Essential hypertension is idiopathic; however, it is accepted as a complex polygenic trait with underlying genetic components that remain unknown. Our supposition is that the pathogenesis of primary hypertension involves the activation of the sympathetic nervous system. In this symposium, I will summarize our findings obtained from experimental animal models of hypertension and introduce new mechanisms of neurogenic hypertension. One pivotal region controlling the arterial pressure set point is the nucleus tractus solitarii (NTS). Since bilateral microinjection of CoCl2, a non-selective blocker of neurotransmission, into the NTS of an animal model of human hypertension (the spontaneously hypertensive rat: SHR) resulted in an attenuated pressor response compared to normotensive Wistar Kyoto (WKY) rats (H. Waki, unpublished data). We therefore propose that alterations in the electrical excitability state of neurons in the NTS could be involved, at least in part, in the mechanisms underlying neurogenic hypertension in the SHR. By performing whole-genome expression profiling on NTS tissues, we found that pro-inflammatory molecules, such as junctional adhesion molecule A (JAM-A) and leukotriene B4 (LTB4), were over-expressed in the NTS in SHRs compared to WKY rats [1, 2]. We also observed the accumulation of endogenous leukocytes inside capillaries within the NTS of SHRs and JAM-A- and LTB4-over-expressing rats [1, 2]. We also confirmed functionally that high levels of JAM-A and LTB4 may, in part, contribute to the development of neurogenic hypertension, and are not secondary to hypertension [1, 2]. Importantly, recent findings further confirmed that JAM-A may be involved in the etiology of not only SHRs but also other animal models of hypertension [3] and essential hypertension in humans [4]. The next question we addressed was how these high levels of pro-inflammatory molecules in the NTS can cause neurogenic hypertension. Despite the specific inflammatory state in the NTS of SHRs, which may be genetically programmed, the transcripts of some inflammatory molecules, such as chemokine (C-C motif) ligand 5 (Ccl5) and its receptors, chemokine (C-C motif) receptor 1 and 3, were down-regulated in the NTS of SHRs compared to WKY rats [5]. This may be a compensatory mechanism to avoid further strong inflammatory activity. Supporting this hypothesis, we found that a high level of LTB4 in the NTS could reduce Ccl5 transcript levels [5]. More importantly, we found that down-regulation of Ccl5 in the NTS of SHRs may be pro-hypertensive, since microinjection of Ccl5 into the NTS of SHRs decreased arterial pressure, but was less effective in WKY rats [5]. Since Ccl5 receptors are involved in the modulation of glutamate transmission from glutamate nerve endings, we hypothesize that the down-regulation of Ccl5 in the NTS may directly affect NTS neurons and hence result in the development of neurogenic hypertension in the SHR. In addition to the above theory for the etiology of hypertension, we hypothesized that localized hypoxia in the NTS may also have a role in neurogenic hypertension [6]. The accumulation of leukocytes in the NTS microvasculature may induce an increase in vascular resistance and hypoperfusion within the NTS; the latter may trigger focal hypoxia, which may affect central neural cardiovascular activity. Therefore, we explored whether increased vascular resistance, low blood perfusion, and low oxygen delivery localized to the NTS can increase arterial pressure. We measured cardiovascular parameters before and after specific branches of the superficial dorsal medullary veins were occluded; we assumed these were drainage vessels from the NTS and their occlusion would produce stagnant hypoxia [7]. Following vessel occlusion, blood flow in the dorsal surface of the medulla oblongata, including the NTS region, showed an ~60% decrease and was associated with hypoxia in neurons located predominantly in the caudal part of the NTS, as revealed by using Hypoxyprobe-1, which is a marker for cellular hypoxia [7]. Arterial pressure increased and this response was significantly pronounced in both magnitude and duration when baroreceptor reflex afferents were sectioned [7]. These results suggest that localized hypoxia in the NTS increases arterial pressure. We propose that this represents a protective mechanism whereby the elevated systemic pressure is a compensatory mechanism to enhance cerebral perfusion. We assumed that this physiological mechanism may also be involved in the pathogenesis of neurogenic hypertension [6, 7]. All told, we suggest that vascular inflammation within the brainstem leads to elevated sympathetic nerve activity by multiple pathways in neurogenic hypertension.