Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

Abstract

BPH/2J mice are a genetic model of hypertension which were selectively bred for elevated blood pressure (BP) in the 1970s alongside a normotensive strain (BPN/3J).1 Recent studies suggest that the hypertension in BPH/2J mice is caused by enhanced activation of the sympathetic nervous system (SNS) because ganglion blockade causes a greater depressor response in BPH/2J mice compared with BPN/3J controls. 2,3 Importantly, cardiovascular regulatory forebrain regions within the hypothalamus and amygdala display markedly greater neuronal activity in BPH/2J compared with BPN/3J mice during the dark-active period of the 24-hour light cycle.2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.A gene array approach has been used to identify differential expression of genes in the hypothalamus between BPH/2J and BPN/3J mice. 5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons. Indeed, orexin is capable of increasing BP, heart rate (HR), and SNS activity.8 Orexinergic neurons originate in the hypothalamus and project to a wide range of brain regions, but in terms of sympathetic control of BP, the Abstract-BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system.Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/ kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively; P<0.001 compared with vehicle). However, when almorexant (100 mg/ kg, IP) was administered during the light-inactive pe...

Role of medial hypothalamic orexin system in panic, phobia and hypertension

“…Moreover, Beige and coworkers have reported that the cardiovascular depressive effect of the combination of selective ORX antagonists (ORX1 and ORX2) was greater and closer to that of the almorexant (dual orexin receptor blocker) in anesthetized rats, suggesting the contribution of both the receptors in evoking cardiovascular response from the PeF (Beig et al, 2015b). These findings support the notion that the ORX system is involved in cardiovascular responses to certain forms of stresses (Beig et al, 2015a;Furlong et al, 2009;Johnson et al, 2010) and genetic models of hypertension (Jackson et al, 2016;Lee et al, 2013;Li et al, 2013).…”

“…almorexant significantly attenuated the blood pressure in BPH/2J mice, suggesting that the enhanced central orexinergic system is a major contributing factor to hypertension in this model (Jackson et al, 2016). Moreover, Beige and coworkers have reported that the cardiovascular depressive effect of the combination of selective ORX antagonists (ORX1 and ORX2) was greater and closer to that of the almorexant (dual orexin receptor blocker) in anesthetized rats, suggesting the contribution of both the receptors in evoking cardiovascular response from the PeF (Beig et al, 2015b).…”

“…Using the immunohistochemical technique, another study also revealed that BPH/2J mice (a genetic model of hypertension) have 29% more ORX neurons as compared to BPN/3J (normal) mice in the lateral hypothalamus (Jackson et al, 2016). The hypertensive role of the orexinergic signaling in BPH/2J mice was confirmed as the systemic injection of an ORX1/2 antagonist;…”

An augmented CO2 chemoreflex and overactive orexin system are linked with hypertension in young and adult spontaneously hypertensive rats

“…) and a recent report on the genetically hypertensive BPH/2J mice (Jackson et al . ). Moreover, hypercapnia (7% CO 2 ) activated more orexin neurons in the hypothalamus in both young and adult SHRs than in age‐matched normotensive rats.…”

Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats

“…In contrast, prepro‐orexin gene knockout mice show a significant lower blood pressure compared to their wild controls . In addition, the upregulation of orexin signalling has been observed in several animal models of hypertension such as spontaneously hypertensive rats (SHR), stress‐induced hypertensive rats, obesity‐related hypertensive Zucker rats, Dahl salt‐sensitive hypertensive rats and BPH/2J Schlager mice . Furthermore, antagonism of orexin receptors significantly lowers blood pressure in some hypertensive models such as SHR and Dahl salt‐sensitive hypertensive rat .…”