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Abstract
This thesis sought to investigate the role of orexin receptors in cardiovascular control, and to determine the role of
the orexin system in essential hypertension.
Immunolabelling revealed that most orexin neurons express orexin receptors (OxR1 and OxR2) themselves, with
65% co-expressing both receptors, whereas sympathetic preganglionic neurons of the intermediolateral column
were only seen to express OxR1. This suggests that much of the actions of orexin receptor antagonists may be on the
orexin neurons themselves, which would potentially reduce all the orexin mediated components of a response at
the same time.
Orexin levels in the CSF were shown to be tonically upregulated in the adult spontaneously hypertensive rat (SHR)
model of essential hypertension, as compared to normotensive Wistar Kyoto (WKY) and Wistar rats. Using orexin
immunolabelling, we determined that the previously reported increased expression of orexin neurons in the medial
hypothalamus is present in pre-hypertensive juvenile SHRs, and therefore precedes the hypertensive state in these
animals. We also discovered a significantly increased orexin neuron population in brains of the BPH/2J Schlager
mouse, another animal model of essential hypertension. This suggests that orexin upregulation may be an indicator,
if not a precursor to essential hypertension across multiple mammalian species.
Both destruction of medial hypothalamic neurons through vivo-morpholinos and targeted rAAV-delivered shRNA
knockdown of orexin within this region were successful in significantly and permanently attenuating hypertension
in the adult SHR. Similar injections had no effect on resting blood pressure in normotensive WKY rats. The consistency
of the reduction seen in both experiments suggests that orexin is the primary source of the hypertensive tone
produced from this region in the SHR.
Thus, this thesis has identified potential pathways for the cardiovascular actions of orexin receptor antagonists,
characterised an overactive and upregulated orexin system in two animal models of hypertension, and
demonstrated that by targeting orexin for knockdown the hypertensive phenotype of the SHR can be attenuated.