Imperatore Roberta, Palomba Letizia, Cristino Luigia
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Viale Campi Flegrei, 80078, Pozzuoli, Italy.
Department of Science and Technology, University of Sannio, Benevento, Italy.
Curr Hypertens Rep. 2017 Apr;19(4):34. doi: 10.1007/s11906-017-0729-y.
Hypertension is one of the most challenging health problems inducing cerebrovascular disease and high percentage of death when associated with diabetes, dyslipidemias, and obesity. Orexin/hypocretin is a peptide expressed by a small number of neurons of the dorsolateral hypothalamus, a brain feeding and autonomic "fight-or-flight" regulatory center. According to this function, orexin has been demonstrated to evoke cardiovascular responses, heart rate, hypertension, hyperarousal, hyperphagia, and obesity. The focus of this review is to provide an overview about the mechanism through which orexin regulates food intake and cardiovascular responses and its role in the pathogenesis of obesity and hypertension which could be of great interest to establish possible new therapies.
In normal rats and mice, central administration of orexin increases food intake, blood pressure, and sympathetic nerve activity and these effects are blocked by selective orexin receptor antagonist SB-334867 or almorexant. Moreover, upregulation of orexin signaling, in combination with elevation of epinephrine and norepinephrine circulating levels, occurs in rats exposed to chronic stress, in models of spontaneous hypertension (SHR and BPH/2J Schlager mice) and in obese mice (ob/ob or mice fed with high fat diet). Therefore, hyperactivity of orexinergic neurons could be a factor in the development of obesity and essential hypertension. Because of their widespread projections to the brain regions involved in appetite and cardiovascular responses, as far down as sympathetic preganglionic neurons in the spinal cord, orexin evokes sympathetically mediated cardiovascular responses. Lasting upregulation of orexin signaling can lead to hyperphagia, obesity, and hypertensive state. Dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists (SORAs) have antihypertensive effects that could be of clinical use for regulation of food intake and hypertension, supporting the role of orexinergic neurons as critical checkpoint in the neurogenic control of metabolic and cardiovascular functions.
高血压是最具挑战性的健康问题之一，与糖尿病、血脂异常和肥胖相关时，会引发脑血管疾病并导致高死亡率。食欲肽/下丘脑泌素是一种由下丘脑背外侧少量神经元表达的肽，下丘脑是大脑的进食和自主“战斗或逃跑”调节中心。根据其功能，食欲肽已被证明可引发心血管反应、心率、高血压、过度觉醒、食欲亢进和肥胖。本综述的重点是概述食欲肽调节食物摄入和心血管反应的机制及其在肥胖和高血压发病机制中的作用，这可能对建立可能的新疗法具有重要意义。
在正常大鼠和小鼠中，中枢给予食欲肽会增加食物摄入量、血压和交感神经活动，这些作用可被选择性食欲肽受体拮抗剂SB - 334867或阿莫雷生阻断。此外，在暴露于慢性应激的大鼠、自发性高血压模型（SHR和BPH/2J施拉格小鼠）以及肥胖小鼠（ob/ob或高脂饮食喂养的小鼠）中，食欲肽信号上调，同时循环中的肾上腺素和去甲肾上腺素水平升高。因此，食欲肽能神经元的过度活跃可能是肥胖和原发性高血压发展的一个因素。由于食欲肽广泛投射到参与食欲和心血管反应的脑区，甚至延伸到脊髓中的交感神经节前神经元，食欲肽会引发交感神经介导的心血管反应。食欲肽信号的持续上调可导致食欲亢进、肥胖和高血压状态。双重食欲肽受体拮抗剂（DORAs）和选择性食欲肽受体拮抗剂（SORAs）具有降压作用，可能在调节食物摄入和高血压方面具有临床应用价值，支持食欲肽能神经元作为代谢和心血管功能神经源性控制中的关键控制点的作用。
