受体阻断可降低自发性高血压大鼠（SHR）的血压，但对正常血压的Wistar-Kyoto（WKY）大鼠无效，这表明食欲素信号上调是SHR高血压表型的基础。然而，尚不清楚是什么导致了这种上调。主要发现及其重要性是什么？通过食欲素免疫标记，我们发现SHR在内侧下丘脑的食欲素神经元比正常血压的WKY大鼠和Wistar大鼠多20%，这与其血压表型高度匹配。相比之下，外侧下丘脑的食欲素神经元则不存在这种匹配关系。原发性高血压可能与内侧下丘脑食欲素神经元增加有关。神经肽食欲素作为其在清醒时控制觉醒和动机行为（包括对心理压力的反应）中的一部分作用，有助于血压调节。最近的研究表明，食欲素受体的药理学阻断可降低自发性高血压大鼠（SHR）的血压，但对正常血压的Wistar-Kyoto（WKY）大鼠无效。目前尚不清楚为什么SHR中的食欲素信号会上调，但一种可能性是这些动物的食欲素神经元比其正常血压的WKY和Wistar亲属更多。为了验证这一可能性，处死了6至16周龄的SHR、WKY和Wistar雄性大鼠，进行灌注，然后将它们的大脑切片并对食欲素A进行免疫标记。在每个大脑的六个标记最好的半脑切片（相隔120μm）中绘制并计数标记的神经元。与WKY大鼠和Wistar大鼠相比，SHR内侧下丘脑（穹窿内侧）的食欲素神经元明显更多（增加20%）（分别为每个半脑切片126±4个、106±5个和104±5个，P<0.05），这与血压表型非常匹配。相比之下，外侧下丘脑的计数与血压表型不匹配（分别为69±2个、50±3个和76±4个）。结果支持了SHR中食欲素信号上调的观点，并表明这至少部分是由于内侧下丘脑食欲素神经元数量增加所致。这些内侧食欲素神经元也参与过度觉醒和应激反应，可能有助于原发性高血压的发展。
