Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. Since the brainstem structure – the nucleus of the solitary tract (NTS) – is a pivotal region for regulating the set-point of arterial pressure and its reflex control, we proposed a role for it in the development of primary hypertension. We have recently identified that some pro-inflammatory molecules, such as junctional adhesion molecule-1 (JAM-1; a leukocyte/platelet adhesion molecule) and leukotriene B4 (LTB4; one of the most potent chemoattractants and activators of leukocytes), were over expressed in the NTS of an animal model of human essential hypertension – the spontaneously hypertensive rat (SHR) compared to normotensive Wistar-Kyoto rats (WKY) (Waki et al. 2007 & 2008). Using immunohistochemistry, we have shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR, but not WKY rats (Waki et al. 2007). The functional significance of high-level expression of JAM-1 and LTB4 in the NTS has also been studied. Adenoviral mediated over expression of JAM-1 in the NTS of normotensive WKY rats produced hypertension over 14 days after viral injection and localized leukocyte adherence to the microvasculature (Waki et al. 2007). LTB4 microinjected into the NTS of WKY rats also induced hypertension over 4 days demonstrating its pro-hypertensive effect (Waki et al. 2008). Although these findings show clearly that the high-level expression of JAM-1 and LTB4 in the NTS can cause hypertension, the question arises as to how this comes about. As a consequence of leukocyte accumulation in the NTS of SHR, we first predicted differences in the level of gene expression of inflammatory mediators such as cytokines in the NTS of SHR relative to WKY. We have screened for abnormally expressed inflammatory mediators in the NTS of SHR using the RT2 Profiler PCR arrays, which were designed specifically to target major cytokines and chemokines. The specific PCR array revealed 12 genes to be differentially expressed between SHR and WKY (more than 2 fold differences). They include IL-6, IFNa1, OX40L and CCL5. Moreover, we identified that IL-6 and CCL5 acutely affect cardiovascular control at the level of the NTS, demonstrating the possibility that abnormal expression of these inflammatory molecules contribute to the hypertensive state via alteration of neuronal circuitry regulating cardiovascular autonomic activity. With the possibility that leukocyte accumulation in capillaries may obstruct blood flow resulting in highly localized hypoxia (Paton et al. 2009), we have also tested whether local disturbance of blood supply in the dorsomedial region of the medulla oblongata including NTS regions evokes hypertension in normotensive rats. We found that arterial pressure was significantly elevated after small veins on the dorsomedial surface of the caudal medulla oblongata were cut and occluded following sino-aortic denervation in anesthetized rats, demonstrating that abnormal circulation at the level of the NTS affects regulatory mechanisms of set-point control of arterial pressure. Whether the elevated arterial pressure is mediated by blood gas disturbance in the NTS awaits investigation. Based on these findings, we propose a new hypothesis that abnormal gene expression of pro-inflammatory molecules causes inflammation of the vasculature in the NTS of SHR. This profile may elevate arterial pressure via both abnormal production of inflammatory mediators and altered circulatory conditions at the level of the NTS. Importantly, to allow translation of our work, these novel insights need to be assessed in hypertensive human brainstem tissue; their confirmation could lead to novel therapeutic approaches for one of the world’s most prevalent diseases.