The Orexin System and Hypertension

Abstract

In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar-Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.

Keywords: Hypertension; Orexin; Salt-sensitive hypertension; Sympathetic nerve activity.

Fig. 1

Hypothesis for high-salt (HS) induced activation of the orexin system in the hypothalamic paraventricular nucleus (PVN) contributing to hypertension in Dahl S rats. A HS diet may increase cerebrospinal fluid (CSF) sodium concentration in Dahl S rats. Circumventricular organs (CVO) in the lamina terminalis may sense increased osmolality and activate orexin-producing neurons. Alternatively, orexin-producing neurons may be directly sensitive to changes in CSF sodium concentration. This may increase orexin release to the PVN and augment PVN neuronal activity resulting in increased sympathetic nerve activity targeting the heart, kidneys, and vasculature and contribute to hypertension. Reduced ability of natriuresis by the kidneys of Dahl S rats may support chronic activation of the orexin system and may explain why the orexin system would not be chronically activated in SD or Dahl salt resistant rats in response to a high-salt diet